Introduction

Endometriosis is, a chronic inflammatory condition characterized by the presence of endometrial tissues outside the uterine cavity, affecting approximately 10% of women worldwide and poses a significant challenge to reproductive health [1]. A significant proportion of endometriosis cases manifest as ovarian endometriomas, which contribute to chronic pelvic pain, dysmenorrhea, and impaired fertility due a proinflammatory pelvic cavity environment [1]. These pathological states significantly affect fertility, with a prevalence as high as 30%–50% among infertile women, underscoring the critical need for effective reproductive management strategies [2].

Given the potential implications of endometriosis for infertility, accurate assessment of ovarian reserve is crucial for optimal treatment strategies. Traditionally, diagnosis and treatment relied on laparoscopic surgery, which carries the risk of damaging healthy ovarian tissue and diminishing ovarian reserve. However, advancements in radiological techniques, such as ultrasonography and magnetic resonance imaging (MRI), now allows for noninvasive evaluation of endometriosis [3]. In parallel, the development of reliable serum markers has improved the assessment of ovarian reserve and the mitigation of infertility risks during endometriosis management. Indeed, recently published European Society of Human Reproduction and Embryology (ESHRE) guidelines recommend assessing ovarian reserve prior to the surgical removal of endometriotic cysts [4]. This assessment is particularly crucial for women desiring pregnancy, as it significantly influences the decision between laparoscopic surgery and medically assisted reproduction, given the potential for a 30%–50% reduction in ovarian reserve postoperatively [5,6]. Thus, a precise ovarian reserve assessment is critical for effective management and personalized treatment strategies in women with endometriosis.

Although serum markers, including anti-Müllerian hormone (AMH), and imaging techniques such as ultrasonography and MRI have advanced the assessment of endometriosis-related ovarian reserve, a more comprehensive approach is still needed. Existing methods have limitations; for instance, AMH levels, while informative, can be influenced by factors, including the presence of endometriomas, which may affect their accuracy when used in isolation [7,8]. Marcellin et al. [9] reported that large endometriosis may lead to an overestimation of AMH levels due to increased blood flow to the affected ovaries. Additionally, the inflammatory state associated with endometriosis may further influence serum AMH levels [10]. Similarly, while ultrasonography offers valuable visualization of ovarian structures, accurately measuring certain parameters in the presence of endometriomas can be challenging [11].

To address these challenges, this study proposes a novel approach for evaluating ovarian reserve in women with unilateral endometriomas. We aimed to develop a comprehensive model that integrates serum AMH levels with various ultrasonographic markers including affected ovary relative volume (AORV), in patients with unilateral endometrioma [12]. Ultimately, the current study has the potential to significantly impact clinical care by refining the assessment of ovarian reserve and facilitating more informed treatment decisions for women with endometriosis.

Methods

Ethical statements: This study was approved by the Institutional Review Board (IRB) of Pusan National University Hospital (IRB No. 2501-013-148). All patients provided informed consent indicating their agreement with the use of their medical records in this study.

1. Patients

This retrospective study was conducted at the Department of Obstetrics and Gynecology at Pusan National University Hospital. Women diagnosed with endometrioma by imaging techniques between October 1, 2015, and October 1, 2023, were included.

Exclusion criteria were as follows: bilateral endometrioma, previous ovarian surgery, irregular menstrual cycles, polycystic ovary syndrome, hyperprolactinemia, abnormal thyroid function tests, and a history of medication use, including gonadotropin-releasing hormone analogs, oral contraceptives, or progestins, within the 3 months preceding recruitment. Body mass index (BMI) was calculated as weight (kg) divided by height (m) squared.

2. Measurement of endometrioma and ovarian size using radiologic technique

Ultrasonography was performed using a 5–9 MHz transvaginal transducer (Voluson E6 General Electric) in the morning during the early follicular phase of a spontaneous cycle, specifically between cycle days 2 and 6. MRI was performed within 1 month of the patient's first visit.

The sizes of the ovary and endometrioma were determined by three diameters: the maximum diameter in the transverse, anteroposterior, and longitudinal axes. Four absolute and four relative sonographic indicators were obtained according to Cosma et al. [12].

･ Mean endometrioma diameter (MED);

･ Endometrioma volume (EV);

･ Healthy ovary antral follicle count (HO-AFC);

･ Healthy ovary volume (HOV);

･ Affected ovary relative size (AORS), i.e., the ratio between the largest diameter of the affected and the healthy ovary;

･ Endometrioma relative volume 1 (ERV1), i.e., the ratio between the EV and the volume of the affected ovary;

･ Endometrioma relative volume 2 (ERV2), i.e., the ratio between the EV and the volume of both ovaries;

･ AORV, i.e., the ratio between the volume of the affected and the healthy ovary.

If multiple endometriomas were detected in the same ovary, the indicator was reported as the sum of the individual indicators for each endometrioma.

3. Assay of AMH and inflammatory markers

All women underwent blood sampling for AMH measurements and inflammatory markers within 1 month of undergoing ultrasonography or MRI. Blood samples were collected after an overnight fast of at least 8 hours. The following measurements were obtained using the Roche Modular DP: a complete blood cell count, including the white blood cells count, percentages of segmented neutrophils and lymphocytes, and the segmented neutrophil-to-lymphocyte ratio (NLR). Serum AMH levels were performed using an AMH/Müllerian inhibiting substance enzyme immunoassay (AMH/MIS EIA) kit (Immunotech version, Beckman Coulter). The intra-assay and inter-assay coefficients of variation were 12.3% and 14.2%, respectively.

4. Statistics

Quantitative variables were expressed as mean±standard deviation, and qualitative variables were presented as frequencies and percentages. Spearman’s correlation coefficient was also used to assess the strength and direction of the association between serum AMH levels and variable parameters (MED, EV, HO-AFC, HOV, AORS, ERV1, ERV2, and AORV) measured using ultrasonography and MRI. A p-value of <0.05 was considered statistically significant. Statistical analyses were conducted using SAS ver. 9.4 (SAS Institute).

Results

In this retrospective study, 146 patients with unilateral endometriomas were included. Their baseline characteristics are summarized in Table 1. The mean age of the participants was 32.01±5.99 years, and the mean serum AMH level of 3.54±3.24 ng/mL. The mean EV was 63.54±84.42 mL as measured by ultrasonography and 59.71±101.90 mL as measured by MRI.

Table 2 shows the correlation between serum AMH levels and various patient characteristics. A statistically significant negative correlation was observed between age and serum AMH levels (rho=‒0.584, p=0.000) and between BMI and serum AMH levels (rho=‒0.191, p=0.021), indicating that AMH levels tend to decrease with increasing age and BMI. Notably, other factors including height, body weight, visual analog scale score, age at menarche, cancer antigen 125 level, and complete blood count parameters were not significantly correlated with serum AMH levels.

Table 3 shows the correlation between serum AMH levels and various parameters obtained from ultrasonography and MRI. Among the ultrasonographic parameters, only the maximum diameter of the healthy ovary showed a statistically significant positive correlation with serum AMH levels (rho=0.222, p=0.007). Notably, AORS, ERV1, ERV2, and AORV did not significantly correlate with AMH levels. In contrast, MRI-derived parameters showed a more pronounced relationship with AMH. Specifically, the maximum diameter (rho=0.173, p=0.037), mean diameter (rho=0.170, p=0.041), and volume of the healthy ovary (rho=0.171, p=0.040) exhibited statistically significant positive correlations with serum AMH levels. Similar to the ultrasonographic findings, AORS, ERV1, ERV2, and AORV derived from MRI were not significantly correlated with AMH.

Discussion

We investigated the relationship between serum AMH levels and imaging markers in women with unilateral endometriomas, with particular emphasis on the contribution of the healthy ovary to overall ovarian reserve. Our findings demonstrate that the size and volume of the healthy ovary, as measured by ultrasonography and MRI, are significantly associated with serum AMH levels. This observation underscores the importance of assessing the healthy ovary when evaluating ovarian reserve in women with unilateral endometriomas.

Accurate assessment of ovarian reserve is crucial when considering surgical intervention for endometriosis, particularly in women who desire future fertility. Although surgical removal of endometriomas can improve symptoms fertility outcomes, it carries an inherent risk of damaging healthy ovarian tissue and compromising ovarian reserve [4-6]. Two commonly used markers for estimating ovarian reserve estimation are AFC and AMH; however, each has limitations in this context. AFC, measured via transvaginal ultrasound, can be unreliable in the presence of endometriomas, as the ovarian cortex can be obscured by endometriomas on ultrasound, potentially leading to an underestimation of ovarian reserve [13-15]. In fact, several studies have reported conflicting results regarding changes in AFC following surgery or medication in endometriosis patients, suggesting that evaluating ovarian reserve based solely on AFC has limitations [16-18]. AMH, a serum marker produced by granulosa cells in developing follicles, initially gained popularity as a universal indicator of ovarian reserve marker due to its perceived stability across various clinical conditions and minimal inter- and intra-cycle variation [19,20]. However, recent studies have challenged this view, demonstrating that AMH levels can fluctuate throughout the menstrual cycle and are influenced by various medications [21-24]. For example, Yin et al. [22] reported that oral contraceptives, metformin, and clomiphene citrate decreased AMH levels. Moreover, interpretation of AMH requires caution in endometriosis, as the size of endometriomas can influence AMH measurements, potentially leading to an overestimation of ovarian reserve; as the size of endometriomas increases, there may be increased blood flow to the endometriomas, leading to a higher-than-expected measurement of AMH levels compared to actual ovarian reserve [7-9]. Consequently, relying solely on AMH for ovarian reserve assessment in women with endometriosis may be insufficient, and incorporating additional markers or imaging modalities may enhance the evaluation accuracy.

Several studies have explored ultrasonographic parameters to assess ovarian reserve in women with endometriosis. Cosma et al. [12] investigated the AORV, the ratio of the affected ovary volume to the HOV, and found that AORV was negatively associated with AMH, suggesting it could be a useful predictor of ovarian reserve. However, in our study, the AORV calculated using ultrasonography and MRI did not correlate with serum AMH levels. Instead, our results support the idea that the healthy contralateral ovary may compensate for the compromised function of the affected ovary, with its size and volume serving as valuable indicators of overall ovarian reserve. For example, in women with a large endometrioma and diminished ovarian reserve, surgery may be necessary. However, if the healthy ovary remains robust, a more conservative approach can be considered. Conversely, if the healthy ovary is smaller, surgery may be warranted to prevent further decline in ovarian reserve, especially in patients with a strong desire for future fertility or those with endometriomas exhibiting features suggestive of malignancy. By incorporating information about the healthy ovary, clinicians can develop more tailored treatment strategies that balance the potential benefits of surgical intervention with the need to preserve ovarian function.

Another potential factor suggesting the systemic condition and ovarian reserve of a woman with unilateral endometrioma is NLR. In this study, the average value of NLR was 2.38±1.86, with the normal range of this ratio falling between 1.0 and 2.0. Values above 3.0 or below 0.7 in adults are considered pathological [25]. When NLR falls between 2.0 and 3.0 range, it may signal early-stage pathological conditions such as cancer, atherosclerosis, infection, inflammation, psychiatric disorders, and stress [25]. Therefore, we might assume that endometriomas are associated with mild systemic inflammatory conditions. Recent studies have highlighted the potential influence of systemic inflammation on AMH concentrations. For example, research on dairy cows has shown reduced postpartum AMH levels associated with elevated inflammatory markers [26]. Similarly, studies in human males have reported an inverse association between C-reactive protein levels and AMH concentration [27]. Furthermore, women of reproductive age with Crohn's disease, a chronic inflammatory condition, tend to exhibit reduced AMH levels [28]. These findings suggest that systemic inflammation may contribute to decreased AMH levels.

However, in the present study, no significant correlation was observed between NLR and serum AMH. This discrepancy may be explained by the nature of endometriosis-related inflammation, which is primarily localized within the pelvic cavity and may not always be reflected in systemic inflammatory markers. Moreover, the relationship between inflammation and AMH has been addressed in only a limited number of studies, particularly in human subjects. Therefore, AMH levels may need to be interpreted with caution in the context of endometriosis, and further research would be beneficial to clarify the potential roles of both localized and systemic inflammation in influencing ovarian reserve markers.

The current study has several limitations. Firstly, the sample size was relatively small, which may limit the generalizability of our findings. While the inclusion of 146 patients comparable to other studies in this field, a larger sample size would provide high statistical power and increase confidence in the results. Secondly, as a retrospective study, the ultrasonographic measurements were reviewed retrospectively, introducing the potential for measurement errors compared with prospective studies [12]. Furthermore, due to the retrospective nature of this study, data on the HO-AFC were not consistently available. As a result, we were unable to evaluate the potential correlation between HO-AFC and the volume of the healthy ovary, which could have further validated the structural-functional association. Future prospective studies should consider incorporating HO-AFC to explore its potential value as an imaging-based marker of ovarian reserve in patients with unilateral endometrioma. Lastly, our study population consisted of women with unilateral endometriomas, which may not be representative of all women with endometriosis. Further research is needed to determine whether our findings can be generalized to women with different types of endometriomas or bilateral disease. In addition, future studies may help identify other potential markers beyond normal ovarian volume that could provide further insight into ovarian reserve and function in this population.

Despite these limitations, our study provides valuable insights into the assessment of ovarian reserve in women with unilateral endometriomas. By demonstrating the significance of the healthy ovary's size and volume, this study complements AMH measurements and aid in clinical decision-making, particularly in endometriosis, where surgical intervention can potentially impair ovarian reserve.

One strength of this study is that both ultrasound and MRI images were analyzed in the same patients. Ultrasound, while widely used in clinical practice, has several limitations—its image quality can be influenced by factors such as operator experience, patient body habitus, and the presence of bowel gas, all of which may introduce variability and affect measurement accuracy [29]. Moreover, ultrasound is susceptible to inter-observer variability and may be technically challenging in cases of obesity or pelvic adhesions. In contrast, measurements obtained from MRI are less prone to such errors, even in retrospective studies, due to the standardized protocols for image acquisition and analysis. Therefore, the use of MRI in this study likely contributes to greater reliability and consistency in imaging-based assessments [30].

In clinical practice, the decision to perform surgery for endometrioma is generally based on the severity of the patient’s symptoms and whether future fertility is desired. For patients who wish to conceive, it is essential to evaluate for other potential causes of infertility. In assessing ovarian reserve, serum AMH levels remain a central parameter. However, based on the findings of this study, in cases of unilateral endometrioma, the volume of the contralateral healthy ovary may also serve as an important consideration.

In contrast, in patients with bilateral endometriomas, no additional reliable indicators beyond AMH have been established to date, and the clinical significance of the normal ovary's volume remains unclear. Further studies are warranted to better understand its potential role. Nevertheless, considering the risk of significant postoperative decline in ovarian function following surgical treatment for bilateral endometriomas, alternative therapeutic approaches—rather than surgery—should be carefully discussed with patients when fertility preservation is a concern.

Future research should focus on validating these findings in larger prospective studies and developing a comprehensive model that integrates various markers to provide a more accurate and individualized assessment of ovarian reserve.

Article information

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

This work was supported by a 2-year Research Grant from Pusan National University to Jong Kil Joo.

Author contributions

Conceptualization: JKJ. Data curation: HJL, EHY. Formal analysis: HJL, JKJ. Funding acquisition: JKJ. Investigation: JKJ. Methodology: JKJ. Supervision: JKJ. Visualization: EHY. Writing-original draft: HJL. Writing-review & editing: HJL, EHY, JKJ, YJN. All authors read and approved the final manuscript.

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Figure & Data

References

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