Introduction
Endometriosis is a chronic inflammatory condition characterized by endometrial-like tissue located outside the uterus, with ovarian endometrioma representing one of its most common manifestations [1]. This disease can significantly affect women’s reproductive health, particularly in those undergoing in vitro fertilization (IVF), where reproductive outcomes may be compromised [2]. Multiple studies have demonstrated that the presence of endometrioma may adversely affect ovarian reserve and the response to stimulation during IVF treatments [3].
There is ongoing debate regarding whether oocyte and embryo quality are reduced in IVF patients with endometriosis compared to those with other infertility etiologies. Several studies have explored correlations between oocyte quality parameters and IVF outcomes across various patient populations, yet findings remain inconsistent regarding the specific impact of endometrioma on oocyte competence [4,5]. A previous study suggested that women with endometriosis-associated infertility tend to have reduced oocyte quality compared to those with other infertility factors, potentially contributing to lower implantation and pregnancy outcomes [6].
Some have proposed that endometrioma primarily affects ovarian reserve rather than oocyte quality itself [7]. In a retrospective study by Benaglia et al. [8], although the number of oocytes collected from women with endometriosis was smaller, fertilization rates, embryo quality, implantation rates, pregnancy rates, and live birth rates were comparable to those in women with other infertility factors. Similarly, Kamath et al. [9] reported that live birth rates per cycle in women with endometriosis were similar between cycles using donor oocytes and cycles using autologous oocytes. Based on such findings, endometriosis does not appear to exert a substantial adverse effect on oocyte or embryo quality.
Nevertheless, previous studies did not directly analyze oocyte quality, but instead evaluated it indirectly by comparing fertilization rates. The assessment of oocyte quality is essential for predicting embryo developmental potential and ultimately the success of IVF procedures. In intracytoplasmic sperm injection (ICSI) cycles, dysmorphic metaphase II (MII) oocytes are frequently associated with reduced fertilization and cleavage rates. Dysmorphic oocytes exhibit cytoplasmic granulation, abnormal cytoplasm (including vacuoles, refractile bodies, or smooth endoplasmic reticulum), abnormal oocyte shape, and alterations of the zona pellucida, perivitelline space, or polar body.
The average oocyte quality index (AOQI) was introduced as a morphological oocyte scoring system in which the total number of abnormalities in MII oocytes is counted, and the index is calculated as the ratio of abnormalities to the total number of MII oocytes [10]. Sigala et al. [10] evaluated abnormalities across seven morphological categories, including cytoplasmic granularity, irregular shape or thickened zona pellucida, intracytoplasmic vacuoles, material within the zona pellucida, anomalies of the first polar body, large perivitelline space, and oocyte shape [10].
In one retrospective study, the AOQI was similar between women with and without endometriosis. However, two specific abnormalities, abnormal oocyte shape and intracytoplasmic vacuoles, were observed more frequently in women with endometriosis [11]. Another retrospective study found that serum anti-Müllerian hormone (AMH) level was inversely associated with cytoplasmic granulation, abnormally amorphous oocytes, extended or granulated perivitelline space, fragmented polar body, and the overall oocyte morphology score represented by the AOQI [12].
Despite increasing interest in the impact of endometriosis on reproductive outcomes, relatively few studies have directly compared oocyte quality indices between women with ovarian endometrioma and those with other forms of infertility. Notably, limited research has examined AOQI differences between women with endometrioma and those with diminished ovarian reserve (DOR) of various etiologies [13,14]. The relationship between ovarian reserve markers and oocyte quality in patients with endometrioma also remains unclear, as current evidence offers conflicting conclusions regarding whether both oocyte quantity and quality are similarly affected [15].
Therefore, this study sought to analyze AOQI differences in women with ovarian endometrioma undergoing IVF and to assess its correlation with ovarian reserve. By doing so, it aims to contribute to a more comprehensive understanding of reproductive outcomes in these patients and to inform clinical decision-making for treatment optimization. This study specifically aims to determine whether the AOQI is higher in women with ovarian endometrioma than in those with unexplained infertility or DOR. In addition, the association between serum AMH levels and AOQI was also assessed.
Methods
1. Study population
This study was conducted at Seoul National University Bundang Hospital. We included 92 ICSI cycles (49 women) in which one to five MII oocytes were obtained between January 2023 and September 2024. The study was approved by the Institutional Review Board of Seoul National University Bundang Hospital (IRB No. B-2508-989-109), and the requirement for informed consent was waived because of its retrospective design.
Each cycle was assigned to one of three groups according to the primary indication for IVF treatment: current or recurrent ovarian endometrioma (34 cycles), unexplained infertility (26 cycles), and DOR, defined as a serum AMH level <1.0 ng/mL (32 cycles). Demographic and clinical information was retrieved from electronic medical records.
Exclusion criteria included patients with a prior history of endometrioma surgery without evidence of current endometrioma, as well as those undergoing IVF for other indications such as tubal factor infertility or male factor infertility.
2. Ovarian stimulation and IVF procedure
Ovarian stimulation protocols were selected based on patient age, ovarian reserve, and previous response to stimulation, following standard clinical practice at our institution [16]. Pituitary suppression was performed using either a gonadotropin-releasing hormone (GnRH) agonist long protocol or a GnRH antagonist protocol. Recombinant follicle-stimulating hormone and/or human menopausal gonadotropin was administered for stimulation, with dosing individualized to each patient’s characteristics.
Ovulation was triggered with human chorionic gonadotropin (hCG) once at least two follicles reached a diameter of ≥18 mm. Transvaginal ultrasound-guided oocyte retrieval was performed 35 to 36 hours after hCG administration. Retrieved oocytes were incubated in culture medium, and ICSI was performed on MII oocytes following standard laboratory procedures.
3. AOQI assessment
The AOQI was calculated for each cycle. First, oocytes were evaluated under a microscope by experienced embryologists, and one or more dysmorphic features were documented. Dysmorphic features were categorized into six groups and further classified into 15 detailed items: cytoplasmic granulation (granulation or central granules), abnormal cytoplasm (vacuoles, refractile bodies, or smooth endoplasmic reticulum), abnormal shape (oval, amorphic, or dark), abnormal perivitelline space (extended or containing debris), abnormal polar body (fragmentation, double, or large), and abnormal zona pellucida (thin or thick) (Figure 1). The AOQI was then determined as the ratio of the total number of abnormalities to the total number of MII oocytes in each cycle. Among 251 MII oocytes obtained, 208 (82.9%) had at least one dysmorphic feature.
4. Statistical analysis
Statistical analyses were performed using SPSS ver. 25.0 (IBM Corp.). Continuous variables were presented as median values with interquartile ranges. Categorical variables were reported as number (percentage). The Kolmogorov-Smirnov test was applied to assess normality. Comparisons among the three groups were conducted using the Kruskal-Wallis test for continuous variables, followed by appropriate post hoc tests. Categorical variables were compared using the chi-square test or Fisher exact test when applicable. The relationship between serum AMH levels and AOQI was examined using Spearman’s rho for the overall cohort as well as separately for each of the three groups. Multiple linear regression analysis was also performed to identify independent factors associated with AOQI, adjusting for the presence of ovarian endometrioma and serum AMH levels.
Results
Women with ovarian endometrioma were significantly younger than those with unexplained infertility and DOR (p<0.001) (Table 1). The median serum AMH levels were highest in the unexplained infertility group and lowest in the DOR group (p<0.001 for all comparisons).
The number of MII oocytes retrieved was significantly higher in the unexplained infertility group compared to the other groups (p<0.05). The median AOQI value was significantly higher in the endometrioma group (1.50) than in the unexplained infertility group (1.00) (p=0.037), although it did not differ significantly from the DOR group (1.42).
With regard to specific oocyte abnormalities, cytoplasmic granulation was most prevalent in the endometrioma group compared to the other two groups (p<0.05), whereas abnormal cytoplasm was least prevalent in the endometrioma and unexplained infertility groups compared to the DOR group (p<0.001) (Figure 2).
Despite these morphological differences, fertilization rates were comparable across all three groups (Table 1). The endometrioma group showed the highest percentage of top-quality embryos (36.7%), which was significantly higher than that of the DOR group (0%, p=0.043).
In the overall study population, median serum AMH levels demonstrated significant positive correlations with both the number of total MII oocytes and the number of dysmorphic MII oocytes, while showing a significant negative correlation with AOQI (r=–0.242, p=0.020) (Table 2). When each group was analyzed separately, this negative correlation between serum AMH level and AOQI was statistically significant only in the endometrioma group (r=–0.429, p=0.011) (Table 3). Regression lines illustrating these associations are shown in Figure 3, depicting the relationship between serum AMH levels and AOQI in the overall study population (Figure 3A) and in the endometrioma (Figure 3B), unexplained infertility (Figure 3C), and DOR (Figure 3D) groups.
Because the median AOQI was significantly higher in the endometrioma group and a significant negative correlation between serum AMH level and AOQI was observed in both the endometrioma group and the overall cohort, a multiple linear regression analysis was performed using two variables: presence of endometrioma and serum AMH level. Female age was not associated with AOQI (r=–0.164, p=0.118), and therefore was not included in the multiple linear regression model.
Multiple linear regression analysis showed that serum AMH level remained a significant independent factor negatively associated with AOQI (unstandardized coefficient=–0.176; 95% confidence interval, –0.327 to –0.024; p=0.024), whereas the presence of endometrioma was not a significant factor (Table 4).
Discussion
Our study addressed an important gap in the current literature by specifically examining the relationship between oocyte quality and ovarian reserve in women with endometrioma, comparing them not only with those who had unexplained infertility but also with those who had DOR. Previous studies primarily compared endometriosis patients with normal controls or patients with tubal factor infertility, without adequately accounting for the potential confounding effect of DOR, which frequently coexists with endometriosis [17,18].
In our study, women with ovarian endometrioma demonstrated significantly higher AOQI values (indicating poorer oocyte quality) compared to those with unexplained infertility. However, we also observed that higher AMH levels corresponded to better oocyte quality among women with ovarian endometrioma. This finding suggests that oocyte quality varies according to ovarian reserve even among women who share the same diagnosis of endometrioma. Multiple linear regression analysis further revealed that endometrioma itself was not a significant factor associated with AOQI; instead, serum AMH level remained the only significant independent factor. Thus, the elevated AOQI observed in the endometrioma group appears to be primarily attributable to reduced ovarian reserve rather than the direct impact of endometrioma.
In our study, female age and AOQI were unrelated, and therefore age was not included as a variable in the multiple linear regression analysis. For reference, we also found no correlation between female age and AMH (r=–0.140, p=0.184). This finding warrants further consideration, particularly given that our endometrioma group included women with a broad range of AMH levels and our DOR group included women across a wide age spectrum. Consequently, within this study population, there appeared to be no negative relationship between age and AMH.
In our study, cytoplasmic granulation was the predominant oocyte abnormality in the endometrioma group, whereas abnormal cytoplasm was more prevalent in the DOR group. The higher prevalence of cytoplasmic granulation among women with endometrioma may reflect the inflammatory microenvironment associated with endometriotic lesions. Endometriomas are known to produce elevated levels of inflammatory cytokines, reactive oxygen species, and iron derived from hemolyzed blood, all of which may diffuse into adjacent ovarian tissue and disrupt folliculogenesis [7]. Such oxidative stress can impair mitochondrial function in oocytes, potentially resulting in cytoplasmic granulation as a morphological indicator of mitochondrial clustering or dysfunction [6].
Our findings are consistent with several prior studies that have reported altered oocyte morphology in women with endometriosis. Xu et al. [18] identified a higher incidence of cytoplasmic granularity and vacuolization in oocytes from endometriosis patients compared with those from women with tubal factor infertility. Likewise, Goud et al. [17] observed that oocytes from women with advanced-stage endometriosis exhibited increased oxidative stress markers and mitochondrial DNA deletions, both of which correlated with abnormal cytoplasmic appearance.
The major strength of our study lies in its comparative design, which incorporated three distinct patient groups representing different infertility etiologies. Additionally, our detailed assessment of specific oocyte abnormalities, as opposed to simply categorizing oocytes as normal or abnormal, provided deeper insights into potential mechanisms by which endometriosis influences oocyte development.
Nonetheless, several limitations should be acknowledged. First, our analysis was limited to cycles in which one to five MII oocytes were retrieved, which may not fully represent the range of ovarian responses seen in these populations. It is possible that the effects of DOR were accentuated by excluding cycles with greater oocyte yields. Second, final embryo development was evaluated without distinguishing between embryos derived from dysmorphic versus morphologically normal oocytes, as our study was not intended to investigate the specific developmental potential of dysmorphic oocytes. Future research should assess embryo development separately for dysmorphic and normal oocytes to clarify their respective contributions to reproductive outcomes.
Collectively, the AOQI may serve as a comprehensive marker that reflects both morphological and cytoplasmic characteristics of oocytes. Our study demonstrates that women with ovarian endometrioma exhibit distinct patterns of oocyte morphological abnormalities, particularly cytoplasmic granulation, compared with those with unexplained infertility or DOR. Prospective studies with larger sample sizes and long-term follow-up are needed to further elucidate the relationship between oocyte morphology, developmental competence, and reproductive outcomes in women with endometrioma.
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