Effect of endometrioma size and bilaterality on clinical, surgical, and laboratory parameters in endometriosis: A retrospective study

In this retrospective study, endometrioma size and bilaterality were associated with distinct differences in clinical, surgical, and laboratory parameters in patients with endometriosis. Larger and bilateral endometriomas have been associated with lower preoperative AMH values, suggesting a greater disease burden and a potential adverse effect on ovarian reserve. These findings underscore the clinical relevance of endometrioma morphology in preoperative evaluation and patient counseling. Furthermore, our results provide valuable information to address inconsistencies regarding the relationship between endometrioma size and AMH. Nevertheless, prospective studies with larger cohorts and longitudinal follow-up are needed to confirm these associations and to inform individualized clinical management strategies.

Endometriosis is a chronic inflammatory disease defined as the presence of endometrium-like tissue outside the uterus and is seen in 2% to 10% of women of reproductive age. However, this rate increases to 50% in women with chronic pelvic pain and/or infertility. [ 1 , 2 ] Endometriosis may be asymptomatic or cause symptoms, such as dysmenorrhea, dyspareunia, pelvic pain, and infertility. [ 3 ] The most common form of endometriosis is endometrioma, which is ovarian endometriosis. Endometriomas may be unilateral or bilateral. [ 4 ] Although the theory of retrograde menstruation is considered in pathogenesis, its cause is still not clearly understood. [ 5 ] Endometrioma treatment may vary depending on factors such as the patient’s age, severity of symptoms, and desire for fertility. Medical (analgesia and/or hormonal therapy) and/or surgical (laparoscopy or laparotomy) methods can also be used for treatment. The main method for endometriosis treatment is personalized treatment. [ 6 ] Endometriosis surgery is a particularly specialized operation for peritoneal adhesions and organ adhesions caused by endometriosis and should be performed by experienced clinicians. [ 7 ] However, recurrence is frequently observed after surgery. The recommended surgical method is laparoscopic excision of endometriomas >4 cm and adhesiolysis. [ 8 ] Although many different markers have been investigated for the diagnosis of endometriosis, the actual diagnosis is made by surgical removal of the foci and pathology report. [ 9 ] Nevertheless, studies have shown that some of the new markers investigated for diagnosis are promising. [ 10 ] Among these noninvasive diagnostic methods, CA-125 has maintained its place in diagnosis for many years. [ 2 , 3 ] In addition, anti-Müllerian hormone (AMH) is considered an important marker of ovarian reserve for fertility follow-up in endometriosis patients. [ 4 ] However, several studies comparing endometrioma size and AMH levels have shown that endometrioma size and AMH levels are not always inversely proportional. They suggested that increased endometrioma size was associated with higher AMH levels. [ 11 , 12 ] This has shown that more studies on the relationship between AMH and endometrioma are needed. The aim of this study was to investigate the clinical, demographic, and laboratory characteristics that are primarily considered in the management of patients with endometrioma, focusing on the effects of cyst size and laterality.

Conceptualization: İnci Halilzade. Data curation: Uğurcan Zorlu, Elçin İşlek Seçen. Formal analysis: İnci Halilzade. Funding acquisition: İnci Halilzade, Uğurcan Zorlu, Elçin İşlek Seçen, Özlem Uzunlar. Investigation: İnci Halilzade. Methodology: İnci Halilzade, Uğurcan Zorlu, Elçin İşlek Seçen, Özlem Uzunlar. Project administration: İnci Halilzade. Resources: İnci Halilzade, Uğurcan Zorlu, Elçin İşlek Seçen, Özlem Uzunlar. Software: İnci Halilzade, Uğurcan Zorlu, Elçin İşlek Seçen, Özlem Uzunlar. Supervision: Özlem Uzunlar. Validation: İnci Halilzade, Uğurcan Zorlu, Elçin İşlek Seçen, Özlem Uzunlar. Visualization: İnci Halilzade, Uğurcan Zorlu, Elçin İşlek Seçen, Özlem Uzunlar. Writing – original draft: İnci Halilzade. Writing – review & editing: Özlem Uzunlar.

Between June 2022 and June 2024, 210 patients aged 18 to 50 years who underwent surgery for endometrioma at the Ankara City Hospital participated in the study. Ethics committee approval was obtained from the Ethics Committee of Ankara City Hospital. Our study was conducted in accordance with the Declaration of Helsinki and in compliance with the national ethical standards. This was a retrospective, observational study. Patients with endometriosis were selected as those who underwent surgery for pelvic pain or infertility according to the revised American Fertility Society classification. All the pathological results were consistent with those of endometriosis. Patients with gynecological comorbidity, active infection, malignancy, or chronic autoimmune disease were excluded. Considering that adenomyosis frequently accompanies endometriosis and that genital tract dysbiosis may affect inflammatory and ovarian reserve parameters, [ 13 ] neither condition was systematically assessed nor used as an exclusion criterion in this retrospective study. Within the scope of this retrospective study, a total of 242 patients who underwent surgery for endometrioma were initially screened. Of these, 11 patients were excluded due to the presence of tubo-ovarian abscess developing on the basis of endometrioma, 3 patients were excluded because postoperative pathological examination revealed malignancy, and 18 patients were excluded due to chronic autoimmune diseases. Ultimately, 210 patients were included in the final analysis. Demographic characteristics, obstetric history, body mass index (BMI), menstrual history, infertility history, preoperative antral follicle count (AFC), preoperative basal follicle stimulating hormone (FSH) levels, preoperative AMH levels, preoperative CA-125 levels, preoperative basal estradiol levels, type of operation (laparotomy or laparoscopy), methods used in the operation, and the presence of adhesions were compared according to endometrioma size and bilaterality. Endometrioma size was classified as ≤30, >30 to ≤50, >50 to ≤70, and >70 mm. In patients with unilateral multiple endometriomas or bilateral endometriomas, endometrioma size was defined as the mean diameter of all cysts. The presence and absence of bilaterality were considered as subgroups. BMI was calculated using the following formula: BMI = weight (kg)/height (m) 2 . All endometrioma surgeries were performed by the same team specializing in endometriosis at our hospital. rAFS was used as the adhesion score. Given the large number of variables and subgroup comparisons in the initial analyses, along with relatively small sample sizes in certain subgroups, an alternative stratification approach was adopted to improve statistical stability and interpretability. Based on previous studies indicating that a 50 mm threshold is clinically relevant for evaluating the impact of endometrioma size on ovarian reserve parameters, [ 14 ] patients were stratified according to both endometrioma size (≤50 mm vs >50 mm) and the presence of bilaterality, resulting in 4 study groups: bilateral ≤ 50 mm, bilateral > 50 mm, unilateral ≤ 50 mm, and unilateral > 50 mm. All demographic, clinical, laboratory, and surgical parameters were subsequently compared among these groups. All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 25.0 (IBM Corp., Armonk). Normality of continuous variables was assessed using histograms and the Shapiro–Wilk test. Normally distributed variables are presented as mean ± standard deviation, and categorical variables as numbers and percentages. Patients were initially stratified according to endometrioma size (≤30 mm, >30–≤50 mm, >50–≤70 mm, and >70 mm) and bilaterality (unilateral vs bilateral). Continuous variables were compared using independent-samples t tests or 1-way ANOVA for normally distributed data, and the Mann–Whitney U or Kruskal–Wallis tests otherwise. Categorical variables were compared using the chi-square test. To further evaluate the combined effect of size and bilaterality, patients were additionally categorized into 4 groups: ≤50 mm unilateral, ≤50 mm bilateral, >50 mm unilateral, and >50 mm bilateral. Overall comparisons across these groups were performed using 1-way ANOVA or the Kruskal–Wallis test for continuous variables and the chi-square test for categorical variables, with only overall P -values reported. An exploratory binary logistic regression analysis was conducted to identify factors associated with the presence of a large (>50 mm) and bilateral endometrioma (>50 mm and bilateral = 1; all other groups = 0). Variables included in the model were age, AMH, and CA-125, selected based on significant overall group differences and clinical relevance. To reduce the risk of overfitting due to the limited number of events, the number of covariates was intentionally restricted, and only clinically relevant continuous variables were included. Results are reported as odds ratios with 95% confidence intervals. All tests were 2-sided, and a P -value < .05 was considered statistically significant. The logistic regression analysis was performed for hypothesis-generating purposes, and no causal inference was intended.

After applying the inclusion and exclusion criteria, 210 patients were included in the analysis (Fig. 1 ). The demographic and clinical characteristics of the participants are summarized in Table 1 . A total of 88 participants had endometriomas ≤30 mm, 67 had endometriomas >30 to ≤50 mm, 39 had endometriomas >50 to ≤70 mm, and 16 had endometriomas >70 mm. No significant differences were observed between the groups in terms of age or reproductive history including gravida and parity. However, a significant difference was observed in BMI, with the >70 mm group showing the lowest BMI. The combination of size and bilaterality was statistically significant for BMI ( P  = .035). Although there were no significant differences in basal FSH and estradiol levels between the groups ( P  = .19 and P  = .36, respectively), a trend was noted where ovarian reserve markers decreased with increasing endometrioma size. The mean AFC tended to be higher in unilateral cases and declined with increasing cyst size, although this was not statistically significant ( P  = .28) (Table 1 ). Demographic and clinical characteristics by endometrioma size and bilaterality. The data is presented as mean ± standard deviation and numbers (%). Bold values indicate statistically significant findings ( P < .05). AFC = antral follicle count, BMI = body mass index. Flow diagram. (Flow diagram of patient selection according to STROBE guidelines.) Pelvic pain, infertility, and surgical characteristics were significantly influenced by endometrioma size and bilaterality (Table 2 ). The incidence of pelvic pain was significantly higher in the participants with larger endometriomas and bilaterality. Specifically, 72.47% of participants with >70 mm endometriomas experienced pelvic pain compared to 47.56% in the ≤30 mm group ( P  = .004). Similarly, infertility rates increased with endometrioma size, with 45.35% of participants in the >70 mm group experiencing infertility compared to 28.82% in the ≤30 mm group ( P  = .008). Preoperative AMH and CA-125 levels also varied significantly across the groups. The >70 mm in size and with bilaterality group had the lowest preoperative AMH levels (1.65 ± 0.1 ng/mL) and the highest CA-125 levels (52.45 ± 9.6 U/mL) compared to the ≤30 mm in size and without bilaterality group (AMH = 2.91 ± 0.2 ng/mL, CA-125 = 32.58 ± 5.3 U/mL), with P values of .009 and .008, respectively. Regarding surgical procedures, cautery hemostasis was more commonly used in larger endometriomas, with 88.65% of patients in the >70 mm in size group undergoing this procedure, while the rate of sutured hemostasis decreased accordingly. The rate of endometrioma-associated adhesions was significantly higher in participants with larger endometriomas >70 mm in size and the highest rate in the bilaterality group (62.04%) ( P  = .049) (Table 2 ). Pelvic pain, infertility, laboratory, and surgical characteristics by endometrioma size and bilaterality. The data is presented as mean ± standard deviation and numbers (%). Bold values indicate statistically significant findings ( P 50 mm) and bilaterality into 4 groups: unilateral ≤ 50 mm (n = 101), bilateral ≤ 50 mm (n = 54), unilateral > 50 mm (n = 33), and bilateral > 50 mm (n = 22). Comparisons across these groups revealed significant differences in several demographic, clinical, laboratory, and surgical parameters (Table 3 ). Patients with larger endometriomas (>50 mm), particularly those with bilateral involvement, exhibited significantly lower preoperative AMH levels ( P  < .001) and higher CA-125 concentrations ( P  < .001) compared with patients with smaller and unilateral cysts. In addition, the prevalence of pelvic pain, infertility, and associated adhesions increased progressively across groups, with the highest rates observed in the bilateral > 50 mm group ( P  = .031, P  = .044, P  = .019, respectively) (Table 3 ). Clinical and laboratory characteristics according to endometrioma size and bilaterality (4-group overall comparison). Bold values indicate statistically significant findings ( P < .05). Continuous variables are presented as mean ± standard deviation and were compared across the 4 groups using 1-way ANOVA or the Kruskal–Wallis test, as appropriate. Categorical variables are presented as percentages and were compared using the chi-square test. P values represent overall comparisons across the 4 groups only. Two-sided P  < .05 was considered statistically significant. AMH = anti-Müllerian hormone, BMI = body mass index. An exploratory binary logistic regression analysis was performed to identify factors associated with the presence of large (>50 mm) and bilateral endometriomas (Table 4 ). Variables were selected based on statistically significant overall differences across the 4 groups. To minimize overfitting, the model was intentionally restricted to a limited number of clinically relevant continuous variables. Low AMH levels were independently associated with the presence of large (>50 mm) and bilateral endometriomas (odds ratio [OR] = 0.12, 95% confidence interval [CI]: 0.04–0.41; P  = .002). Age was not independently associated with large and bilateral endometriomas (OR = 1.10, 95% CI: 0.98–1.24; P  = .104). Similarly, although higher CA-125 levels showed a trend toward an association, this relationship did not reach statistical significance in the multivariable model (OR = 1.06, 95% CI: 0.99–1.14; P  = .081) (Table 4 ). Exploratory logistic regression analysis for large (>50 mm) and bilateral endometriomas. Dependent variable: large and bilateral endometrioma (>50 mm and bilateral = 1; all other groups = 0). AMH = anti-Müllerian hormone, CI = confidence interval.

This study aimed to investigate the clinical and demographic characteristics of patients with endometriomas, focusing on the effects of cyst size and bilaterality. Our findings demonstrate that larger endometrioma size and bilateral involvement are associated with disease-related laboratory and clinical profiles. No significant differences in age were observed across endometrioma size categories or according to bilaterality, which is consistent with previous reports indicating that age is not a major determinant of endometrioma size or laterality. [ 15 ] In contrast, BMI was significantly lower in patients with larger cysts. This finding is in accordance with earlier studies suggesting an inverse relationship between cyst size and BMI in women with endometriomas. [ 16 ] Although the underlying mechanisms remain unclear, this association may reflect the complex interactions between endometriosis, metabolic processes, and systemic inflammation. Further studies are needed to understand the underlying mechanisms. With respect to ovarian reserve, mean AFC was higher in unilateral endometrioma cases and showed a non-significant downward trend with increasing cyst size. This pattern may be attributable to the direct detrimental effects of larger, particularly bilateral, cysts on ovarian tissue, folliculogenesis, and vascularization. [ 17 ] In addition, basal FSH and estradiol levels remained within normal ranges across all groups, with no significant intergroup differences. These findings are consistent with previous studies reporting that circulating hormonal markers do not always parallel changes in ovarian reserve or disease severity in endometriosis. [ 18 ] Such discrepancies may be explained by compensatory mechanisms within the hypothalamic–pituitary–ovarian axis, as well as interindividual variability in metabolic, immune, genetic, and environmental factors. Pelvic pain and infertility were significantly more prevalent among patients with larger and bilateral endometriomas in our study, supporting the concept that increasing cyst size and bilateral involvement are associated with greater symptom burden and reproductive impairment. [ 19 ] Although the association between cyst size and infertility duration did not reach statistical significance, the observed trend toward longer infertility duration in patients with larger cysts suggests a potential cumulative adverse effect of endometriomas on fertility over time. [ 20 ] Surgical approaches also differed modestly according to cyst size and bilaterality, with laparoscopic suturing being more frequently employed in cases involving larger cysts. Furthermore, adhesions were significantly more common in patients with larger and bilateral endometriomas. This finding is consistent with previous literature demonstrating a strong association between disease severity and the presence of adhesions, particularly in advanced or bilateral cases, which may further complicate surgical management and adversely affect reproductive outcomes. [ 17 ] Comparative analyses in the present study demonstrated that both endometrioma size and bilaterality were associated with differences in AMH and CA-125 levels. These findings suggest that cyst size and bilaterality may serve as important clinical indicators reflecting disease severity and ovarian involvement in patients with endometriosis. CA-125 is a well-established biomarker of inflammatory activity and disease burden in endometriosis, with elevated levels more frequently reported in patients with extensive or advanced disease. [ 21 ] In our cohort, higher CA-125 levels were observed in patients with larger and bilateral endometriomas, and although CA-125 demonstrated a positive association with large and bilateral disease in regression analysis, this relationship did not reach statistical significance. However, given the nonspecific nature of CA-125 and its susceptibility to variation due to multiple inflammatory and clinical conditions, these findings should be interpreted with caution. In our study, exploratory logistic regression analysis showed that lower AMH levels were independently associated with the presence of large (>50 mm) and bilateral endometriomas, further supporting the observed relationship between more extensive disease and diminished ovarian reserve. Although AMH is widely used as a marker of ovarian reserve, its interpretation in the context of endometriosis remains controversial. Several studies have demonstrated a negative association between increasing endometrioma size, bilaterality, and AMH levels, [ 22 , 23 ] whereas others have reported no significant relationship [ 24 ] or even higher AMH levels in patients with larger endometriomas. [ 11 , 12 ] Given the well-documented detrimental effects of endometriomas on ovarian tissue and follicular density, [ 25 ] the observation of elevated AMH levels in larger cysts appears biologically implausible. Moreover, overestimation of ovarian reserve based on falsely elevated AMH levels in the presence of large endometriomas may influence surgical decision-making toward more aggressive approaches, potentially increasing the risk of surgery-related ovarian damage and further compromise of ovarian reserve. [ 4 ] Therefore, larger, well-designed studies are required to clarify the complex relationship between endometrioma characteristics and AMH levels, and replication of existing findings will be essential to resolve ongoing inconsistencies in the literature. Several limitations of this study should be acknowledged. As a limitation of this study, the large number of variables and relatively small sample sizes in certain subgroups necessitated an additional literature-based reclassification using a 5 cm cutoff and bilaterality. Consequently, the regression analysis based on this reclassification was exploratory in nature and should be interpreted with caution. The lack of longitudinal follow-up also limits the assessment of temporal changes in ovarian reserve and disease progression. A further limitation of this study is that concomitant adenomyosis and genital tract dysbiosis were not systematically assessed, and their potential confounding effects cannot be excluded. Despite these limitations, a key strength of this study lies in the relatively large and well-defined cohort, along with systematically collected clinical, biochemical, and surgical data, which enhances the robustness and reliability of the findings.