{"paper_id":"e00d4d48-ee12-4b09-9bd8-be94dadfe160","body_text":"Endometriosis affects approximately 10% of women\nof reproductive age and is among the most prevalent gynecological disorders ( 1 ,  2 ). Its prevalence rises to 40\n-60% in women with dysmenorrhea and 30-40% in those\nexperiencing infertility. Ovarian endometriomas, present\nin 17-44% of women with endometriosis, consist of endometrial tissue and fluid resulting from the accumulation\nof menstrual debris. Endometriomas have been shown to\nadversely affect ovarian response to stimulation, oocyte\nyield, and embryo implantation. Women with endometriosis generally exhibit a reduced response to gonadotropins ( 3 ,  4 ), often requiring substantially higher doses per\ncycle compared with women with tubal-factor infertility.\nPrior ovarian surgery may further contribute to diminished ovarian reserve and response in this population ( 5 ).\nSurgical intervention, particularly laparoscopic cystectomy, remains the most common treatment for endometriomas ( 6 - 8 ). Diagnosis and management traditionally\nrely on laparoscopy or laparotomy. Laparoscopic procedures require anesthesia and carry approximately a 3%\nrisk of minor complications, including nausea, vomiting,\nand shoulder pain, and a 0.5% risk of major complications, such as intestinal perforation. Notably, over 90% of\nthe excised endometrioma tissue often includes healthy\novarian tissue, potentially reducing ovarian reserve and\nincreasing gonadotropin requirements in women under-going assisted reproductive techniques. Following bilateral ovarian cystectomy, 2.6% of women may experience\npremature ovarian failure or early menopause ( 9 ). Recurrence rates after conservative surgery range from 6.4% to\n43.3, rising to 21.5% within two years and 40-50% within\nfive years in the presence of adhesions ( 10 - 13 ).\nGiven the potential complications of surgery, there has\nbeen growing interest in non-invasive approaches, including ultrasound-guided procedures. Cyst aspiration is a minimally invasive option; however, it is associated with a high\nrecurrence rate and often requires repeated interventions. An\nalternative 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\nwall ( 14 - 16 ). The sclerotherapy procedure typically involves\npercutaneous puncture of the ovarian endometrioma to aspirate its contents, followed by ethanol instillation into the cyst\ncavity for a defined period before removal ( 17 ).\nStudies have demonstrated that alcohol sclerotherapy\nsubstantially reduces endometrioma recurrence and results\nin higher oocyte retrieval and antral follicle counts (AFCs)\ncompared with ovarian cystectomy. The primary objective\nin managing endometriomas remains the preservation ovarian reserve and the improvement of pregnancy outcomes,\nparticularly in women planning future conception ( 18 - 21 ).\nCurrent evidence on endometriosis and its subtypes is\nlimited by imprecise prevalence data and a lack of quantified impact on ovarian response. Although surgical risks,\nparticularly the inadvertent removal of healthy ovarian tissue, are recognized, supporting data remain sparse. Reported\nrecurrence rates after surgery vary, and factors influencing\nrecurrence require further clarification ( 22 ,  23 ). While sclerotherapy has been suggested as an effective alternative,\ncomparative data with traditional surgery are insufficient,\nparticularly regarding long-term ovarian reserve and fertility\noutcomes. This study hypothesizes that ethanol sclerotherapy\nbetter preserves ovarian reserve and improved reproductive\noutcomes compared with laparoscopic cystectomy. The primary objectives are to assess whether sclerotherapy results\nin higher oocyte yield, increased AFCs, improved pregnancy\nrates, and fewer complications. Accordingly, we applied this\napproach to women with primary or recurrent endometriomas and diminished ovarian reserve to evaluate its impact on\nassisted reproductive outcomes.\n\nThis 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\nTehran University of Medical Sciences (IR.TUMS.MEDICINE.REC.1398.019) and registered with the Iranian\nRegistry of Clinical Trials (IRCT20191206045629N1).\nWritten informed consent was obtained from all the participants prior to enrollment.\nParticipants were infertile women aged 20-40 years\nwith primary or recurrent endometriomas, whose male\npartners had normal semen parameters.\nBased on previous findings ( 24 ), the mean number of\noocytes retrieved in groups with and without ovarian aspiration and ethanol sclerotherapy was 8.7 ± 4.1 and 6.0\n± 2.7, respectively. Assuming a significance level of 0.05\nand a power of 80%, a sample size of 40 participants per\ngroup was calculated.\nAlthough clinical pregnancy was the primary outcome,\nsample size estimation was based on oocyte yield due to\nthe absence of reliable prior data on clinical pregnancy\nrates 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\npower calculation. A post-hoc analysis using the observed\nclinical pregnancy rates confirmed that the achieved sample size would have been sufficient to detect a clinically\nmeaningful difference. This limitation is acknowledged,\nand future studies are encouraged to power studies directly for clinical pregnancy.\nWomen aged 20-40 years with recurrent endometriomas\nfollowing prior ovarian surgery were eligible for inclusion. Additional criteria included baseline follicle-stimulating hormone (FSH) ≤10 IU/L, anti-Müllerian hormone\n(AMH) ≤1 ng/mL ( 24 ,  25 ).\nPatients were excluded if they had a history of liver,\nkidney, or heart disease; endometriomas larger than 10 cm\nor smaller than 3 cm; cysts with a wall thickness >5 mm;\nor suspicion of malignancy.\nPre-treatment evaluations included hormonal blood tests\nand transvaginal ultrasounds. Ovarian stimulation was performed using gonadotropins to promote the development\nof multiple follicles, followed by ovulation triggering with\na human chorionic gonadotropin (hCG) agonist.\nCONSORT 2010 flow diagram.\nOocyte retrieval was carried out under transvaginal ultrasound guidance. Semen samples were obtained from\nthe patients’ male partners with normal semen parameters\nafter 2-3 days of sexual abstinence on the day of oocyte\nretrieval. Sperm preparation was performed on the same\nday according to standard laboratory protocols.\nFertilization was achieved via conventional insemination, and resulting embryos were cultured for several\ndays. The highest-quality embryos were selected for\ntransfer into the uterus. Luteal phase support was provided with progesterone, and a pregnancy test was performed\n14 days after embryo transfer, followed by appropriate\nfollow-up based on the results.\nEligible patients underwent transvaginal ultrasound on\nthe second or third day of menstruation to assess AFC,\nendometrioma size, and serum levels of luteinizing hormone (LH), FSH, AMH, estradiol, and CA125. These assessments were used to identify suitable candidates for\nthe study.\nFollowing evaluation, participants were randomly assigned to either the intervention or the control group,\ncomprising 39 and 40 patients. The control group received three ampoules of Dipherelin (triptorelin, Ipsen) at\na dose of 3.75 mg every 28 days. The intervention group\nreceived intravenous prophylaxis with 1 g ceftriaxone and\n0.5 g metronidazole two to three days after menstruation\nto prevent infection and manage endometriosis-related\nsymptoms.\nPatients were placed in the lithotomy position under\ngeneral anesthesia. After vaginal antiseptic preparation\nwith betadine (Behvazan, Iran) and confirmation of\nsterile conditions, cyst contents were aspirated under\ntransvaginal ultrasound guidance and sent for cytological analysis. The cyst cavity was irrigated with 0.5 cc\nof heparin (Caspian Tamin, Iran) in 500 cc of sterile\nnormal saline (daropakhash, Iran) and subsequently\naspirated. Approximately 80% of the cyst volume was\nfilled with 98% ethanol, which was aspirated after 15\nminutes. Patients were monitored for at least eight\nhours postoperatively and, if no complications occurred, were discharged with instructions to take 400\nmg cefixime (Pharabi, Iran) and 500 mg of metronidazole (daropakhash, Iran) orally every 12 hours for one\nweek. Additionally, patients received intramuscular\ninjections of three ampoules of Dipherelin (3.75 mg,\nIpsen, France) every 28 days.\nIn 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\nembryo transfer. In cases of a positive β-hCG (baseline\nβ-hCG >25 mIU/mL, taken approximately 12-14 days\nfrom expected conception), transvaginal ultrasound was\nperformed three weeks later. Clinical pregnancy was confirmed upon detection of a fetal heartbeat. The proportion\nof women achieving clinical pregnancy following assisted reproductive techniques was considered a secondary\noutcome.\nThe primary outcome was clinical pregnancy, defined\nas the presence of a fetal heartbeat on ultrasound. Secondary outcomes included chemical pregnancy rate (positive β-hCG 14 days post-transfer), number of retrieved\noocytes, number of metaphase II oocytes, embryo number\nand quality, total gonadotropin dose administered, endometrioma recurrence rate at six months post-treatment,\nand implantation and conception rates.\nEligible participants were allocated to the intervention\n(n=39) or control (n=40) group using balanced block randomization with blocks of four. Patients were blinded to\nthe assigned intervention; however, double-blinding was\nnot feasible, as the attending physicians were aware of the\nprocedures.\nData were analyzed using SPSS version 21.0 (IBM\nCorp., Chicago, IL, USA). The normality of continuous\nvariables was assessed with the Kolmogorov-Smirnov\ntest. 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\nwas considered statistically significant.\n\nA total of 80 participants were included in the study.\nThe mean age was 32.85 ± 4.75 years in the intervention\ngroup and 31.68 ± 4.13 years in the control group, with no\nstatistically significant difference (P=0.345). The mean\nduration of infertility was 6.05±1.45 years in the intervention group and 5.80 ± 1.20 years in the control group, also\nwithout significant difference. No significant differences\nwere observed between groups regarding other baseline\ncharacteristics, including husband’s age, body mass index\n(BMI), FSH, LH, thyroid stimulating hormone (TSH), antral follicular count, CA125, and AMH. Detailed data are\npresented in Table 1.\nBaseline characteristics of participants in our groups\nData are presented as men ± SD. P values were calculated using Independent t test. BMI;\nBody mass index, FSH; Follicle stimulating hormone, LH; Luteinizing hormone, TSH; Thyroid stimulating hormone, AMH; Anti-müllerian hormone, and CA125; Cancer Antigen 125.\nPathological 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\nfollowing sclerotherapy.\nNo significant differences were observed between the\ngroups regarding total gonadotropin dose (IU) (P=0.560),\nduration 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\nfollicles (P=0.050) and total number of oocytes retrieved\n(P=0.042,  Table 2 ).\nComparison of IVF outcomes between the study groups\nData are presented as mean ± SD. P values were calculated using the t test. D3; Day 3\nembryos, and IU; International units.\nDetailed comparisons of embryo quality and pregnancy\noutcomes, including both significant and non-significant\nresults, are summarized in Table 3.\nComparison of pregnancy outcomes between the two study\ngroups\nData are presented as n/N (%). P values: *; Chi-square test and**; Fisher’s exact test.\n\nThis study evaluated the effects of ethanol sclerotherapy in women with primary endometriosis and diminished\novarian reserve, focusing on its impact on assisted reproductive outcomes. Our results demonstrated that ethanol\nsclerotherapy may be a safe and effective alternative for\nmanaging recurrent endometriomas. No significant differences in complication rates were observed between\ngroups. However, the intervention group showed significantly higher embryo quality, as well as greater chemical and clinical pregnancy rates, whereas conception and\nimplantation rates did not differ significantly between\ngroups.\nThese findings align with prior research ( 25 ,  26 ). They\nreported 12% recurrence rate following ethanol sclerotherapy, with a mean follow-up of 17 months. No major\ncomplications were observed, although minor issues occurred, including mild abdominal pain in three patients\n(10.7%) and abdominal ethanol extravasation in two patients (7.1%).\nIn a prospective study, Lee et al. ( 27 ) applied 20% ethanol for sclerotherapy and compared outcomes between\nsurgical and conservative approaches. They reported that\nthe number of retrieved, mature, and fertilized oocytes was\nsignificantly lower in the resection group compared with\nthe other treatment groups. However, clinical pregnancy\nrates per initiated cycle, per embryo transfer, implantation\nrates, and miscarriage rates were similar across all groups.\nFollow-up for up to one year post-ethanol sclerotherapy\nindicated that the potential benefits of this method extend\nbeyond initial treatment outcomes.\nSeveral studies have reported varying recurrence rates\nfollowing ethanol sclerotherapy. Suzuki et al. ( 28 ) observed an 11.1% recurrence rate, while Aflatoonian et al.\n( 29 ) using 98% ethanol, reported a 20% recurrence rate at\nsix months. Yazbeck et al. ( 30 ) found a 12.9% recurrence\nrate over a 10 -month follow-up. A meta-analysis indicated that ethanol retention resulted in a lower recurrence\nrate compared to ethanol lavage ( 31 ). Furthermore, repeated monthly aspirations reduced recurrence from 91.5\nto 27.9% over two years, and by the sixth aspirations,\nrecurrence decreased to 5.4%. Variations in recurrence\nrates are likely due to differences in clinical characteristics (e.g., cyst size and primary vs. recurrent), procedural\ndetails (sclerosing agent type, dwell time, volume), and\nfollow-up duration ( 27 ).\nIn addition to recurrence, ethanol sclerotherapy has\nbeen associated with favorable IVF outcomes. Yazbeck\net al. ( 30 ) reported that the ethanol sclerotherapy group\nhad more mature oocytes and a higher cumulative clinical\npregnancy rate compared to surgical cohorts. Similarly,\nSalem et al. ( 32 ) found improvements in ovarian responses to gonadotropin stimulation and an increased number\nand quality of embryos. Koike et al. ( 33 ) also observed\na higher number of high-quality embryos in the ethanol-treated patients, consistent with our findings. Chang et al.\n( 17 ) emphasized that ethanol retention was more effective\nthan aspiration alone, reporting relapse rates of 13.3%\nversus 32.1% over one year. In contrast, Aflatoonian et al.\n( 29 ) and Chang et al. ( 17 ) found no significant differences\nin chemical pregnancy, ongoing pregnancy, or live birth\nrates between retention and aspiration groups, likely due\nto larger cyst sizes in their studies.\nIn the present study, ethanol was retained for ten minutes, resulting in a 20% recurrence rate, comparable to\nseveral previous reports. No significant differences in\nIVF outcomes were observed between the groups. Notably, overall recover defined as achieving pregnancy or\nabsence of persistent symptoms or cysts was higher in\npatients receiving prolonged ethanol sclerotherapy (7-10\nminutes). Patients with smaller cysts (≤5.05 cm), lower\nCA125 levels (≤62.03 IU/mL), and longer treatment durations exhibited the best recovery rates, suggesting that\nextended dwell time may enhance success, particularly in\nlarger cysts and those with clear contents.\nThe findings of the present study indicated that embryo\nquality, while generally good in both groups, was significantly higher in the intervention group, consistent with\nprevious reports ( 27 - 29 ). Although endometriosis does\nnot necessarily impair embryo quality per se, as noted by\nYilmaz et al. ( 34 ), women with endometriomas may experience reduced fertility due to altered endometrial receptivity or the limitations of conventional morphological\nassessments in predicting embryo potential.\nThis study on the efficacy of aspiration and ethanol\nsclerotherapy for primary and recurrent endometriomas\ncarries important clinical implications for assisted reproductive technologies (ART). The observed improvements\nin embryo quality and pregnancy outcomes suggest that\nless invasive approach may serve as a viable alternative\nto conventional surgery, particularly in recurrent cases,\nand 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\npreserving ovarian reserve and optimizing reproductive\noutcomes. Further research is warranted to validate these\nresults and to evaluate long-term reproductive and clinical outcomes.\nA potential limitation of this study is the relatively short\nfollow-up period, as endometriosis may progress over\ntime, and delayed ovarian stimulation could reduce pregnancy rates and increase recurrence. Additional limitations\ninclude a modest sample size, restrictive inclusion criteria that may limit generalizability, reliance on subjective\noutcome measures, and insufficient control for potential\nconfounders. Potential sources of bias include selection\nbias from self-enrollment, investigator bias if outcome assessments are not blinded, and attrition bias due to loss to\nfollow-up. Future studies should incorporate larger, welldefined cohorts and rigorous, standardized data collection\nto strengthen reliability and applicability of the findings.\n\nThe statistically significant improvements in clinical\nand 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\nIVF. This intervention appears to enhance both the quality\nand number of retrieved oocytes and to increase clinical\npregnancy rates compared with conventional approaches.\nBy effectively reducing endometrioma size and supporting ovarian function, ethanol sclerotherapy represents a\nvaluable adjunct in assisted reproductive techniques, especially for women with endometriosis-related fertility\nchallenges.","source_license":"public-domain-us","license_restricted":false}