Postoperative Reproductive Outcomes in Patients with Endometriosis-Associated Infertility: A Single-Center Retrospective Study

Out of 849 patients admitted to our reproductive medicine unit, only 102 patients met the inclusion criteria. Groups A and B included 71 and 31 patients, respectively. The median age of the patients was 33.5 years (range: 21–46 years) at the time of the initial presentation. The age distribution of the cohort (<35 vs. ≥35 years old) showed no significant difference. Most patients (76.5%) suffered from primary infertility prior to diagnosis, whereas 23.5% of patients had one or more early pregnancy losses in their history. The median follow-up time was 70 months (range: 36–197 months). The patients’ characteristics and symptomatology are summarized in Table 1 . Almost half of the patients (45.1%) reported preoperative complaints such as dysmenorrhea, dyspareunia, chronic pelvic pain, and menstrual abnormalities. Approximately a fifth of these cases (18.6%) complained of dysmenorrhea, and a sixth (15.7%) complained of chronic intermenstrual pelvic pain. Abnormalities in the menstrual cycle were recorded in 17 patients (16.7%). This ratio was higher in group B than in group A without statistical significance (25.8% vs. 12.7%, p = 0.25). Clinical characteristics of patients at baseline SD, standard deviation; p < 0.05 indicates statistical significance. *In the remaining patients, pregnancy was achieved spontaneously. In 67.6% of the entire cohort, pregnancy was achieved by ART, while the remaining patients achieved pregnancy naturally. A third of the patients (35.1%) had already undergone one or more abdominal surgeries before presenting to our clinic. The previous surgeries were not for endometriosis, and the diagnosis of endometriosis had not been made before. According to the results of the analysis, the chance of postoperative pregnancy decreases by 25% with each previous abdominal operation ( p = 0.03). Regarding the remaining general characteristics, preoperative findings, and complaints, there were no statistically significant differences between both groups. Table 1 illustrates the clinical characteristics of patients at baseline. A mild form of endometriosis (rASRM stage I) was found mostly in patients of group A (49.3% vs. 22.6%, p < 0.05, respectively), while severe endometriosis (rASRM stage IV) was significantly more common in group B (58.0% vs. 15.5%, p < 0.05, respectively). In particular, bowel endometriosis, deep infiltrating endometriosis, and pelvic adhesions were observed significantly more often in group B ( p = 0.02, p < 0.05, and p < 0.05, respectively). Only 3 of 14 patients (21.4%) with deep infiltrating endometriosis were able to carry the pregnancy to term. DE was found to decrease the likelihood of conceiving postoperatively (hazard ratio [HR] 0.18, 95% CI: 0.06–0.58, p = 0.004). The rates of simultaneous uterine pathologies such as fibroids, polyps, etc., were comparable between both groups (32.4% vs. 38.7%, p = 0.34, respectively). The intraoperative findings are summarized in Table 2 . Intraoperative findings and surgical procedures EL, endometriosis lesions; SD, standard deviation. Bold values indicate statistical significance ( p < 0.05). Although all patients underwent laparoscopic surgery for endometriosis excision, not all patients had their endometriosis completely removed. Solely in 51.9% of the patients, all endometriotic lesions could be removed by local excision or partial peritonectomy, while the remaining cases still had endometriotic lesions postoperatively. In the Cox regression analysis, complete endometriosis resection proved to be a positive factor with regard to fertility (HR 2.2, 95% CI: 1.4–3.6, p = 0.001; Table 3 ). When comparing the CPR, the log-rank test also showed a significant difference between patients with complete (CPR = 83.0%) and incomplete (CPR = 55.1%) removal of the endometriosis ( p = 0.0007). Independent predictive factors of postoperative CPR p < 0.05 values indicate statistical significance. *In comparison to incomplete resection and coagulation. **In comparison to other ovarian surgeries (excision and incision). In 36 patients (35.3%), peritoneal endometriosis coagulation was performed. Postoperatively, 31 of the 36 patients (86.1%) were able to conceive. The log-rank test showed, with a p value of 0.002 that there was a statistically significant difference between the patients who received coagulation and those who did not. Ovarian endometriosis in 76.1% of affected cases was treated by excision and ablation. Excision and incision as surgical techniques had no statistically significant effect on pregnancy ( p > 0.05). The HR showed an approximately 7.74-fold higher chance of postoperative conception by performing ablation as a surgical measure for ovarian endometriosis ( Table 3 ). Overall, 22.5% of the patients experienced a recurrence of endometriosis. Eleven of 23 patients (47.8%) became pregnant despite the recurrence of the disease. In comparison, the pregnancy rate in patients without recurrent endometriosis was significantly higher at 76.9% ( p = 0.003). The recurrence was also proved to be an unfavorable prognostic factor with regard to fertility in the Cox regression analysis (HR = 0.4, 95% CI: 0.28–0.73, p = 0.005), i.e., endometriosis recurrence reduces the postoperative chance of pregnancy by 60% ( Table 3 ). Furthermore, infertility duration (HR = 0.85 95% CI: 0.73–0.98, p = 0.02), bowel endometriosis (HR = 0.26, 95% CI = 0.08–0.82, p = 0.02), higher rASRM score (HR = 0.70, 95% CI: 0.57–0.84, p = 0.0002), and pelvic adhesions (HR = 0.45, 95% CI: 0.28–0.73, p = 0.001) are all significant negative predictive factors for the occurrence of a postoperative pregnancy. The other clinically relevant variables, such as age, BMI, and preoperative symptoms, did not demonstrate any significant impact on the occurrence of pregnancy after reproductive surgery.

Endometriosis follows an unpredictable disease course, and patients often exhibit decreased compliance with long-term adjuvant drug therapy. Regular follow-up and care are crucial, especially until family planning is completed. Given its heterogeneous nature, multidisciplinary care with specialized expertise is essential. Infertility management represents a distinct aspect of endometriosis care. With the rise in the prevalence of other infertility co-factors, such as advanced maternal age and obesity, treatment complexity has increased, necessitating personalized approaches. Both national and international guidelines offer invaluable diagnostic and therapeutic frameworks. Our study’s findings align closely with the “Treatment of Endometriosis-Associated Infertility” section in the ESHRE guidelines, potentially making a significant contribution to future research. However, due to limited prospective randomized data and a lack of robust evidence, a universal recommendation for operative laparoscopy in endometriosis-associated infertility, particularly routine excision of ovarian endometriomas before ART, cannot be unequivocally endorsed [ 19 ]. The primary surgical challenges include the risk of diminishing ovarian reserves and decreased serum AMH concentration during endometrioma excision, as well as potential damage to ovarian vascular structures during hemostatic coagulation [ 21 , 22 ]. Ablative techniques for surgical management of endometriomas seem to offer more tissue-sparing approaches for the purpose of ovarian preservation compared to cystectomy and sclerotherapy. However, any advantages of these techniques individually regarding conception have not been revealed so far. Based on current data, optimizing fertility may involve surgical techniques followed by ART [ 23 ]. Thus, it remains unclear whether operative laparoscopy or expectant management is the best therapeutic option for such patients. As in many other fields of medicine, a gold standard for this clinical scenario is lacking, so factors should be considered throughout decision-making. However, if surgery is indicated, complete excision of the endometriotic wall is recommended to reduce the recurrence rate [ 24 ]. In the context of previous studies [ 17 , 25 ], it has been observed that surgery had a positive effect on the occurrence of pregnancy. In our study, clinical pregnancy was achieved after operative laparoscopy in 70% of endometriosis-associated infertility patients. Of these, one-third became pregnant naturally and two thirds through ART. Additionally, complete excision and/or coagulation of endometriotic lesions on the ovary and/or peritoneum resulted in significantly improved CPR (83.0% vs. 55.1%). Patients in whom all endometriosis lesions could be removed showed a 2.2 times higher chance of conceiving. In a meta-analysis [ 26 ] involving endometriosis-associated subfertile patients from two randomized and four non-randomized studies with a follow-up of up to 36 months, pregnancy rates after operative laparoscopy were examined. The control arm of this analysis included patients treated with hormones or solely underwent diagnostic laparoscopy or laparotomy. An increased rate of pregnancy was observed in patients who underwent laparoscopic surgery, particularly significant in the non-randomized studies (RR of 1.45, p < 0.01). Another Cochrane analysis [ 27 ] based on three RCTs found that operative laparoscopy in infertile women with endometriosis increased the pregnancy rate with an odds ratio of 1.89 (95% CI: 1.25–2.86) compared to diagnostic laparoscopy. However, Moini et al. [ 28 ] found no significant difference in the pregnancy rate between operative and diagnostic laparoscopy in their study involving a total of 38 infertile patients with stage I and II (rASRM) endometriosis ( p = 0.49). In the recently published multicenter-retrospective study “Surgery and ART for Endometriomas” (SAFE) [ 29 ], colleagues evaluated the reproductive outcome after laparoscopic excision of ovarian endometriosis (mean size: 3.6 ± 1.5 cm) compared with infertility due to other reasons. Excision of ovarian endometriosis was associated with a greater need for gonadotropin doses for ovarian stimulation and a lower number of retrieved oocytes. However, this difference was not significant in the subgroup of women over 35. Moreover, the embryo utilization rates, pregnancy rates, and delivery rates between the two study groups remained comparable. Another finding of our current study was the association between complete elimination of endometriotic lesions and a low recurrence rate. As a result, CPR was significantly higher in patients without recurrence than in those with recurrence (76.9% vs. 47.8%). Thus, recurrence might be established as an independent prognostic factor, reducing the chance of fertility by 60%. In the literature, the recurrence rate is described as reaching 50% of patients after a 5-year follow-up of the primary surgery [ 22 ]. A reduced rate of recurrence and further surgeries could be achieved via complete excision of the cyst wall [ 24 ]. On the other hand, recurrence does not affect the outcome of the ART procedure, which makes expectant management in the recurrence situation conceivable [ 30 ]. Furthermore, bowel endometriosis as well as deep infiltrating endometriosis was associated with persistent infertility in our study. Particularly, deep infiltrating endometriosis was an independent prognostic factor for infertility. However, in a small number of cases with deep infiltrating endometriosis and bowel endometriosis, the impact of surgery on infertility could not be adequately analyzed in our cohort. An improvement in the pregnancy rate of up to 74% with a higher natural conception rate in infertile patients with bowel endometriosis has already been reported [ 31 ]. However, despite the positive role of surgery in reducing pain and improving reproductive outcomes, we highly emphasize the importance of balancing the risks and benefits of surgical interventions and tailoring the surgery’s aggressiveness according to the patient’s case [ 32 ]. This study has several limitations. First, it is a retrospective study with a monocentric design. However, the latter could also be perceived as a strength because it ensured uniform surgical training among the surgeons and the use of similar standardized techniques. Second, the pregnancy rates were analyzed in natural and ART cycles together, making it challenging to assess the surgery’s impact on each cycle separately. Third, this study did not consider adenomyosis or previously failed ART cycles. In the literature, adenomyosis is described as an important co-factor in infertile women with endometriosis [ 33 ].

Our results support the positive role of surgical elimination of endometriosis in infertile women. Excisional surgery helps increase the postoperative pregnancy rates. However, existing data are controversial. An individual treatment concept should be developed for each patient based on their preferences, pain status, and previous therapies.

Endometriosis is a chronic inflammatory, estrogen-dependent disease characterized by the presence of endometrial-like glands and/or stroma outside the uterus [ 1 , 2 ]. Its prevalence peaks in women of reproductive age and is estimated to affect up to 50% of patients with infertility [ 3 , 4 ]. Endometriosis significantly influences spontaneous pregnancy rates and outcomes of artificial reproduction cycles. Couples with a partner affected by endometriosis are estimated to be three times less likely to conceive each month compared to healthy controls [ 5 ]. Similarly, patients with endometriosis are 35% less likely to conceive after an In Vitro Fertilization – Embryo Transfer (IVF-ET) cycle, exhibiting lower fertilization and implantation rates, as well as a reduced count of retrieved oocytes [ 6 ]. Although the correlation between endometriosis and infertility is widely recognized, the exact mechanisms of endometriosis-associated infertility remain undetermined. However, a multifactorial mechanism mainly driven by the harsh peritoneal microenvironment and adhesiogenesis has been suggested [ 7 , 8 ]. Patients with endometriosis often experience impaired folliculogenesis, reduced oocyte quality, distorted pelvic anatomy, abnormal tubal contractions, irregular uterine peristalsis, and decreased endometrial receptivity [ 9 , 10 ]. Moreover, increased intraperitoneal concentrations of activated macrophages, interleukins, and oxidative stress markers are believed to negatively influence embryogenesis and placentation [ 9 , 11 ]. Additionally, patients with ovarian endometriomas face accelerated follicular atresia and subsequent loss of ovarian reserve [ 12 , 13 ], reflected in a faster decline in serum concentrations of Anti-Müllerian hormone (AMH) compared to healthy women [ 14 ]. Given the complex and interwoven mechanisms of endometriosis-associated infertility, selecting the appropriate therapeutic approach (hormonal, surgical, or expectant) is often challenging for clinicians. The treatment of endometriosis-associated infertility should be individualized based on factors such as age, duration of infertility, comorbidities, patient preferences, and a careful assessment of the risks and benefits of the chosen therapeutic approach. Currently, surgery is considered the gold standard of endometriosis treatment as it is the only approach with a cytoreductive effect on endometriosis, whereas available medical treatments are primarily suppressive. Despite potential risks to ovarian vasculature and ovarian reserve, excisional surgery for deep pelvic endometriosis has been reported to optimize pregnancy outcomes in both spontaneous and Assisted-Reproduction Technologies (ART) cycles [ 15 ]. Spontaneous pregnancy rates after endometriosis surgery range between 24.8% and 58.6% [ 16 , 17 ]. Similarly, recent meta-analyses have highlighted the favorable reproductive outcomes associated with excisional surgery for endometriosis in patients undergoing ART [ 15 ]. Consequently, complete excision of endometriosis is recommended whenever anatomical challenges and technical considerations do not compromise the safety of the procedure [ 18 , 19 ]. Notably, excisional surgery for colorectal endometriosis has been shown to reduce recurrence by up to 3% over the subsequent 5 years [ 20 ]. The aim of this study was to assess the potential benefits of excisional surgery for endometriosis on the reproductive outcomes of patients with endometriosis-associated infertility and to identify the clinical variables that may influence pregnancy rates.

The authors have no conflicts of interest to declare.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

This retrospective cohort study was conducted at the Unit of Reproductive Medicine, Department of Obstetrics and Gynecology, University Hospital of Goethe Frankfurt University, Frankfurt, Germany. The study included patients with complete medical records and follow-up data who were diagnosed with and underwent surgery for endometriosis-associated infertility between January 1, 2007, and January 31, 2017. Informed consent was waived due to the retrospective nature of the study. The study protocol was revised and approved by an independent Institutional Review Board at Frankfurt’s University Hospital and the University Center for Tumor Diseases (IRB approval number: 19-487, issued on January 28, 2020). The need for informed consent was waived by the internal Ethical Committee due to the retrospective nature of this study. The study adhered to the ethical standards of the Declaration of Helsinki (1964) and the guidelines of the Committee on Publication Ethics (COPE). The manuscript was prepared following the Reporting of Studies Conducted using Observational Routinely-collected Health Data (RECORD) statement, validated by the Enhancing the Quality and Transparency of Health Research (EQUATOR) network ( www.equator-network.org ). During the study period, a total of 849 patients with a diagnosis of infertility were treated at our center. Patients with incomplete medical records or follow-up data, male factor infertility, tubal occlusion, coexisting endocrine diseases, polycystic ovarian syndrome, or congenital Müllerian anomalies were excluded. The study included patients with histologically proven endometriosis and infertility, with infertility defined as the inability to achieve spontaneous conception after 1 year of regular unprotected intercourse. Patients were examined and managed by an interdisciplinary team comprising a urologist, andrologist, reproductive medicine specialist, and endometriosis surgeon. Clinical examination and transvaginal ultrasound evaluation were performed to assess the pelvis and possible endometriotic lesions. Magnetic resonance imaging scans were conducted in suspected cases of deep endometriosis. Pain intensity for dysmenorrhea, dyspareunia, dysuria, and dyschezia was measured using the Numeric Analogue Scale (NAS). Surgical procedures were performed by experienced senior surgeons, with intraoperative complete excision of endometriosis attempted. Coagulation of superficial peritoneal lesions was performed in some cases, and representative biopsies were obtained for pathological examination. Deep endometriosis was defined as invasion of “endometrial-like” tissue with a depth of >5 mm according to ESGE/ESHRE/WES recommendations. Intraoperative findings, including endometriosis dissemination and adhesion sites, were described and staged using the revised American Society for Reproductive Medicine (rASRM) classification system. Asymptomatic bowel lesions were left in situ to avoid unnecessary complications and due to the lack of convincing evidence regarding the benefit of endometriosis excision in asymptomatic patients. Endometriosis was confirmed upon histopathologic examination in all patients. The type and timing of postoperative conception depended on various factors such as patients’ age, the extent of endometriosis, as well as the expectations and wishes of the couple. Due to the multifactorial nature mentioned above, an individualized concept was planned for each patient, with the primary goal being to achieve pregnancy in the shortest time possible and to minimize the duration without endometriosis-specific postoperative therapy. In cases of ovarian endometriomas, especially in recurrent situations, postoperative management began with the GnRH ultra-long protocol, followed by ART. AMH levels were used to predict ovarian response and to calculate the dosing of gonadotrophins according to the recommendations of the ESHRE guideline on ovarian stimulation. Since there is no cut-off for live birth even for low AMH levels, we did not exclude patients with very low ovarian reserve from ART treatment. However, in patients with AMH >3 ng/mL, we administered GnRH analogs before stimulation and switched to antagonist protocols to prevent ovarian hyperstimulation syndrome. Patients under 35 years of age had sufficient time for spontaneous attempts, whereas patients over 40 years of age were recommended to undergo prompt ART. Patients under 35 years of age with anovulatory periods longer than 6 months received timed intercourse/IUI after triggering ovulation followed by ART in case of persistent infertility. Treatment plans were tailored to the individual patient regarding the duration of infertility, AMH level, sperm quality, and quality of life. Our goal in all age groups was to minimize the time to pregnancy. According to the ASRM ethical criteria, ART was no longer indicated for patients over the age of 43. The patient data used in this study were provided by the certified Endometriosis and Reproductive Center of the University Hospital Frankfurt. After the basic reproductive diagnostics had been carried out, the patients were presented to our endometriosis counselors for reproductive surgery. The follow-up of all patients was obtained by postoperative examination within 6 weeks in the office and during the treatment of infertility in the department of reproductive medicine. The patients’ data regarding pregnancy and delivery were updated prior to the statistical analysis. Spontaneous conception was attempted for 3–6 months postoperatively, or ART was applied in cases of tubal infertility or low AMH serum concentration. Based on this, patients were divided into two groups: “Group A” included patients who conceived, and “Group B” included patients who did not. The patient data were archived electronically in an anonymous form using Excel 2018 (Microsoft Corporation, USA). The demographic and operative data of patients were recorded as mean ± standard deviation. Continuous variables with a normal distribution were compared using the t test. The mean differences and 95% confidence intervals (95% CIs) were calculated with two-sided p values. Categorical variables were evaluated using Pearson’s χ 2 and Fisher’s exact test as appropriate, including the Mann-Whitney test and unpaired Student’s t test. Univariate and multivariate analyses were performed using the Cox regression models. Statistical analyses were processed using BiAS software (version 11.10.). All statistical tests were two-sided, considering p < 0.05 as statistically significant.

The study protocol was revised and approved by an independent Institutional Review Board at Frankfurt’s University Hospital and the University Center for Tumor Diseases, known as UCT (IRB approval number: 19-487 issued on the of January 28, 2020). The need for informed consent was waived by the internal ethical committee due to the retrospective nature of this study.

Khayal Gasimli: conception, design, interpretation, and manuscript. Dilara Akpinar: data collection. Bahar Gasimli: manuscript. Annette Bachmann: revising the manuscript. Norbert Maczó, Harald Krentel, and Rudy Leon De Wilde: revising the manuscript. Antoine Naem: data analysis and manuscript. Sven Becker: conception, supervision, design, and interpretation. Morva Tahmasbi Rad: conception, supervision, design, and interpretation.