Endometriosis and infertility: pathophysiology, treatment strategies, and reproductive outcomes

Abstract

Endometriosis is a chronic gynecological disorder characterized by ectopic endometrial-like tissue, leading to pain, dysmenorrhea, and infertility. This review explores classification systems, the mechanisms of endometriosis-related infertility, and the impact of endometriosis subtypes on fertility outcomes. Medical therapies, such as hormonal suppression, alleviate symptoms but are unsuitable for women who wish to conceive. Surgery may enhance natural conception rates in select cases but may have a negative impact on ovarian reserve. Assisted reproductive technologies, such as intrauterine insemination and in vitro fertilization, provide effective fertility treatments. However, endometriosis can negatively affect oocyte quality and implantation rates.

Given the complexity of endometriosis and its varying impact on fertility, a personalized, multidisciplinary approach is recommended. This review proposes an updated treatment algorithm that integrates clinical, imaging, and other infertility causes to optimize treatment outcomes. Future research is needed for refining classification systems and indications for fertility-preservation treatments, as well as improving assisted reproductive technology success rates.

Introduction

Endometriosis, a chronic gynecological condition, is characterized by the presence of endometrial-like tissue outside the uterine cavity, commonly affecting the ovaries, fallopian tubes and pelvic peritoneum. This ectopic tissue triggers chronic inflammation and fibrosis, leading to significant symptoms, including chronic pelvic pain, dysmenorrhea, and infertility. Affecting an estimated 2–10% of women of reproductive age, endometriosis has profound implications not only for quality of life but also for reproductive health. [1]

Classification systems for endometriosis

Since 1979, several classification systems have been developed to categorize the stages and extent of endometriosis, with a primary focus on the severity and anatomical distribution of lesions. Among the most widely used systems are those established by the American Fertility Society (AFS) and its successor, the American Society for Reproductive Medicine (ASRM) [2]. The Enzian classification was introduced as a complementary system to the revised ASRM framework, offering a more detailed description of deeply infiltrating lesions [2]. The main goal of these staging systems is to standardize disease descriptions, facilitate patient counseling, and enable research by categorizing patients into homogenous groups based on symptoms and prognoses. However, it does not provide an adequate prognosis regarding fertility outcomes [3].

According to Nisolle et al., endometriosis can be categorized into three main types based on morphology and pathogenesis: superficial peritoneal endometriosis, ovarian endometriomas, and deep infiltrating endometriosis (DIE) [2]. Superficial peritoneal lesions are typically confined to the peritoneal surface, while ovarian endometriomas are cystic lesions that might impair ovarian reserve. DIE, characterized by lesions penetrating deeper than 5 mm into the peritoneum, is often associated with severe symptoms [2].

To address the limitations of existing classification systems in predicting fertility outcomes, Adamson et al. (2010) developed the Endometriosis Fertility Index (EFI). This tool integrates clinical and surgical findings to estimate the likelihood of spontaneous conception following surgical intervention [4]. The EFI’s utility and implications will be discussed further in subsequent sections.

Estimated fertility index (EFI) and prognosis

The EFI, which incorporates factors such as age, duration of infertility, and surgical findings, serves as a valuable predictor of post-surgical fertility outcomes. Higher EFI scores (> 7) are associated with better spontaneous pregnancy rates, while lower scores suggest a need for assisted reproductive technologies (ART) [5, 6].

Recent studies demonstrate that the EFI can be estimated preoperatively using advanced ultrasound imaging and clinical data, such as hysterosalpingo-foam sonography (HyFoSy). This non-invasive estimation can guide decision-making between surgery and ART, especially in patients with mild endometriosis or without severe pain [6–8].

In the ESHRE 2022 publication, while no formal recommendation was made, the Guidline Development Group(GDG) concluded that women should be counseled about their chances of achieving spontaneous pregnancy after surgery[1]. EFI is recommended as a validated, reproducible, and cost-effective tool to identify patients who may benefit from ART following surgery. Additionally, other fertility factors, such as the partner’s sperm analysis, should be considered when making decisions about further treatment.

However, it should be emphasized that only two of the ten EFI points relate to actual disease staging, with the remainder based on history, tubal status, and ovarian function. As such, EFI cannot replace a true anatomical and phenotypic disease classification.

After addressing the pathophysiological link between endometriosis and infertility, we will evaluate the benefits and limitations of surgical and medical treatments, focusing on their effects on both natural conception and ART. Last, we will suggest an algorithm for patients with endometriosis and infertility.

Mechanisms and theories of infertility in endometriosis

Anatomical disruption

Anatomical disruption is a key mechanism by which endometriosis impairs fertility. Pelvic adhesions and distorted tubo-ovarian anatomy, commonly seen in endometriosis, hinder critical reproductive processes such as ovulation, oocyte pickup, and tubal transport. Adhesions restrict ovarian mobility, preventing the fallopian tube from capturing released oocytes, while chronic inflammation perpetuates adhesion formation and fibrosis, further exacerbating anatomical distortions. In severe cases, these changes can completely block the transport of sperm and ovum, preventing conception [8–11].

Pain and dyspareunia

Pain, including dyspareunia, plays a significant role in endometriosis-related infertility by impairing sexual function and reducing the frequency of intercourse. Dyspareunia may present as superficial pain at the vaginal introitus or deep discomfort during penetration, both of which can persist even after surgical treatment. The avoidance of sexual activity diminishes opportunities for natural conception. While medical and surgical treatments can alleviate pain, the contraceptive effects of hormonal therapies often complicate fertility efforts. For severe cases, where pain precludes sexual intercourse, patients may opt for intrauterine insemination (IUI) or advanced ART, highlighting the multifaceted impact of endometriosis on both sexual health and fertility outcomes [11, 12].

Peritoneal inflammation

Peritoneal inflammation is a hallmark of endometriosis, creating an environment that adversely impacts gamete interaction, fertilization, and implantation. Elevated levels of cytokines, prostaglandins, and reactive oxygen species (ROS) in the peritoneal cavity disrupt the reproductive microenvironment. Macrophages in peritoneal fluid secrete inflammatory mediators that impair sperm motility and may reduce oocyte and embryo quality. These inflammatory changes not only hinder natural conception but also pose challenges for ART, where the quality of gametes and the uterine environment are critical for success [3, 13].

Immune dysregulation

Endometriosis is associated with immune dysfunction, including altered natural killer cell activity, reduced cytotoxic T-cell function, and impaired clearance of ectopic endometrial cells. These immune changes contribute to the persistence of endometriotic lesions and an unfavorable environment for conception [10].

Ovarian reserve

Ovarian endometriomas may impact ovarian reserve, a key factor in fertility. Ovarian reserve, determined by the resting primordial follicles pool, declines with age and can be assessed using antral follicle count (AFC), serum anti-Müllerian hormone (AMH) and Follicular-stimulating hormone (FSH) levels [10]. A 2021 meta-analysis by Tian et al. highlighted that AFC is significantly lower in ovaries affected by endometriomas, and a comparison between affected and contralateral healthy ovaries in unilateral cases confirmed this finding [14]. Similarly, another meta-analysis by Muzii et al. demonstrated lower AMH levels in patients with unoperated endometriomas, indicating diminished ovarian reserve [15]. This may negatively affect ovarian stimulation in ART, with fewer retrieved oocytes and embryos. The size and bilaterality of endometriomas further influence ovarian response, with larger cysts and bilateral cases showing decreased response although pregnancy and live birth rates remain unaffected. Although conflicting findings exist, as some studies report similar or superior responses in affected ovaries under specific conditions, the overall evidence emphasizes the negative impact of endometriomas on ovarian reserve and the importance of individualized management strategies for preserving fertility in affected women [10, 11, 16].

Reduced ovarian reserve with endometriomas is likely due to both mechanical damage and the toxic effects of their cyst fluid, which contains high levels of free iron and reactive oxygen species. These substances induce oxidative stress, fibrosis, and cortical damage, impairing follicular maturation and leading to follicular depletion [17].

Histological studies confirm reduced follicular density and increased fibrotic tissue in ovaries affected by endometriomas compared to benign cysts. Excessive primordial follicle activation, driven by signaling pathways like PI3K/PTEN/Akt/FOXO3, contributes to “burn-out” of the follicular pool [18]. Women with endometriomas also show a higher risk of early menopause, particularly those who are nulliparous or do not use oral contraceptives [19].

Impaired ovulation

The impact of endometriosis on ovulation remains controversial, with studies yielding mixed results. For instance, a 2009 study by Somigliana et al. found that ovulation occurred in only 31% of affected ovaries in women with monolateral endometriomas, compared to an expected 50% in healthy ovaries, suggesting a statistically significant reduction [20]. However, a larger prospective study monitoring 244 women over 1199 cycles found no significant difference in ovulation rates between affected ovaries (50.3%) and healthy ones (49.7%)[20]. Despite these findings, clinical evidence on spontaneous ovulation rates in women with endometriosis remains limited and inconclusive. Factors such as hyperprolactinemia, which disrupts luteinizing hormone pulsatility and hypothalamic function, and luteinized unruptured follicle syndrome, where the dominant follicle fails to release an oocyte, may contribute to ovulation failure. Additionally, altered estrogen and progesterone secretion patterns can result in abnormal luteal phases, further compromising ovulation in these women [11].

Oocyte quality, embryo transport, sperm function and motility, sperm-oocyte interaction

Endometriosis-related alterations in the inflammatory microenvironment contribute to impaired fertility [10]. Proinflammatory peritoneal fluid in these patients is linked to disrupted embryo transport [21] and compromised sperm function, including DNA fragmentation [22], reduced mobility, and impaired sperm-oocyte interaction [23]. Despite these challenges, the overall reproductive outcomes in ART are not significantly different, underscoring the multifactorial nature of endometriosis-associated infertility [10]

The impact of endometriosis on oocyte and embryo quality remains complex and partially unresolved. While studies indicate that oocytes from women with endometriosis may exhibit altered morphology, lower cytoplasmic mitochondrial content, and in vitro maturation failure, the overall effect on embryo quality is less clear [11, 24]. Meta-analyses suggest a reduced number of mature (MII) oocytes retrieved during in-vitro fertilization (IVF) in cases of endometriomas, but fertilization and high-quality embryo rates remain comparable to those in women without endometriosis [25].

A recent meta-analysis of 22 studies found that endometriosis does not affect embryo morphology, with comparable high-quality embryo rates, cleavage rates, and embryo formation rates across disease stages [26]. However, other studies have shown mixed results, with some suggesting altered embryo kinetics and reduced viable pregnancy rates in women with endometriosis [11]. Additionally, oocyte donation studies indicate reduced implantation and pregnancy rates when oocytes are sourced from donors with endometriosis, further supporting an effect of the disease on embryo quality. However, such studies may not fully represent the general population of younger women with endometriosis-related infertility [10, 11].

The pathophysiological mechanisms underlying these effects include dysregulated steroidogenesis and alterations in the intrafollicular microenvironment. Granulosa cells in women with endometriosis show decreased P450 aromatase expression, altered progesterone secretion, and increased apoptosis, leading to impaired follicular function. Follicular fluid from these patients often exhibits oxidative stress, with an imbalance in ROS and antioxidants causing DNA damage in oocytes and reduced oocyte quality. Exposure to endometriotic cyst fluid has also been linked to increased fragmentation and apoptosis in embryos [10].

Endometrial receptivity

The eutopic endometrium in women with endometriosis often exhibits reduced receptivity due to altered expression of implantation-related molecules, such as integrins and HOXA10. This impairs embryo implantation even in the absence of severe anatomical disease [27].

Endometrial receptivity, a critical factor for successful implantation, is often impaired in women with endometriosis during both natural and ART cycles treatments. This may be due to a complex interplay of molecular, hormonal, and inflammatory factors. The eutopic endometrium exhibits abnormalities, such as reduced expression of implantation-related molecules like integrins and HOXA10, which disrupt decidualization and the receptive endometrial phenotype necessary for embryo nidation. Progesterone resistance, coupled with estrogen dominance, exacerbates these issues by promoting inflammation, angiogenesis, and cell proliferation while inhibiting critical processes such as glandular maturation and stromal transformation. Dysregulated signaling pathways, including PI3K/AKT and NOTCH, further diminish key transcription factors like FOXO1 and IGFBP1, essential for decidualization and implantation. Additionally, the immune microenvironment of the endometrium in endometriosis is predominantly pro-inflammatory, with increased activation of macrophages and reduced regulatory T cells, creating a hostile environment for embryo implantation. While clinical studies yield conflicting results regarding the extent of implantation defects during ART cycles, the evidence strongly suggests that the altered endometrial microenvironment, rather than anatomical distortions alone, plays a significant role in the reduced fertility observed in women with endometriosis [10].

Adenomyosis and other causes

Endometriosis and adenomyosis often coexist, and their combined presence can significantly worsen fertility outcomes. Adenomyosis contributes to infertility through various mechanisms, including increased junctional zone thickness, altered uterine peristalsis that disrupts utero-tubal transport, and biochemical, functional, and epigenetic changes in both eutopic and ectopic endometrium [11, 28].

Accurate diagnosis is essential and primarily relies on imaging. Transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI) are the main diagnostic tools, with TVUS detecting features such as myometrial cysts, heterogeneous echotexture, asymmetrical wall thickening, and an ill-defined endometrial–myometrial junction [29]. MRI offers greater precision in equivocal cases and identifies adenomyosis based on junctional zone thickening, where a measurement exceeding 12 mm is considered diagnostic. Structured reporting systems such as morphological uterus sonographic assessment (MUSA) and MRI-based classifications have enhanced diagnostic accuracy [29]. Women with adenomyosis undergoing ART face more pronounced reproductive challenges compared with those with endometriosis alone. Meta-analyses have reported a 31% to 43% reduction in pregnancy rates in women with adenomyosis [30, 31]. Furthermore, the miscarriage risk in adenomyosis is approximately three times higher following ART [30] with a live birth rates reduction of 55% [31]. These differences underscore the importance of tailored preconception counseling and specialized management strategies for women with adenomyosis compared to those with endometriosis alone [32].

Beyond infertility, adenomyosis, particularly in its diffuse form, is increasingly recognized as a risk factor for obstetric complications. A 2025 meta-analysis demonstrated significantly higher rates of preterm birth, fetal growth restriction, placental abnormalities, cesarean delivery, and postpartum hemorrhage in women with diffuse adenomyosis compared to controls [33]. These findings underscore the importance of early diagnosis, preconception counseling, and individualized reproductive and obstetric care for this patient population.

Types of endometriosis and impact on fertility

Endometriosis significantly impacts fertility, with its effects varying by type [2].

Peritoneal endometriosis is the most underdiagnosed due to the limitations of non-invasive imaging techniques such as ultrasound and MRI. Diagnosis typically requires laparoscopy with biopsy, though this is not routinely recommended for infertile women before IVF [2]. This type creates a pro-inflammatory environment that disrupts reproductive functions, including sperm motility, oocyte fertilization, and embryo implantation. Hormonal resistance, particularly to progesterone, reduces endometrial receptivity, further impairing fertility [34–37]. Surgical treatment may increase the chance of spontaneous pregnancy, but is not recommended prior to IVF [1].

Ovarian endometriomas, affecting 15–44% of women with endometriosis, directly harm ovarian physiology [2]. These cysts induce oxidative stress and disrupt blood flow, leading to follicular loss, reduced ovarian reserve, and impaired oocyte quality [38, 39]. While surgical removal may alleviate symptoms and may increase the chance of spontaneous pregnancy, it can also damage healthy ovarian tissue, necessitating careful consideration and considering fertility preservation prior to surgery [1].

DIE involves lesions penetrating deep into pelvic structures and is linked to severe pain and dyspareunia that may reduce fertility. Chronic inflammation and mechanical disruption impair gamete transport and embryo implantation, often in conjunction with adenomyosis [2]. While surgical management may improve spontaneous pregnancy in some cases, the associated risks, especially for extensive procedures, require thorough evaluation [1].

Managing endometriosis: effects of treatment modalities on fertility outcomes

Management of endometriosis-associated symptoms involves medical and surgical approaches, tailored to the patient’s symptoms, disease severity, and reproductive goals.

Natural conception

Medical treatment

Medical treatments commonly used for treating endometriosis symptoms are combined oral contraceptives, progestins, progesterone-secreting IUD, GnRH agonists and antagonists. They reduce endometriotic lesion activity by suppressing ovarian function and preventing ovulation. Although several studies have reported that serum AMH level is not influenced by current hormonal contraceptive use [40–43], other studies demonstrated reduction on AMH levels with hormonal contraceptive use [44–46]. Bernardi et al. [47] in a large cross-sectional study demonstrated that AMH levels are significantly lower (25.2% lower mean AMH levels) among current users of most forms of hormonal contraceptives, but that the suppressive effect of hormonal contraceptives on AMH levels is reversible upon discontinuation of therapy.

Hormonal therapies alleviate pain and may reduce recurrence risk after surgery, but their contraceptive nature makes them unsuitable for women who are trying to conceive. In addition, we must consider that patients suspend hormonal therapies for pain relief when trying to conceive. Therefore, we need to ensure the highest possible efficiency during this period [2].

According to ESHRE 2022 [1], hormonal suppression treatments, such as GnRH agonists, are not recommended to improve natural fertility in women with endometriosis. Similarly, postoperative hormone therapy solely to enhance future pregnancy rates is not advised. However, hormone therapy may be offered to women who are not currently trying to conceive as it does not negatively impact future fertility and can manage pain symptoms.

Surgical treatment

Surgical treatment for endometriosis is primarily aimed at restoring pelvic anatomy and alleviating symptoms, with its benefit on natural conception varying by the type, severity of the disease and other infertility factors. For superficial endometriosis, randomized trials and meta-analyses have shown that laparoscopic excision or ablation of lesions can significantly increase spontaneous conception rates compared to diagnostic laparoscopy alone [48]. In cases of endometriomas, excision of cysts larger than 3 cm is associated with increased natural conception rates compared to drainage or vaporization, although surgery may reduce ovarian reserve and cause adhesions [2, 49]. Current guidelines recommend surgery only in specific scenarios, such as large cysts obstructing ART procedures, pain, or suspicion of malignancy [10].

For DIE, surgery is often performed to relieve pain and treat organ involvement, such as hydronephrosis and bowel constriction. Natural pregnancy rates following DIE surgery varies widely, with systematic reviews reporting rates between 24 and 44%, but these findings are limited by a lack of control groups and heterogeneity in patient populations [50–52]. Radical excision of DIE, including bowel resection, when necessary, may offer some fertility benefits but comes with significant risks of complications, such as fistula formation and anastomotic leakage, which may affect reproductive outcomes. A more conservative approach tailored to the patient’s symptoms and reproductive goals is increasingly advocated, particularly given the high recurrence rates and the need to balance surgical radicallity with the patient's desire for conception [2, 10].

According to ESHRE 2022, Surgical treatment for endometriosis-associated infertility is recommended for symptomatic women with rASRM stage I/II to improve spontaneous pregnancy rates, with a weak recommendation due to limited high-quality evidence. For endometrioma, surgery may be considered, but its routine use for fertility purposes is not supported by strong evidence. Surgery for deep endometriosis should primarily be offered to alleviate symptoms and may not directly improve natural conception rates. The latest EHERE recommendation is that decision regarding surgery for infertility-associated endometriosis should consider pain symptoms, patient age and preferences, prior surgical history, other infertility factors, ovarian reserve, and the estimated EFI [1].

Assisted reproductive technologies (ART)

ART offers the most effective treatment for endometriosis-associated infertility. By bypassing tubal and peritoneal barriers, ART achieves higher pregnancy rates compared to natural conception.

The impact of endometriosis on IVF outcomes remains a debated topic, with mixed findings in the literature. Early studies and a meta-analysis by Barnhart et al. (1983–1998) [53] suggested lower retrieved oocyte and decreased fertilization, implantation, and pregnancy rates in patients with endometriosis compared to those with tubal infertility. However, contemporary data, such as the Norwegian retrospective study, indicate comparable live birth rates (66.0% vs. 66.7%) [54], while the 2022 SART report [55]showed no significant differences in IVF outcome between endometriosis patients compared to other infertility groups. The findings are complicated by diagnostic challenges, underreporting, and variability in disease stage and treatment history.

Disease severity appears to influence the outcome. Patients with advanced stages (ASRM III-IV) exhibit lower implantation and pregnancy rates compared to those with milder disease or tubal factor infertility, as shown by studies such as Kuivasaari et al. [56] and meta-analyses [28]. Endometriomas are associated with reduced ovarian response and higher gonadotropin requirements but generally do not affect embryo quality or live birth rates [57, 58]. DIE is a stronger predictor of poor IVF outcomes, significantly reducing pregnancy rates compared to superficial disease (58% vs. 83%) [59, 60]. Variability in diagnostic approaches, disease characterization, and confounding factors, such as the presence of adenomyosis, complicates interpretation, underscoring the need for more standardized research methodologies [28].

Over the years, IUI with controlled ovarian stimulation has emerged as an intermediary treatment option between expectant management and IVF for unexplained infertility, including in women with superficial endometriosis. There is some limited evidence, from randomized controlled trials, recommending IUI with controlled ovarian stimulation for women (< 35 y) with ASRM stage I/II endometriosis as first-line infertility treatment. However, the effectiveness of IUI in endometriosis is debated, as studies like those by Omland and colleagues [61] reported inferior results in endometriosis patients compared to unexplained infertility, while other research highlighted that surgical intervention might contribute more significantly to outcomes than IUI alone [49, 62].

For advanced cases or when other treatments fail, ART, including IVF, are often employed [2]. It is estimated that about 25% of IVF cycles are performed in women with endometriosis. Despite its widespread use, the effectiveness of ART in endometriosis remains contested due to inconsistent findings from meta-analyses and study heterogeneity. Women with endometriosis may have less oocyte, lower fertilization rates, and impaired implantation. Factors such as diminished ovarian reserve, altered folliculogenesis, and impaired endometrial receptivity are thought to contribute to suboptimal ART outcomes. No specific controlled ovarian stimulation protocol has been shown to yield superior results, with both antagonist and agonist protocols producing similar pregnancy and live birth rates. Thus, while ART offers hope for many, its success in endometriosis patients may be influenced by disease severity and individual ovarian response [28].

According to ESHRE 2022, medically assisted reproduction (MAR), IUI and IVF are recommended for managing infertility associated with endometriosis, with recommendations varying based on the stage of the disease and individual patient characteristics. For women with rASRM stage I/II endometriosis and good ovarian reserve, IUI with controlled ovarian stimulation is suggested as a first-line treatment to improve live birth rates. However, IUI is typically considered only for cases with no significant male factor infertility or tubal dysfunction, and it is not recommended for women with advanced stages of endometriosis (rASRM stage III/IV). For patients with moderate-to-severe disease, such as rASRM stage III/IV endometriosis or those with compromised tubal function, low EFI, or recurrent treatment failure, IVF is the preferred approach [1].

Effect of IVF on endometriosis

The potential impact of elevated estradiol levels during gonadotropin stimulation in IVF on endometriosis progression has raised concerns due to the estrogen-dependent nature of the disease. However, studies provide reassuring evidence. One study reported that 77% of patients experienced symptom improvement 3–6 months after IVF, with stable endometrioma sizes and only 11% reporting worsening symptoms [63]. Additionally, research by D’Hooghe et al. [64] demonstrated that patients with stage III/IV endometriosis undergoing IVF had lower cumulative disease recurrence rates compared to those undergoing IUI, despite higher gonadotropin doses and estradiol levels. These findings suggest that gonadotropin stimulation during IVF does not worsen endometriosis and may even have protective effects against recurrence [28].

IVF protocols

Historically, the long GnRH agonist protocol was widely used in women with endometriosis undergoing ART, based on the rationale that prolonged suppression of endometriotic activity might enhance reproductive outcomes. However, current evidence does not support the superiority of this approach. The 2022 ESHRE guidelines issued a strong recommendation against the routine use of prolonged GnRH agonist pretreatment, citing a lack of benefit in improving live birth rates compared to other protocols [1]. This is consistent with findings from a 2023 systematic review by Kuan et al., which reported no significant differences in clinical pregnancy or live birth rates between the long GnRH agonist and GnRH antagonist protocols [65]. While the agonist protocol may result in a higher yield of oocytes, the antagonist protocol offers a shorter, less burdensome regimen with comparable efficacy. These data support a shift toward individualized protocol selection, tailored to patient characteristics rather than historical convention. Nonetheless, challenges persist in identifying the specific subgroups of patients who may benefit from pretreatment, optimizing the duration of therapy, and addressing underlying endometrial dysfunction [2]. Further research is warranted to elucidate these aspects and refine ART strategies in women with endometriosis.

Surgical treatment

The impact of surgery on ART outcomes in women with endometriosis is complex and context dependent. Some studies suggest that surgery for deep infiltrating endometriosis (DIE), particularly when extensive resection is performed, may improve IVF outcomes [66]. However, these studies are not randomized controlled trials (RCTs) and carry a high risk of selection or allocation bias. Furthermore, the overall rates of intraoperative and postoperative complications are estimated at 2.1% and 13.9%, respectively, and may include ureteral and small bowel injuries, as well as rectovaginal and ureteral fistulas. Therefore, DIE surgery solely to improve IVF outcomes is not recommended [67].

Surgery for ovarian endometriomas prior to ART is controversial. While surgical excision can address issues such as pain, rapid growth, or suspected malignancy, it often reduces ovarian reserve, especially for bilateral or recurrent endometriomas, as evidenced by lower antral follicle counts, diminished serum AMH levels, and compromised response to gonadotropins post-surgery. Surgical intervention prior to IVF is generally recommended only in specific scenarios, such as the presence of hydrosalpinxes, pain, rapid endometrioma growth, or when large lesions obstruct ovarian access during oocyte retrieval. Meta-analyses indicate that while surgery may facilitate spontaneous conception within 6–12 months for some women, it does not consistently improve ART outcomes and may necessitate higher gonadotropin doses for ovarian stimulation. The decision to pursue surgery before IVF requires careful consideration of the patient’s ovarian reserve, disease severity, and individual circumstances. Standardized approaches to evaluating surgical techniques and the timing of ART post-surgery are needed to clarify the risks and benefits of surgical management in this population [10, 28].

According to ESHRE 2022, routine surgery before ART for rASRM stage I/II endometriosis or ovarian endometrioma is not recommended, as there is no proven benefit for live birth rates, and surgery may negatively affect ovarian reserve (strong recommendations). However, surgery for endometrioma may be considered to address endometriosis-related pain or improve follicle accessibility (GPP). The decision to perform surgical excision of deep endometriosis lesions before ART should be guided by pain symptoms and patient preference, as its impact on reproductive outcomes remains uncertain due to a lack of randomized studies [1].

Fertility preservation

Elizur et al. (2009) reported the first case of fertility preservation in a woman with severe endometriosis and Cobo et al. (2020) showed CLBR of 61.9% (in women ≤ 35y) and 28.4% (in women > 35y) in women with endometriosis following fertility preservation. Therefore, fertility preservation is feasible and should be considered in some women with endometriosis. Though promising, fertility preservation (FP) poses challenges due to limited evidence on its efficacy, cost-effectiveness, and associated risks. Subgroups, such as women with bilateral endometriomas or those undergoing repeat surgeries, stand to benefit most from FP, especially when spontaneous conception is unlikely. Vitrification of oocytes is the preferred method due to its established success, particularly when conducted before ovarian surgery or in younger patients with a higher ovarian reserve. Ovarian tissue cryopreservation may be considered in cases where ovarian hyperstimulation is contraindicated. Despite its potential, widespread FP adoption in endometriosis requires further research to refine indications and ensure cost-effectiveness. [2, 10]

Infertility management

Management strategies for endometriosis-related infertility must consider the chronic nature of the disease and its impact on reproductive outcomes. While many patients may conceive spontaneously, those who do not could benefit from a multidisciplinary approach that considers ART, surgery, or a combination of both for the best outcome.

One of the major gaps in reproductive medicine is the role of imaging in endometriosis. Frequently, ART treatments are initiated without a structured imaging-based assessment of the full extent of endometriosis. High-quality imaging techniques such as 2D/3D transvaginal ultrasound using morphological uterus sonographic assessment (MUSA) [68] and MRI performed according to the international deep endometriosis analysis (IDEA) [13] and deep pelvic endometriosis index (dPEI) [69]protocols are now capable of accurately identifying deep infiltrating lesions, endometriomas, and adhesions. These tools enable non-invasive, preoperative mapping of disease extent and localization, which is already standard practice in the surgical management of endometriosis. Since the decision regarding infertility treatments should also consider the extent of the disease, we believe this approach should similarly be applied prior to initiating ART treatments. In addition, the lack of standardized classification represents a fundamental barrier to scientific progress. If fertility outcomes are interpreted based on incomplete or outdated staging systems, like ASRM, we will continue to draw conclusions based on flawed or irrelevant metrics.

Due to the lack of RCT's there are limited evidence-based recommendations for the treatment of endometriosis and infertility so there is a need to tailor a personalized algorithm for each woman to optimize fertility outcome. Ziegler et al. [49] suggested an algorithm emphasizing a holistic, stepwise approach, considering disease severity, patient age, ovarian reserve, and reproductive goals. We suggest updating this algorithm based on recent findings (Fig. 1).

Fig. 1.

Suggested algorithm 2025, Sheba Medical Center. COH Controlled Ovarian Hyperstimulation, IUI Intrauterine Insemination, US Ultrasound, AFC Antral Follicle Count, AMH Anti-Müllerian Hormone, FSH Follicle-Stimulating Hormone, EFI Endometriosis Fertility Index, IVF In Vitro Fertilization, MRI Magnetic Resonance Imaging

Most women with endometriosis who wish to conceive need to stop their hormonal treatment for endometriosis; therefore, their symptoms may return, and the disease may progress. We suggest first to complete detailed imaging, such as MRI or transvaginal 3D ultrasound, to identify all endometriotic lesions, as well as fallopian tube patency evaluation (HSG or US ExFoam) and sperm analysis before discontinuing medical treatment. If these tests are normal, medical treatment can be discontinued to attempt a natural pregnancy. After stopping the medication, it is also possible to assess ovarian reserve parameters (AMH, FSH, AFC). This approach offers an estimated EFI score before stopping endometriosis treatment.

In the general infertility population, it is generally advised that young women (< 35 years old) starts fertility evaluation and treatment only after trying to conceive spontaneously for more than one year. However, in patients with endometriosis, one might consider shortening this period if their symptoms worsen. Young women (< 35 y) with patent tubes, normal ovarian reserve, and normal sperm parameters can be treated as unexplained infertility, starting with controlled ovarian stimulation and IUI. In older women (≥ 39), those with moderate-to-severe endometriosis or women with low ovarian reserve, tubal adhesions, or sperm impairment IVF should be considered as first-line treatment.

Surgery for endometriosis-associated infertility should be considered only for indications such as pain and severe quality of life impairment, atypical endometrioma, hydrosalpinx, hydronephrosis, bowel constriction or recurrent IVF failure. Fertility preservation prior to surgery should be considered mainly for cases with bilateral endometriomas, unilateral endometrioma > 3 cm, or recurrent ovarian surgeries.

Due to its complexity, if surgery is indicated, it should be performed by qualified surgeons experienced in endometriosis surgeries. Following surgery, patients are stratified based on their prognosis, with good-prognosis cases (high EFI and normal ovarian reserve) offered 3–4 month trial of natural conception, while patients with low EFI offered IVF.

Multidisciplinary collaboration and ongoing counseling and follow-up are critical throughout the treatment journey in women with endometriosis and infertility. We believe that our modified algorithm balances medical, surgical, and ART interventions to optimize fertility outcomes while minimizing risks.

Author contributions

Writing—original draft: J.M; conceptualization, writing-review, editing and supervision: E.B, S.E, R.O. All authors reviewed the manuscript.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval and consent to participate

Not applicable.

Consent for publication

Not applicable.