Ovarian reserve appraisal in women with ovarian endometrioma continues to be a challenging and debated topic in reproductive medicine. This diagnostic complexity arises from several fundamental inquiries about disease pathogenesis and patient management. These include the potential influence of endometrioma per se on ovarian reserve, the adverse effect of ovarian surgery on ovarian reserve, and the adequacy of the most established ovarian reserve measures, anti-Müllerian hormone (AMH) and antral follicle count (AFC) to accurately assess ovarian reserve in these women.

While standards for evidence-based clinical guidelines stipulate the use of systematic reviews, uncritically accepting the results of a single systematic review may have several masked risks (1). Indeed, several systematic reviews and meta-analyses exploring ovarian reserve appraisal in cases with ovarian endometrioma were published in the last decade. However, they had contrasting results, instigating confusion and potentially leading to obverse clinical management.

In the general population of reproductive age, among various tests, AFC and AMH are considered the most sensitive and reliable non-invasive methods of ovarian reserve evaluation (2, 3), with no superiority dispute between the two. Two independent systematic reviews and meta-analyses examined the impact of endometriotic cystectomy during the reproductive age, the first employing AMH and the second AFC, and they have reached contradictory conclusions. The first, by Raffi et al. in 2012, reported that surgery had a harmful effect on AMH (4), while the second, by Muzii et al. in 2014, using AFC, found that it did not affect the ovarian reserve (5). Drawing an inference on whether endometriotic cystectomy genuinely influences the ovarian reserve from these two independent systematic reviews is limited. This controversy may have resulted from different methodologies and standardizations of each systematic review containing the surgical technique, endometrioma size, laterality, previous ovarian surgery, and postoperative time interval evaluations. This controversy may also raise questions about the suitability and reliability of both AMH and AFC as ovarian reserve measures in women with endometrioma.

The purpose of the present review is to critically assess available systematic reviews and meta-analyses that have explored the impact of ovarian endometrioma and endometriotic cystectomies on ovarian reserve measures, AMH, and AFC. Looking deeper into the methodology of these systematic reviews may clarify the bias range, uncover the discrepancies between the reports, distinguish high-quality assessments, explain clinical implications, and assist in decision-making.

To reach the objective of this review, the PubMed database was searched for manuscripts that included the syntaxes (and their MeSH terms): endometriosis OR endometrioma AND ovarian reserve OR anti-Müllerian hormone OR antral follicle count. The research was restricted to systematic reviews (with or without meta-analysis) published in peer-reviewed journals for clinical studies performed in humans and English from inception until November 2, 2023. Systematic reviews that examined ovarian reserve measures, specifically AMH and AFC, in women with ovarian endometrioma before or after surgery were applicable for evaluation.

Systematic reviews that targeted women with non-endometriotic ovarian cysts, gonadal or non-gonadal malignancy, polycystic ovary syndrome, diabetes mellitus, thyroid disease, human immunodeficiency virus, autoimmune disease (such as systemic lupus erythematosus or rheumatoid arthritis), inflammatory bowel disease, and BRCA variants were excluded. Furthermore, systematic reviews that targeted females in childhood, adolescence, and peri- or postmenopausal were omitted from the evaluation. In addition, papers that evaluated women following a minimally invasive approach to managing an endometrioma, such as ablation, laser vaporization, or ethanol sclerotherapy, were excluded. Additionally, papers that aimed to evaluate salpingectomy, hysterectomy, and uterine artery embolization were omitted from the evaluation. As well, reviews that targeted acupuncture in women with endometriosis or explored the hemostatic approach following endometriotic cystectomy were excluded.

This review is a comprehensive and critical summary of all systematic reviews that assess the performance of AMH and AFC in managing cases of endometrioma. Nine eligible reviews were analyzed after conducting a systematic search on PubMed.com. The systematic reviews varied in terms of the level of evidence, as per an identical broad scoring system. Each review was evaluated transparently, using a pre-formulated list of 20 key entries essential to the systematic review’s methodology and including hefty aspects of ovarian endometrioma characteristics related to ovarian reserve measures. This methodology helps to assess the certainty of evidence in systematic reviews, strengthens clinical practice recommendations, and assists in decision-making.

Three fundamental questions linked to the reliability of ovarian reserve measures when tackling ovarian endometrioma in the reproductive age are in discussion nowadays. The first is the impact of endometriotic cystectomy on the short and long-term of ovarian reserve. The second is the reliability of AMH and AFC in accurately estimating ovarian reserve in cases with ovarian endometrioma. The third is the impact of endometrioma per se on ovarian reserve as a function of time in such cases.

Moderate to high-quality evidence shows that endometriotic cystectomy, which is typically performed using the striping technique, is harmful to the ovarian reserve. Following the operation, serum AMH levels significantly decrease, starting in the early postoperative period and continuing until the late postoperative period, which lasts 9-18 months (29). This negative effect is more pronounced in bilateral cases than unilateral cases, equivalent to an ovarian reserve decline of 39.5% and 57.0%, respectively (25). Consequently, this decrease could have a detrimental effect on the reproductive life span. Histological studies of endometriotic cystectomy back up this conclusion and indicate that this damage is due to the unintentional removal of normal ovarian follicles near the pseudo-capsule, which is almost unavoidable even with experienced surgeons (30–32). This iatrogenic damage seems to be a composite result of the manipulation of the cortex, tearing of tissue planes, bleeding, and coagulation injury.

Furthermore, there is moderate to high-quality evidence that AMH is a much more sensitive biomarker of ovarian reserve than AFC in cases with ovarian endometrioma. Therefore, it should be the ovarian reserve biomarker of choice for women’s guidance in this setting, especially before surgery. In such cases, counseling women relying merely on AFC may be misleading for clinical practice recommendations.

The results obtained in the recent meta-analysis, assessing both AMH and AFC in parallel, in the same women, in the same setting, and at the same postoperative time points (29), corroborate basically the conclusions of the earlier systematic reviews evaluating AMH or AFC separately (4, 5, 23). It is, therefore, clear now that the discordancy between these systematic reviews on ovarian reserve findings is not the result of variances in methodology and standardization but rather the low sensitivity of AFC in detecting ovarian reserve changes in cases with ovarian endometrioma. These findings also support the notion that AFC is underestimated in cases with an intact endometrioma during the reproductive age.

Four essential and relevant concerns to endometrioma should be considered when evaluating the reliability of ovarian reserve measures in this setting during reproductive age. These concerns include previous ovarian surgery, the diameter of the endometrioma, its laterality, and the postoperative timing of ovarian reserve evaluation. All of these concerns were incorporated into the list of 20 key entries formulated a priori to examine the level of evidence of each of the systematic reviews in this critical contemporary review.

It has been found that both recurrent endometriotic cystectomy and bilateral endometriotic cystectomy can have a severe damaging impact on ovarian reserve. Previous studies have shown that there is a significant risk of premature ovarian insufficiency, either early or late, in such situations (33–35). Furthermore, it is essential to consider the timing of ovarian reserve appraisal following surgery, as natural changes can occur over time. For example, in women in their 30s, the natural decline in AMH is about 5% per year (36). However, the impact of surgery can exceed this natural decline by a considerable margin equivalent to 5-10 years (25). In addition, the diameter of the endometrioma may also significantly affect the damage to the ovarian reserve caused by endometriotic cystectomy. Recent research suggests that the threshold to distinguish between endometriomas that may or may not interfere with the ovarian response is 4 cm in diameter (37). Conversely, other investigators have reported that in women with no previous history of ovarian surgery, serum AMH levels were increased in cases with large endometriomas (38, 39). Due to the significance of AMH level association with endometrioma diameter and its related broader implications, prospective well-conducted studies with repeat measures of endometrioma diameter and AMH concentrations are vitally required.

A third fundamental question, which is still debated and not yet settled, is whether endometrioma per se may adversely affect ovarian reserve in the reproductive age. In the in-vitro setting, endometrioma was shown to instigate intra-ovarian inflammatory reactions attributed to the high concentration of free iron, reactive oxygen species, proteolytic enzymes, and inflammatory molecules. Macrophages, cytokines, and vasoactive substances mediate these reactions, which may damage adjacent ovarian cortical tissue. Various molecular, histological, and morphological evidence supports such mechanisms. However, the evidence is far from being conclusive (40).

In the clinical setting, two previous systematic reviews have explored this question, the first employing AMH and the second AFC, showing that an intact endometrioma may harm ovarian reserve (24, 27). However, several methodological concerns were raised in the results section and Table 2 . Furthermore, no changes were found in serum AMH levels at baseline comparing unilateral and bilateral endometrioma cases, challenging the concept that endometrioma per se might have a negative impact on ovarian reserve (29). Further targeted randomized, well-controlled studies and adequately designed systematic reviews and meta-analyses are needed to explore this question adequately.

We acknowledge that our search for systematic reviews relied on one search engine, PubMed.com. For common clinical questions, PubMed.com is a reliable engine that can narrow the search and provides the highest-quality, most relevant, and most readable hits. Cochrane, considered the gold standard for clinical systematic reviews, recommends searching PubMed.com as one of the most commended databases.

Moderate to high-quality evidence shows that endometriotic cystectomy is detrimental to ovarian reserve. Ovarian reserve damage is more pronounced in bilateral than unilateral cases and in women with previous ovarian surgery. Furthermore, moderate to high-quality evidence demonstrates that AMH is significantly sensitive to surgical impact on ovarian reserve, while AFC is not. Serum AMH should be the ovarian reserve biomarker for counseling women with endometrioma during the reproductive age, especially before surgery. Although there is some evidence that endometrioma per se may harm ovarian reserve, it is not robust. Furthermore, there is good evidence to challenge this notion. The impact of endometrioma diameter on ovarian reserve before or following surgery is still unclear. Further targeted RCTs, systematic reviews, and meta-analyses based on solid methodological grounds are essential to investigate open questions, increase the level of evidence, refine quantitative estimates, and decrease heterogeneity.

JY: Conceptualization, Data curation, Investigation, Methodology, Writing – original draft. HT: Supervision, Validation, Writing – review & editing.