Integrating IVF and Surgical Management in Endometriosis-Associated Infertility: A Review

Infertility affects up to half of individuals with endometriosis, with mechanisms including distorted pelvic anatomy, inflammation, and reduced ovarian reserve. Surgery may improve spontaneous fertility in some patients, but evidence is conflicting, and outcomes depend on disease localization and surgical expertise. Assisted reproduction techniques (ART), especially in vitro fertilization (IVF), provide outcomes comparable to non-endometriosis patients in early-stage disease, though live birth rates are reduced in advanced stages. Combined strategies using surgery and ART show mixed results, and guidelines currently do not recommend surgery solely to improve ART outcomes. Individualized, patient-centered management integrating fertility goals, symptom burden, ovarian reserve, and age is essential for optimizing outcomes.

The central pillar of medical management for endometriosis symptoms, namely pain, is hormonal therapy, although analgesics and neuropathic medications can be utilized. The medications used as hormonal therapy in endometriosis either suppress ovarian activity or act directly on hormone receptors or enzymes found in the lesions; these treatments are generally contraceptive in nature [ 28 ]. As such, these are not often directly used to enhance fertility, but may be used in individuals during periods they are not seeking fertility or as an adjunct to surgery or ART, which may be more directly used to enhance fertility. Possible therapies prescribed include oral contraceptives, progestogens, gonadotrophin-releasing hormone (GnRH) agonists and antagonists, a levonorgestrel intrauterine system, and aromatase inhibitors (e.g., letrozole) [ 28 ]. A Cochrane review found no significant differences in pregnancy rates when comparing all ovarian suppression agents to placebo or no treatment [ 29 ]. Similarly, no difference was found when comparing different medical agents to each other [ 29 ]. Therefore, neither the European Society of Human Reproduction and Embryology (ESHRE) nor the American Society for Reproductive Medicine (ASRM) recommend medical therapies alone for the management of endometriosis-related infertility [ 15 , 28 ]. Medical therapies can also be utilized as an adjunct in the surgical management of endometriosis. However, the time to conception is a vital consideration for patients with endometriosis, and hormonal suppression therapy will delay attempts to conceive. In those not aiming to conceive shortly after surgery, medical therapies should be considered for ongoing symptom management and possibly as a mechanism to reduce recurrence [ 28 ]. That said, a Cochrane review did not find a clear benefit for pre-surgical only or both pre- and post-surgical hormonal suppression therapy for endometriosis-related fertility; post-surgical medical therapy may have increased pregnancy rates, although the effect size was small [ 28 , 30 ]. Consequently, the ESHRE guideline does not recommend the use of post-surgical medical therapy when surgery is performed for fertility purposes, unless the individual wishes to delay conception [ 28 ]. In this context, fertility rates will not be negatively impacted and there may be benefit for endometriosis-related pain [ 28 ]. Similarly, the ASRM guideline found no evidence of benefit to fertility with post-operative medical therapy [ 15 ]. That said, there may be some practical considerations that are difficult to capture in meta-analyses; for example, use of hormonal medications in the perioperative period to suppress ovulation may prevent the physical obstacle of follicular or hemorrhagic cysts, which may increase bleeding, or may be a generator of acute pain in the postoperative phase. Similarly, menstruation may be optimally suppressed in the perioperative period in the context of increased inflammation and pain during menstruation amongst patients with endometriosis.

When managing endometriosis-related infertility, it is important to consider whether a combination of the available approaches, i.e., surgery and ART, can lead to greater success. A Norwegian cohort study compared individuals with rASRM stages I–II endometriosis who underwent surgical excision versus diagnostic laparoscopy only, and found that time to pregnancy and live birth rate were improved in the group which was treated surgically prior to ART [ 61 ]. A small retrospective study found that laparoscopic treatment of endometriosis after one or more failed IVF cycles significantly improved both spontaneous and ART pregnancy rates compared to controls with failed IVF cycles who did not receive laparoscopic treatment [ 62 ]. The benefit of surgical intervention was also observed in cases with more severe disease [ 62 ]. In contrast, multiple systematic reviews and meta-analyses found no significant differences in fertility outcomes when individuals with endometriosis underwent sequential surgery followed by ART versus ART only [ 49 , 63 , 64 ]. Live birth, clinical pregnancy rates, or oocyte yield did not vary significantly when comparing surgical management before ART with studies not specifying prior surgery; a slight reduction in clinical pregnancy was noted in stages I–II disease [ 49 ]. For individuals with rASRM stages III–IV endometriosis, surgical treatment prior to ART was associated with lower live birth rate and clinical pregnancy rate, and with fewer oocytes retrieved per cycle compared to those who did not undergo surgery [ 49 ]. Similarly, another meta-analysis found that there were no significant differences in clinical pregnancy rate, live birth rate, or mean number of oocytes retrieved in endometriomas treated surgically versus those untreated [ 63 ]. This conclusion remained valid when comparing laparoscopic treatment of endometriomas to transvaginal aspiration of endometriomas, where no significant differences in ART outcomes were observed [ 63 ]. Overall, the data on sequential surgery and ART in endometriosis-related infertility remains limited and conflicting. At present, neither ESHRE nor ASRM recommend surgery prior to ART [ 15 , 28 ], even if surgery can improve endometriosis-associated pain or accessibility of follicles during IVF. An advantage of performing surgery prior to ART is the possibility of calculating the EFI to identify couples who would benefit most from ART post-surgically [ 22 ]. However, the growing literature on non-invasive imaging and its transferability to a non-surgical EFI may be optimistic as an alternative tool to triage patients to surgery or ART [ 24 – 26 ]. The management of endometriosis-related infertility should be patient-centered, and, when considering sequential surgery and ART, an individualized treatment plan would be of benefit. From the fertility perspective, important factors which may influence the decision to proceed with surgery versus ART include age, number of years of infertility, and stage of endometriosis. However, there may be other clinical reasons for which surgery is indicated, such as the management of chronic pelvic pain, and these should be taken into consideration.

The goal of surgical management in endometriosis is to restore normal pelvic anatomy and reduce disease burden. A Cochrane review found that laparoscopic treatment of rASRM stages I and II endometriosis may improve spontaneous pregnancy rate [ 31 ], and this approach is recommended by ESHRE [ 28 ]. On the other hand, another systematic review and meta-analysis identified that operative laparoscopy probably yields little or no difference in clinical pregnancy rates compared with diagnostic laparoscopy [ 32 ]. These two reviews [ 31 , 32 ], published close in time but based on different sets of articles, reached divergent conclusions. Moreover, most studies focus on clinical pregnancy as the primary endpoint, rather than the more relevant outcome of live birth. As such, the insufficient and conflicting evidence likely underpins ASRM’s conclusion that the benefit of surgical treatment for rASRM stages I and II endometriosis is not strong enough to recommend surgery solely to improve fertility [ 15 , 31 ]. For rASRM stages III and IV, there is a paucity of high-quality evidence, particularly from randomized controlled trials [ 28 ]. A meta-analysis of observational studies suggested that surgery for DE may improve pregnancy rates; however, the data were too heterogenous to draw strong conclusions [ 33 ]. A more recent retrospective cohort study supported this finding, reporting significantly higher clinical pregnancy rates and live birth rates in individuals with DE who underwent first-line surgery compared to those with DE who underwent first-line ART [ 34 ]. However, in most studies reporting pregnancy after surgery for DE, several key aspects remain unclear: whether patients wished to conceive before or after surgery, whether a child wish was active or passive, whether fertility was already completed or absent, the mean time to conception, and whether pregnancies occurred spontaneously or through assisted reproduction. Consequently, operative laparoscopy should currently be considered a treatment option for DE primarily in symptomatic women with a desire to conceive, in whom the indication for surgery is mainly symptom-driven [ 28 ]. Regarding endometriosis, a systematic review of observational studies found that pregnancy rates after surgical treatment were similar to those achieved with ART [ 35 ]. Reflecting these uncertainties, ESHRE could not formulate a strong recommendation for surgery to improve fertility in individuals with endometrioma or DE, and recommend that the decision for surgery should be guided by other factors, including the presence or absence of pain symptoms, patient age and preferences, history of previous surgery, presence of other infertility factors, ovarian reserve, and estimated EFI [ 28 ]. Similarly, ASRM suggests that, in individuals with rASRM stages III and IV endometriosis without other factors contributing to infertility, surgery may improve fertility, although this is not consistently observed [ 15 ]. In this context, it is important to emphasize that, according to all guidelines, post-surgical outcomes are operator-dependent, and any surgical procedure carries inherent risks and the potential for complications [ 33 ]. Counter-intuitively, surgery may potentially lead to the formation of de novo adhesions [ 36 ]. In the case of endometrioma excision, although cystectomy reduces recurrence in comparison to fenestration or coagulation [ 37 ], adjacent ovarian parenchyma surrounding the cyst may be inadvertently removed during the procedure [ 38 ], compromising residual ovarian reserve. In fact, anti-Müllerian hormone levels have been shown to decrease post-operatively [ 39 , 40 ]. Alternative minimally invasive approaches for the management of ovarian endometriosis aimed at preserving healthy ovarian cortex include ablative techniques such as sclerotherapy or laparoscopic laser vaporization using different energy sources, including a CO 2 laser. Sclerotherapy, performed by aspiration of the endometrioma and instillation of a sclerosing agent (often ethanol) into the cyst for a predetermined time period [ 37 ], has been proposed as an alternative treatment option in order to minimize damage to ovarian tissue [ 41 ]. This technique can be performed both laparoscopically or via ultrasound guidance, and is an effective and safe therapeutic option when considering recurrence rates [ 41 , 42 ]. Encouragingly, meta-analysis has shown increased pregnancy rates with ultrasound-guided sclerotherapy in comparison to surgical excision [ 42 ]. Similarly, CO 2 laser vaporization represents an ablative approach in which the cyst “pseudo-capsule” is not excised but ablated with minimal thermal spread [ 43 ]. A randomized trial including patients with bilateral endometriomas reported that mean ovarian volume and antral follicular count after surgery were significantly higher in the laser-treated ovaries compared to those treated by stripping [ 44 ]. The evidence regarding endometrioma recurrence with vaporization is conflicting, with some studies showing that excision of the pseudocyst capsule with cystectomy leads to lower recurrence rates [ 45 , 46 ]. However, the reproducibility of surgical outcomes is known to be heavily influenced by surgical expertise. Moreover, when considering vaporization, access to specific energy sources and variations in center-specific protocols should be taken into account when interpreting the available evidence. The limitations in the generalizability of current data, together with the paucity of long-term reproductive outcome studies, suggest that the advantages of vaporization should be interpreted cautiously, and further high-quality research is needed to clarify its long-term reproductive impact or potential benefit.

Although there are few studies evaluating the efficacy of intra-uterine insemination (IUI) and ovarian stimulation (OS) on pregnancy rates in endometriosis-related infertility, there is weak evidence that IUI with OS increases pregnancy rates compared to expectant management or IUI alone [ 28 ]. Therefore, IUI and OS can be offered to individuals with ASRM stages I–II endometriosis, particularly within 6 months of surgical treatment of endometriosis [ 28 ]. In individuals with more advanced stages of the condition, the benefit of IUI and OS is unclear [ 28 ]. There is some evidence that IUI with OS is not cost-effective compared to ART [ 47 , 48 ], and one could argue that attempting this method simply delays starting ART. In this context, mounting evidence suggests that endometriosis does not significantly impair IVF outcomes, and that endometriosis represents an appropriate indication for IVF. There are various OS protocols implemented for ART, principally with GnRH agonists or antagonists. At present, there is no specific protocol with better outcomes for endometriosis [ 28 ]. Individualized considerations are important when considering IUI and OS as opposed to ART, such as the clinical scenario of the patient with endometriosis, especially age, ovarian reserve, and other comorbidities which may impact outcomes. The available evidence suggests that live birth rates with ART are not negatively impacted in individuals with endometriosis of any severity compared to non-endometriosis controls [ 28 , 49 ]. However, when these data are stratified by disease severity, individuals with rASRM stages III and IV endometriosis may have less favorable ART outcomes. A systematic review and meta-analysis found that the mean number of oocytes retrieved, clinical pregnancy rate, and live birth rate were all significantly lower in this cohort compared to controls without endometriosis. When considering rASRM stages I and II endometriosis, there were no significant differences in live birth rate, clinical pregnancy rate, or number of oocytes retrieved compared to non-endometriosis controls undergoing ART [ 28 ]. However, robust intra-patient ovarian response comparisons (between the affected ovary and the contralateral unaffected ovary) are scarce, and controls in available studies are often not well matched. Nevertheless, a recent review indicated that: (1) endometriosis has little impact on ovarian response, with only a slight reduction in stimulation when endometriomas exceed 4 cm, while follicular steroidogenesis remains intact; (2) oocyte quality, fertilization rates, and embryonic development are unaffected, with no increase in aneuploidy; and (3) endometrial receptivity is largely preserved [ 50 ]. The rate of unexpected poor response to ovarian stimulation has been reported to be higher in women with endometriosis compared with controls, yet this difference only persisted among those who previously underwent ovarian surgery, and, in any case, the cumulative pregnancy rate remained comparable between endometriosis and controls [ 50 ]. With regard to bilateral ovarian endometriomas, or large (> 4 cm) unilateral cysts, there is evidence suggesting that it may be associated with reduced response to stimulation and lower oocyte retrieval rates, mainly due to the “space-occupying” effect of the cyst, technical difficulties in accessing the follicles, and the need to avoid cyst puncture to minimize infectious risk [ 28 ]. The assessment of embryo morphology and ploidy is methodologically challenging due to heterogeneous grading systems, as well as confounding by ovarian reserve and stimulation regimens. Overall, the evidence does not support a detrimental effect of endometriosis on embryo quality [ 51 ]. Studies assessing euploidy are limited and yield conflicting results: Juneau et al . [ 52 ] reported similar euploid rates between groups, whereas Yan et al . [ 53 ] found a modest reduction in women with endometriomas, likely due to higher gonadotropin doses as a consequence of reduced ovarian reserve. When confounders such as age and prior ovarian surgery are accounted for, cumulative live-birth and euploidy rates appear comparable to non-affected patients. Therefore, evidence does not support that embryo morphology and ploidy are affected in women with endometriosis. Overall, the evidence indicates that the presence of endometriosis does not significantly compromise IVF outcomes [ 50 ]. A diagnostic delay is a typical experience of those with endometriosis, with some patients waiting over a decade for a diagnosis [ 54 , 55 ]. Age is an important predictor of ART success [ 56 , 57 ], and therefore a timely diagnosis of endometriosis-related infertility is vital. In fact, individuals diagnosed with endometriosis after undergoing ART were found to undergo a greater number of ART cycles and have a lower live birth rate compared to those whose diagnosis of endometriosis preceded ART [ 58 ], highlighting the importance of an accurate diagnosis in order to maximize ART success. A paramount concern for individuals with endometriosis, apart from live birth rates, is how these treatments can affect their symptoms long term. Patients can be reassured that a systematic review did not find increased rates of endometriosis symptoms or exacerbated pelvic pain with ART [ 59 ]. However, ART is not without its risks, which include ovarian hyperstimulation syndrome and, specifically in patients with endometriosis, infection of endometrioma and damage to surrounding structures when conducting oocyte retrieval, due to significant pelvic adhesions, presence of endometrioma, and distorted anatomy [ 60 ]. While ART is an essential strategy in the management of endometriosis-related infertility, it is important to consider individuals’ preferences in its use, as some patients may not be comfortable undergoing ART for cultural, religious, or other reasons.

The principal strategies for managing endometriosis-related infertility are surgery and ARTs. Key factors influencing the decision to proceed with surgery or ART include age, partner-related factors, concomitant factors for infertility, duration of infertility, reproductive goals, and, possibly, disease stage [ 15 ]. The evidence for surgical management of endometriosis-related infertility remains conflicting; however, it may enhance natural fertility, with the added benefit of treating pain symptoms [ 31 , 32 ]. In contrast, ART should be prioritized when this aligns with patient preference, in the presence of tubal occlusion, and/or when a favorable ovarian reserve makes the benefits of ovarian stimulation and oocyte retrieval outweigh the risks [ 15 ]. The EFI can provide a useful framework for identifying patients most likely to benefit from ART following surgery [ 22 ]. Ultimately, decision-making should be patient-centered and individualized, integrating fertility prognosis with symptom burden and broader reproductive goals, in order to optimize outcomes.

Endometriosis is a complex disease characterized by heterogenous clinical manifestations [ 1 ]. The condition occurs when tissue similar to the lining of the uterus (endometrium) is found outside the uterine cavity, commonly on the ovaries, ligaments of the pelvis, and peritoneum, although it can also affect the intestines, bladder, and distant sites throughout the body [ 2 ]. The symptoms of the disease vary depending on where the deposits of tissue are located, but a central feature is chronic pelvic pain [ 3 ]. In addition to varying clinical manifestations, the phenotype of the condition can vary from superficial deposits of endometrial-like tissue, to “chocolate” cysts of endometriosis on the ovaries, to deep infiltrating nodules and extensive adhesions [ 1 ]. Endometriosis predominantly affects women of reproductive age, with a prevalence of 5–10% [ 4 ]. Between 30–50% of individuals with endometriosis are affected by infertility [ 2 , 5 ], and one-third of couples investigated for infertility are found to have endometriosis [ 2 ]. Infertility is defined as the failure to establish a clinical pregnancy after 12 months of regular, unprotected sexual intercourse or due to an impairment of a person’s capacity to reproduce either as an individual or with his/her partner [ 6 ]. There are multiple mechanisms by which endometriosis can contribute to infertility [ 2 , 5 ]. Contributing factors may be diminished ovarian reserve, anatomical distortion and resulting dysfunction, altered peritoneal environment, inflammatory changes, and other unknown factors [ 5 ]. As the majority of medical agents utilized to manage endometriosis symptoms are contraceptive in nature, the main active treatment strategies for endometriosis-related infertility, when needed, are medically assisted reproduction (MAR) and surgery [ 3 ]. In many instances, natural conception is possible, whereby no treatments are required [ 7 ]. MAR includes intrauterine insemination (IUI), as well as assisted reproduction techniques (ART) such as in vitro fertilization (IVF) [ 3 ]. The latter has the advantage of partially bypassing the distorted pelvic anatomy and is the only feasible therapeutic option after bilateral salpingectomy, or in the case of severe tubal disease or severe male factor infertility. Conversely, surgery aims to restore pelvic anatomy while also removing endometriosis lesions, which may contribute to the pro-inflammatory peritoneal and pelvic environment [ 2 , 3 ]. This narrative review will explore the multifactorial relationship between endometriosis and infertility, and is reported according to the Scale for the Assessment of Narrative Review Articles (SANRA) (see Supplementary Material) [ 8 ]. We will explore the pathophysiology of endometriosis-related infertility in order to understand the current evidence on the management options for this condition. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Endometriosis is a complex, multifaceted, chronic inflammatory condition [ 9 ]. The retrograde menstruation theory, in which endometrial tissue and protein-rich fluid flows into the peritoneal cavity through the fallopian tubes during menstruation, is the prevailing pathophysiological explanation for the development of endometriosis [ 9 ]. As retrograde menstruation is a physiological process seen in up to 90% of women, other factors are required to explain the adherence and proliferation of endometrial-like cells seen in endometriosis [ 2 ]. One such factor may be the distinct immune profile seen in ectopic endometriosis tissue compared to eutopic endometrium [ 9 ]; however, it is difficult to determine whether altered immunity is the cause of endometriosis or secondary to the condition [ 9 ]. Alternate hypotheses regarding the pathophysiology of endometriosis include the spread of endometrial cells via the lymphatic system and veins, and metaplasia of the coelom, embryonic cells lining the abdominal organs [ 9 ]. The latter theory proposes that multipotent mesenchymal stem cells differentiate into endometrial tissue at distant locations, leading to foci of endometriosis [ 2 , 3 ]. However, this fails to explain the development of non-pelvic endometriosis lesions [ 10 ]. Bone marrow-derived stem cells may be the explanation for extrapelvic endometriosis and may contribute to the continued growth of endometriosis lesions established by retrograde menstruation [ 9 ]. Genetic predisposition is an additional factor leading to the development of endometriosis, as the condition has a heritability of approximately 50% [ 11 , 12 ] and specific genome-wide significant loci associated with endometriosis have been identified [ 13 ]. There are multiple mechanisms through which endometriosis may lead to infertility. One such mechanism is impaired ovarian function due to inflammatory damage and mechanical distortion of the surrounding ovarian parenchyma by endometriomas in situ, and/or due to iatrogenic damage to the healthy ovarian tissue during surgical intervention. Furthermore, additional mechanical barriers for natural fertility include distorted pelvic anatomy by extensive adhesions and abnormal anterograde (towards the uterine cavity) and/or retrograde (towards the peritoneal cavity) transport. Dyspareunia may also play a role as the resulting difficulties with sexual intercourse can negatively affect natural fertility [ 2 , 3 , 5 , 14 , 15 ]. Inflammatory milieu in the pelvis and impaired receptivity of the eutopic endometrium are considered to be possible additional factors. However, evidence remains conflicting, with data from oocyte donation cycles suggesting that receptivity may not always be impaired [ 16 ]. In the presence of immunological changes such as in concomitant autoimmune diseases, the embryo–maternal interactions may be affected, with some evidence of a negative impact on embryo implantation [ 17 , 18 ]. Concomitant adenomyosis may further disrupt the uterine microenvironment, particularly when the endo-myometrial interface is involved. In any case, growing evidence suggests that implantation failure is predominantly attributable to embryonic factors, thereby challenging the concept of altered receptivity, both in general and in the context of endometriosis [ 19 ].

The definition and use of classification and staging systems for endometriosis remain complex and widely debated, as several schemes have been developed with varying primary purposes. The need to account for deep endometriosis has progressively reshaped these systems, leading to the introduction of new tools. In the specific context of endometriosis-related infertility, the most widely adopted staging system is the revised American Society for Reproductive Medicine (rASRM) classification, which represents the historical foundation for subsequent staging systems. It provides a standardized description of the severity of endometriosis at the time of surgery, taking into account the location, size, and depth of the lesions visualized, as well as the presence of adhesions [ 20 ]. According to this classification, stages I–II are considered minimal-to-mild disease, and stages III–IV are considered moderate-to-severe disease [ 20 ]. Of note, this classification does not account for endometriosis outside of the pelvis, does not incorporate deep endometriosis (DE) involving visceral organs (e.g., bowel, bladder), and does not correlate with the clinical severity of the condition [ 21 ]. Despite these limitations, because ovarian involvement weighs heavily in this scoring system, the rASRM classification is the one showing a partial, albeit imperfect, association with endometriosis-associated infertility. The Endometriosis Fertility Index (EFI) represents the only scoring system specifically designed to integrate both clinical factors and a functional assessment of the tubes, ovaries, and fimbriae [ 22 ]. This index utilizes the surgical staging of endometriosis severity along with historical factors (age, number of years infertile, and pregnancy history) to predict the likelihood of natural, non-ART pregnancy at 36 months post surgery. The score starts at 0, with the lowest probability of pregnancy, to 10, the highest probability of pregnancy at 36 months post-operatively [ 22 ]. A systematic review and meta-analysis by Vesali et al . [ 23 ] has shown that there was a significant difference in pregnancy rates across all EFI score categories, supporting the validity of the tool in addressing natural fertility. Although originally designed as post-surgical staging system, several studies have suggested that the EFI score can be estimated non-invasively using transvaginal ultrasound with ultrasonographic tubal patency testing [ 24 – 26 ]. However, an expert consensus has stated that imaging cannot reliably replace surgical visualization for accurate EFI calculation [ 27 ].

Below is the link to the electronic supplementary material. Supplementary file1 (PDF 535 KB) Supplementary file1 (PDF 535 KB)