Bibliography in Assisted Reproductive Technology (ART)

In an ever-evolving field marked by rapid scientific progress and increasing clinical complexity, it is essential to remain updated on key innovations, best practices, and the most relevant publications.

Compiled and reviewed by the clinical team at the xxxxxx—one of Paris’ most established and active ART centers—this summary offers a concise yet rigorous overview of recent advances in the field. Drawing from high-impact international journals, the work highlights emerging techniques, evolving protocols, and critical findings in ART.

With this bibliographical review, we aim to offer an original tool to aid in scientific monitoring, positioned between the conventional abstract and the often lengthy and time-consuming full reading of the original article. This hybrid format ensures substantial time savings by enabling the rapid and targeted identification of publications that, based on their content, warrant an in-depth reading.

Regular updates will follow to keep pace with the dynamic landscape of ART.

Does Pre-IVF Surgery Improve Outcomes in Women with Endometriosis?

Dr François durand

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Dr Cécile François

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Endometriosis and Infertility Management

Endometriosis is a complex and heterogeneous disease affecting 5-10% of reproductive-aged women, with up to 30-50% of these patients experiencing infertility. The condition can significantly impact fertility through various mechanisms, including mechanical distortion of pelvic anatomy, inflammation, reduced oocyte quality, and diminished ovarian reserve. Diagnosis primarily relies on transvaginal ultrasound (TVS), with surgical confirmation being the gold standard for minimal/mild endometriosis (MME). Treatment strategies, including surgery and In Vitro Fertilization (IVF), must be highly individualized, considering the patient’s age, ovarian reserve, symptom severity, and reproductive objectives. While surgery can alleviate symptoms and, in some cases, improve fertility, it carries risks, particularly to ovarian reserve. Fertility preservation, primarily through oocyte cryopreservation, is an increasingly important option for women with endometriosis, especially those with factors like advanced age, bilateral endometriomas, or a history of multiple

  • Endometriosis is commonly found in women who experience conception delay and women with the condition are nearly twice as likely to suffer from infertility.
  • The prevalence of endometriosis in infertile patients is up to 25–50%, 10 times higher than in the general population.
  • Mechanisms by which endometriosis affects fertility include:
    • Mechanical distortion of pelvic anatomy (e.g., fallopian tube distortion due to adhesions).
    • Impairment of gamete and embryo transport.
    • Reduced oocyte and embryo quality.
    • Diminished ovarian reserve.
    • Altered immune and endocrine function, and dysregulation of hormonal/cell-mediated functions involved in endometrial receptivity.
    • Inflammatory state: Peritoneal endometriosis, even when not macroscopically visible, is linked to infertility, likely due to an inflammatory state affecting spontaneous fertility and ovulation. Inflammatory mediators such as IL-8, TNF-alpha, and intercellular adhesion molecules (ICAMs) contribute to fallopian tube distortion through the mechanical effects of pelvic adhesions.
  • Endometriosis is a very heterogeneous disease requiring tailored treatment based on specific diagnosis.
  • Transvaginal ultrasound (TVS) is widely accepted as the first-line diagnostic imaging technique.
  • Laparoscopic surgery remains the “gold standard” for diagnosing stage I/II (minimal/mild) endometriosis, offering histological confirmation.
  • Mapping the disease through thorough history and accurate TVS is crucial as endometriosis is rarely confined to a single site, but more commonly involves multiple structures.
  • No definitive non-invasive diagnostic biomarker currently exists, despite exploration of blood, cervicovaginal fluid, and urine analysis. However, some studies are exploring potential biomarkers, such as saliva-based miRNA signature profile as a novel diagnostic tool for screening endometriosis-related infertility.
  • Ovarian endometriomas (OMAs) are present in 17–44% of endometriosis patients and can significantly reduce ovarian function and the pool of primordial follicles due to massive amounts of free iron, reactive oxygen species, proteolytic enzymes and inflammatory molecules.
  • The presence of endometriosis significantly reduces anti-M€ullerian hormone (AMH) levels.
  • Surgical excision of ovarian endometriomas poses a significant risk to ovarian reserve. A meta-analysis showed a statistically significant decline in Anti-Müllerian Hormone (AMH) levels, dropping from 3 ng/mL preoperatively to 1.87 ng/mL postoperatively, marking a substantial decrease of 38%. Unilateral cystectomy showed a 30% reduction in AMH, while bilateral was 44%.
  • Mechanisms of ovarian reserve damage during surgery include mechanical removal of the healthy ovarian cortex, the coagulation of residual ovarian tissue after excision, and the inflammation and edema caused by surgery.
  • The Antral Follicle Count (AFC) in the affected ovary is significantly lower than that in the contralateral ovary, supporting the hypothesis that most of the damage to the ovarian reserve occurs prior to surgery.

The role of preoperative and postoperative AMH and AFC in assessing ovarian function after surgery is still unclear due to factors like AMH reduction by OMAs themselves and visualization difficulties for AFC

  • Oocyte Morphological Assessments: AI and Deep Learning (DL) technologies are transforming oocyte quality assessment by offering objective and consistent analysis of meiotic stages (MII, MI, GV), enabling a more accurate prediction of fertilization potential.
    • DNN-based systems can classify human oocytes by meiotic maturity with high accuracy (96.4% in validation, 95.7% in testing).
    • Enhanced U-Net models precisely segment key characteristics like ooplasm, zona pellucida, and perivitelline space in low-resolution MII oocyte images, showing superior accuracy over traditional methods.
    • CNNs and SVMs have improved the prediction of oocyte developmental potential, with CNN models capable of predicting fertilization potential with over 86% accuracy and distinguishing mature MII oocytes with 98.9% precision by pinpointing the first extruded polar body. This precision aids in identifying optimal sites for sperm injection during ICSI.
    • The aim is to identify specific oocyte features (physical traits, cellular formations, morphometric and morphokinetic parameters, cytoplasmic movements) that embryologists use, to leverage them for AI applications, focusing on live birth potential. AI can unlock hidden patterns in collected clinical data and improve decision-making.
  • Semen Analysis: AI and DL are transforming sperm selection for IVF and ICSI by expanding beyond traditional semen parameter analysis to automated sperm detection, comprehensive semen analysis, and assessments of sperm viability and DNA integrity.
    • AI systems, trained on detailed sperm datasets, accurately identify optimal sperm morphology and classify sperm by motility, improving upon the variability of traditional methods. Automated classifiers can achieve up to 94% accuracy rates in classifying sperm morphology.
    • Deep learning algorithms can accurately detect morphological abnormalities in sperm acrosome and vacuole regions in real-time on standard laptops.
    • Computer-Assisted Sperm Analysis (CASA) systems, enhanced with AI, allow for precise and quick analysis of sperm trajectories, improving accuracy and efficiency in semen analysis and male infertility prediction.
    • AI also shows promise in predicting sperm with high DNA fragmentation rates, a known cause of male infertility and ART failure.
  • Embryo Selection and Ploidy Prediction: AI-based tools offer a standardized, non-invasive approach to prioritizing high-quality embryos for transfer by analyzing morphological features and predicting euploidy (normal chromosome number).
    • Time-lapse incubators, combined with AI, provide continuous monitoring, aiding in selection.
    • AI models show potential in accurately predicting embryo ploidy from images and videos, with accuracy ranging from 44% to 85%, and can be improved by combining image analysis with clinical data. For example, one AI model effectively predicts embryo ploidy with 65.3% accuracy, improving to 77.4% post-optimization, and showing high-scoring embryos by AI to be twice as likely to be euploid.
    • Studies demonstrate AI’s potential to significantly decrease the number of cycles required to reach a clinical pregnancy and increase the first cycle clinical pregnancy rate when used as an adjunct to embryologists’ expertise. The EMBRYOLY algorithm, for example, could have increased the first cycle pregnancy rate from 19.8% to 44.1% and reduced cycles to clinical pregnancy from 2.01 to 1.66.
    • This is particularly beneficial for clinics where PGT-A is not common or available, as AI can assist in ranking embryos without prior knowledge of ploidy status. AI can provide reproducible recommendations and enhance objectivity in embryo assessment, harmonizing practices across centers and countries.
    • AI can also predict the developmental potential of cleavage-stage embryos, distinguishing between good and poor quality, and assisting in sorting embryos with high quality when embryologists face difficulty in selection.
  • Micromanipulation Procedures: AI, with its advanced image-processing capabilities, is revolutionizing embryology by providing precise guidance for intricate procedures such as ICSI and assisted hatching.
    • Deep learning CNNs can identify critical morphological features in oocytes and embryos, enhancing precision in ICSI and assisted hatching (AH) procedures with accuracies of 98.9% and 99.41%, respectively.
    • Automated Intracytoplasmic Sperm Injection (ICSIA) robots have demonstrated effectiveness by automating key IVF steps, achieving high survival rates for injected human oocytes and leading to successful fertilizations and births.
    • AI can detect the optimal location for ICSI to avoid membrane ruptures, offering a promising non-invasive tool to increase IVF outcomes.
  • Treatment decisions should be individualized based on patient symptoms and reproductive objectives.
  • For minimal/mild endometriosis (MME), laparoscopic management enhances fecundity and increases the chances of spontaneous conception in appropriately selected cases. However, it is not routinely recommended in asymptomatic patients with the sole purpose of diagnosing and treating potentially present MME.
  • For small OMAs, surgical treatment prior to IVF does not increase pregnancy chances.
  • For voluminous OMAs with doubtful ultrasonographic appearance, surgery can be a first-line option and may also increase the chances of subsequent IVF by improving follicular access.
  • A recent survey on surgery for large endometriomas prior to IVF found significant variability in practices, with a median surgical threshold size of 50 mm. Surgeons tended to intervene on smaller lesions than IVF specialists.
  • Laparoscopic cystectomy is a common surgical technique but is associated with a higher risk of reduced ovarian volume and thus ovarian function.
  • A dedicated endometriosis surgeon with extensive experience is crucial to assess how radical to treat the disease, restore pelvic anatomy, and avoid ovarian or tubal injury for better fertility outcomes.
  • Preoperative hormonal treatment is prescribed by 45.9% of surveyed participants, mainly progestins, possibly to reduce the need for surgery before IVF. Post-surgery, hormonal treatments are more frequently prescribed (86.5%).
  • Fertility preservation strategies, initially for cancer patients, now include medical conditions like endometriosis due to the risk of significant loss in ovarian follicle reserve.
  • Oocyte cryopreservation (egg freezing) is a safe and effective technique.
  • Indications for fertility preservation in endometriosis patients include: Patient’s age, particularly after 35, when fertility significantly declines.
  • Presence of bilateral endometriomas.
  • History or risk of multiple surgeries.
  • Reduced preoperative ovarian reserve (e.g., low AMH levels).
  • Combination of ovarian endometrioma and reduced ovarian reserve.
  • Contralateral recurrence before a new surgery after unilateral endometrioma surgery.
  • Women with severe cases or previous surgeries may need multiple treatment cycles to collect enough oocytes for preservation.
  • An algorithm for fertility preservation is proposed, tailored to patient-specific needs and reproductive goals, considering immediate pregnancy desire versus future fertility planning, ovarian reserve (AMH, AFC, age), and high-risk factors.
  • While some studies suggest reduced oocyte quality (e.g., altered morphology, lower mitochondrial content) in endometriosis patients, others show normal oocyte morphology, attributing lower top-quality embryos and clinical pregnancy rates to lower oocyte yield rather than quality.
  • Data from IVF procedures indicate that women with endometriosis may have oocytes with lower in-vitro maturation rates and lower fertilization rates.
  • A study comparing IVF outcomes in patients who had IVF before surgery (IVF-OPS), surgery before IVF (OPS-IVF), and no surgery (control) found the IVF-OPS group had a significantly higher number of retrieved oocytes, number of injected oocytes, number of fertilized oocytes, number of cleavages, number of top cleavage quality, number of Blastocyst, and number of top blastocyst quality compared to the OPS-IVF group.

Pre-IVF Surgery in Women with Endometriosis

The role of surgical intervention for ovarian endometriomas prior to IVF is one of the most contentious areas.

  • Impact on Ovarian Reserve: It is well-established that cystectomy for OMA significantly reduces ovarian reserve. This reduction is consistently observed through a decrease in Anti-Müllerian Hormone (AMH) levels. A comprehensive meta-analysis indicated a 38% decline in AMH levels postoperatively, with specific reductions of 30% for unilateral OMAs and 44% for bilateral ones. The damage to ovarian reserve largely occurs prior to surgery due to the presence of endometriomas themselves, which contain toxic substances like free iron and reactive oxygen species (ROS) that cause fibrosis and follicular damage. Repeated ovarian surgeries are generally discouraged because they further deplete ovarian reserve and lower pregnancy chances.
  • Effect on IVF Outcomes: Multiple systematic reviews and meta-analyses have consistently shown that surgical treatment of OMAs does not significantly improve live birth rates or clinical pregnancy rates after IVF/ICSI. In some cases, it may even lead to a reduction in the number of oocytes retrieved or higher cycle cancellation rates.
  • Indications for Surgery: Surgery for OMAs before IVF is primarily recommended for severe pain relief or to improve the accessibility of follicles during oocyte retrieval, especially for large cysts (e.g., >4 cm or 5 cm). Exclusion of suspected malignancy is also an indication.
  • Timing of Intervention (IVF-OPS vs. OPS-IVF): A retrospective cross-sectional study (Sini et al., 2025) found that performing IVF prior to endometrioma removal surgery (IVF-OPS) resulted in better clinical pregnancy rates (50% vs. 26.3%) and improved embryology laboratory outcomes (e.g., number of top-quality blastocysts, number of injected and fertilized oocytes, number of cleavages and blastocysts) compared to surgery followed by IVF (OPS-IVF). This approach involved cryopreservation of all embryos obtained from IVF cycles, followed by surgery, and then frozen embryo transfer.
  • Surgical Techniques: Laparoscopic cystectomy remains the most common procedure, though it carries risks of ovarian tissue loss. Other techniques like CO2 laser ablation and plasma energy are gaining interest as they may minimize ovarian damage due to limited thermal spread, potentially preserving ovarian reserve more effectively than bipolar diathermy or the stripping technique. Sclerotherapy with ethanol is another option. Experts note significant variability in current practices for OMA management.

The role of surgery for DIE before IVF is more contentious due to a lack of robust randomized controlled trials (RCTs).

  • Conflicting Data on IVF Improvement: Some meta-analyses have found no statistically significant difference in live birth rates or ongoing pregnancy rates between patients who underwent surgery for DIE before IVF and those who did not. However, one meta-analysis by Casals et al. (2021) concluded that surgery prior to IVF for DIE may offer benefit, showing significantly higher pregnancy and live birth rates per patient. Other non-randomized studies have also reported improved pregnancy rates after surgical excision of DIE before IVF.
  • Clear Indications for Surgery: Surgery for DIE is generally indicated for the alleviation of debilitating painful symptoms (especially when medical treatment fails) or to prevent severe complications such as bowel or urinary obstruction, or spontaneous hemoperitoneum, which can occur during ovarian stimulation or pregnancy.
  • First-line IVF: For asymptomatic patients primarily concerned with fertility, first-line IVF, without prior surgery for DIE, is an increasingly accepted approach. This is also supported by the fact that IVF does not appear to worsen endometriosis symptoms or cause disease progression in deep infiltrating endometriosis patients.
  • Anterior Compartment Endometriosis (e.g., Bladder): Studies suggest that surgical treatment of bladder endometriosis can improve fertility (both spontaneous and ART-related) and symptoms.
  • Posterior Compartment Endometriosis (e.g., Rectosigmoid, Uterosacral Ligaments): Surgery for posterior compartment DIE has been associated with improved spontaneous pregnancy rates. Some studies suggest that prior colorectal surgery for endometriosis can improve ICSI-IVF outcomes, particularly for patients with favorable prognosis (younger age, good AMH). However, deep infiltrating endometriosis may involve multiple structures making it difficult to determine the independent impact of each localization on fertility.
  • Parametrial Endometriosis (PaE): This severe form of DIE may impact fertility due to its inflammatory component. However, currently, there is no established superiority in efficacy between surgical treatment and IVF for PaE-associated infertility.

The impact of MME on fertility and its role in improving IVF outcomes are less clear.

  • Mechanisms of Infertility: Reduced fecundity in MME is linked to a proinflammatory microenvironment, increased oxidative stress affecting oocyte quality and ovarian reserve, toxic effects on sperm, uterine dysperistalsis, impaired follicular development, and reduced endometrial receptivity.
  • Impact on Spontaneous Fertility: Laparoscopic surgery (excision or ablation) for MME can improve spontaneous conception rates. It also allows for adhesiolysis if adhesions are present, which can restore normal pelvic anatomy and improve fertility. The “Number Needed to Treat” (NNT) for MME surgery to achieve an additional pregnancy is high (at least 12, potentially 40 for unexplained infertility), indicating a relatively small absolute increase in pregnancy rates.
  • Limited Evidence for IVF Outcomes: Current guidelines, including ESHRE, do not routinely recommend pre-IVF surgery for MME due to a lack of strong, beneficial evidence to enhance live birth rates. While one retrospective study (Opoien et al., 2011) suggested a benefit of surgical ablation of MME prior to IVF/ICSI by linking it to improved implantation, pregnancy, and live birth rates, other meta-analyses found no significant difference or even lower live birth rates following surgery. Some analyses find similar clinical pregnancy and live birth rates between MME patients and controls undergoing IVF.

Endometriosis is a recognized indication for fertility preservation, especially in cases of bilateral OMAs, recurrent surgery, or reduced ovarian reserve.

  • Oocyte Cryopreservation: This is considered the most suitable technique for young patients with endometriosis, particularly given it does not negatively impact ovarian reserve and has low morbidity. Multiple cycles of ovarian stimulation may be necessary to obtain an optimal number of oocytes (at least 10) due to reduced ovarian reserve in endometriosis patients.
  • Key Predictors: Patient age and ovarian reserve are critical predictors of success for fertility preservation outcomes. Studies show that cumulative live birth rates (CLBRs) increase with a higher number of cryopreserved oocytes but decrease with advanced age.
  • Impact of Prior Surgery: Patients with a history of prior ovarian surgery for endometriomas have fewer oocytes retrieved than those without previous surgical interventions.
  • Comparable IVF Outcomes: When an adequate number of oocytes are cryopreserved, IVF outcomes (including live birth rates) in endometriosis patients are comparable to those in patients undergoing fertility preservation for other reasons, suggesting a quantitative rather than qualitative impairment of oocytes.
  • Timing: It is crucial to consider fertility preservation before surgery if the procedure is likely to affect ovarian reserve, especially for patients with bilateral endometriomas or pre-existing low ovarian reserve.
  • Individualized Treatment: The choice between surgery, IVF, or a combination must be highly individualized. Clinicians should consider the patient’s age, symptoms (especially pain), ovarian reserve (AMH and AFC), surgical history, extent and location of the disease, duration of infertility, and other infertility factors (e.g., male factor infertility).
  • Multidisciplinary Approach: A shared, informed decision-making process with the patient is essential. Multidisciplinary referral centers are highlighted as crucial for complex cases.
  • Hormonal Pre-treatment: The benefit of prolonged GnRH analogue therapy (minimum 3 months) before IVF for improving fertility outcomes in women with endometriosis is uncertain, with low-quality data available.
  • Surgical Expertise: The expertise of the surgeon plays a critical role in preserving ovarian function and overall success of the surgery.
  • Need for Further Research: There is a consistent call for more robust randomized controlled trials (RCTs) to define the precise role and benefits of surgery for different types and stages of endometriosis before IVF, especially for deep infiltrating and peritoneal endometriosis.

FAQ

No, pre-IVF surgery for endometriosis does not universally improve IVF outcomes, and the evidence is conflicting and depends on the type and stage of endometriosis. For ovarian endometriomas (OMAs), solid evidence from several meta-analyses demonstrates that surgical treatment does not enhance the outcomes of IVF, including clinical pregnancy or live birth rates. In fact, it can lead to higher rates of cycle cancellation due to poor ovarian response. For deep infiltrating endometriosis (DIE), studies yield conflicting results, with some suggesting a benefit in pregnancy rates after surgery before IVF and others showing no significant difference or even lower live birth rates in higher quality studies after surgery. For minimal/mild endometriosis (MME), routine surgery before IVF is generally not recommended due to a lack of robust beneficial evidence.

Surgical treatment of ovarian endometriomas carries a significant risk of diminishing ovarian reserve. Studies consistently report decreased Anti-Müllerian Hormone (AMH) levels post-surgery, with a substantial reduction of 38% overall, and 30% for unilateral and 44% for bilateral cystectomy. This reduction is due to the inadvertent removal of healthy ovarian tissue, thermal damage during haemostasis or ablation, vascular compromise, and local inflammation. Repeated ovarian surgery further exacerbates this negative impact on ovarian function and the chances of pregnancy. Given this detrimental effect, current guidelines recommend surgery for OMAs prior to ART primarily for pain management or to improve follicular accessibility, not to improve fertility outcomes or prevent disease progression.

Generally, pre-IVF surgery is not routinely recommended for minimal/mild endometriosis (MME) with the sole aim of enhancing IVF outcomes. While some studies suggest laparoscopic management of MME can increase spontaneous conception rates, and one retrospective study linked it to improved IVF/ICSI outcomes, these benefits appear minimal (Number Needed to Treat (NNT) up to 40). More recent meta-analyses indicate that surgery for endometriosis before IVF does not improve ongoing pregnancy or early pregnancy loss rates, and some higher-quality studies suggest lower live birth rates after surgery. The Endometriosis Treatment Italian Club (ETIC) strongly advises against surgery for asymptomatic infertile patients with superficial endometriosis purely for diagnostic and treatment purposes.

Although there is no consensus or strong evidence from randomized controlled trials to routinely recommend surgery for deep infiltrating endometriosis (DIE) as a first-line treatment to improve IVF outcomes for asymptomatic patients, it may be considered in specific situations. These include:

  • Intolerable pain symptoms that cannot be managed by hormonal therapies.
  • Risk of bowel occlusion, subocclusion, hydroureter, or hydronephrosis during ovarian stimulation for IVF and pregnancy.
  • When surgical excision is deemed necessary to restore normal pelvic anatomy for improved follicular access during oocyte retrieval.
  • In women who have failed multiple prior IVF treatments. However, the decision must carefully weigh the potential for severe complications from DIE surgery (e.g., ureteral damage, pelvic abscess) which can delay subsequent infertility treatment.

One study directly compared performing IVF before surgery (IVF-OPS) versus surgery before IVF (OPS-IVF) for ovarian endometriomas and found that IVF-OPS resulted in better outcomes. While the overall clinical pregnancy rates were comparable across IVF-OPS, OPS-IVF, and a control group (IVF without surgery), IVF-OPS led to an improved number of top-quality blastocysts and was superior to OPS-IVF in terms of clinical pregnancy rate (50% vs. 26.3%) and embryology laboratory outcomes. The OPS-IVF group showed lower AMH levels after surgery, which may explain the poorer oocyte and embryo quality. This suggests that surgical intervention for endometrioma may be more beneficial if performed after the IVF program.

The decision to perform surgery on endometriomas is influenced by their size, among other factors, though there is no universally agreed-upon size threshold for pre-IVF surgery. A survey of gynecologists indicated a median threshold size for surgical intervention of 50 mm (interquartile range 40–60 mm). Surgeons, however, showed a tendency to intervene on smaller lesions compared to IVF specialists. Some guidelines, like the CNGOF, discourage surgery before IVF for endometriomas smaller than 6 cm, noting that their presence does not affect embryo quality or IVF outcomes, but may reduce oocyte number and necessitate higher gonadotropin doses. Large endometriomas are recognized to reduce follicle and oocyte counts and can interfere with follicle accessibility during oocyte retrieval.

While laparoscopic cystectomy is the most common procedure (48.2% in a survey), it is associated with significant ovarian tissue loss and decreased ovarian reserve. Techniques such as CO2 laser ablation and plasma energy devices offer promising alternatives as they minimize ovarian damage due to their limited thermal spread, while maintaining comparable recurrence rates. A survey showed that 40.5% of participants would change their practice to use these advanced methods if available. Sclerotherapy with ethanol is another technique that has been studied, involving cyst drainage and exposure of the cyst wall to alcohol solution. The surgeon’s expertise is crucial for preserving ovarian function during these procedures.

Previous ovarian surgery for endometriosis can negatively impact ovarian function and subsequent IVF outcomes. Studies show that patients with a history of endometrioma excision have a significantly lower number of oocytes retrieved and vitrified compared to those without prior ovarian surgery. Repeated surgery for endometriosis does not appear to further improve fertility outcomes and often results in a greater decline in AMH than the initial surgery. From a pro-IVF perspective, surgical treatment is often ruled out in cases of previous surgery and bilateral ovarian endometriomas due to a high risk of severe impairment of ovarian reserve. A recent systematic review even suggested that IVF/ICSI outcomes may be lower in women with a history of previous surgery.

Yes, fertility preservation, particularly oocyte cryopreservation, is increasingly recognized as a suitable option for women with endometriosis, especially when surgery is considered. Endometriosis itself, or its surgical treatment, can detrimentally affect ovarian reserve. Oocyte cryopreservation is considered the most suitable technique for young patients with regular menstrual cycles at risk of future ovarian compromise, as it does not negatively impact ovarian reserve, has low morbidity, and does not require a male partner. It is particularly recommended for women with bilateral endometriomas, a history or risk of multiple surgeries, or reduced preoperative ovarian reserve. While multiple stimulation cycles may be needed to achieve an optimal number of oocytes due to reduced ovarian reserve, if an adequate number of oocytes is cryopreserved, IVF outcomes are comparable to those for other fertility preservation indications. Fertility preservation before surgery is highlighted as a way to protect ovarian reserve from surgical harm.

Personalized treatment is essential for endometriosis-related infertility, as there are no universal guidelines to definitively prioritize surgery or IVF. The decision-making process is complex and must consider a multitude of factors, tailored to the individual patient’s clinical characteristics and desires. Key factors include:

  • Patient’s wishes and preferences.
  • Age and its impact on ovarian reserve and time to conception.
  • Symptomatology (presence and severity of pain, sexual dysfunction).
  • Type and extent of endometriosis lesions (e.g., ovarian endometrioma, deep infiltrating endometriosis, superficial peritoneal endometriosis, parametrial endometriosis) and their location.
  • Ovarian reserve (evaluated by AMH and AFC levels).
  • Previous surgical history for endometriosis, as repeated surgeries can be detrimental to ovarian reserve.
  • Presence of other infertility factors (e.g., tubal patency, male factor infertility, associated adenomyosis).
  • Duration of infertility.
  • Endometriosis Fertility Index (EFI) score.
  • Accessibility of follicles for oocyte retrieval in IVF cycles. Shared and informed decision-making between the patient and the healthcare provider is crucial to ensure the most appropriate treatment pathway.

Bibliography

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Endometriosis is a complex, chronic inflammatory disease that affects approximately 5–10% of women of reproductive age and is a significant cause of pelvic pain and infertility. Infertility is a major concern for women with this condition, affecting 30–50% of them, and endometriosis accounts for about 10% of all patients undergoing Assisted Reproductive Technologies (ART) treatments. The management of infertility in patients with endometriosis presents a considerable challenge, as the optimal approach – whether surgical intervention or In Vitro Fertilization (IVF) – remains a subject of ongoing debate. This document synthesizes key information from the provided source regarding endometriosis-related infertility, the roles of surgery and ART, and the critical factors guiding personalized treatment decisions.

Endometriosis and Its Impact on Fertility

Endometriosis is characterized by the presence of endometrial glands and stroma outside the uterine cavity. The mechanisms contributing to infertility in affected women are multifaceted:

  • Inflammatory Mediators and Peritoneal Environment: The peritoneal fluid in women with endometriosis contains elevated levels of inflammatory mediators, cytokines, and growth factors. This creates a complex inflammatory milieu that can adversely affect oocyte release and quality, as well as endometrial receptivity.
  • Pelvic Anatomical Distortion: The disease promotes fibrin deposition, adhesion formation, scarring, and distortion of peritoneal surfaces and pelvic anatomy. These adhesions can disrupt normal tubal function, impairing gamete and embryo transport.
  • Ovarian Endometriomas (OMAs): Found in up to 44% of patients, OMAs contribute directly to infertility. Their fluid is rich in free iron, reactive oxygen species (ROS), proteolytic enzymes, and inflammatory molecules, leading to oxidative stress and fibrosis in the ovarian cortex. This process can reduce the primordial follicle pool, causing diminished ovarian reserve. Women with endometriomas often exhibit lower Anti-Müllerian Hormone (AMH) levels and a more rapid decline in ovarian reserve compared to age-matched controls.
  • Impaired Endometrial Receptivity: The eutopic endometrium in women with endometriosis may exhibit progesterone resistance and aberrant cell signaling, which can impair embryo implantation.
  • Dyspareunia: Chronic pelvic pain and deep dyspareunia, particularly linked to deep infiltrating endometriosis (DIE), can hinder regular intercourse, further complicating conception.
  • Iatrogenic Damage from Surgery: Surgical interventions, especially on the ovaries, carry the risk of inadvertently removing healthy ovarian tissue, leading to a diminished ovarian reserve.

The average delay in endometriosis diagnosis, often around 7 years, is particularly critical for women facing infertility, as the combined effects of the disease and advancing age can severely compromise their chances of conception.

Surgical Management of Endometriosis for Infertility

The role of surgery in improving fertility for endometriosis patients is highly debated, and treatment strategies must be individualized based on patient wishes, symptomatology, age, and other factors.

  • Minimal/Mild Endometriosis (ASRM Stage I/II): Some randomized controlled trials suggest that excision or ablation of endometriotic lesions and lysis of adhesions during laparoscopy can increase natural pregnancy rates compared to diagnostic laparoscopy alone. Guidelines from societies like ASRM and ESHRE support operative laparoscopy as an option to improve natural, ongoing pregnancy rates in these cases. However, the number needed to treat (NNT) to achieve an additional pregnancy is high (at least 12), and some studies show no significant benefit in fecundity. Notably, surgery should not be performed in asymptomatic women with infertility solely to search for signs of endometriosis.
  • Deep Infiltrating Endometriosis (DIE): The efficacy of surgery for improving fertility in ASRM stage III/IV endometriosis is less clear. Surgical treatment of DIE may be considered to improve pregnancy rates after IVF according to some studies, while others report conflicting results, with some experts suggesting IVF as a first-line treatment for asymptomatic patients prioritizing fertility. Surgery for DIE is often considered when patients experience severe pain, bowel or urinary obstruction, or subocclusion.
  • Ovarian Endometriomas (OMAs): Surgical removal of OMAs can improve natural conception rates. The stripping technique is generally recommended due to lower recurrence risk and higher natural pregnancy probability. However, surgical excision of endometriomas significantly reduces ovarian reserve, with AMH levels dropping by 30-44% after unilateral and bilateral cystectomies, respectively. There’s a reported 2.4–13% risk of premature ovarian failure post-surgery. Despite the potential for natural conception, solid evidence from multiple meta-analyses indicates that surgical treatment of endometriomas generally does not improve IVF outcomes in terms of live birth rates or clinical pregnancy rates. In fact, it may lead to a higher cycle cancellation rate due to poor ovarian response. The most recent ESHRE guidelines do not routinely recommend surgery prior to ART solely to enhance live birth rates. Surgical interventions for endometriomas can damage ovarian parenchyma through mechanisms like accidental removal of healthy tissue, vascular damage from electrocoagulation, and autoimmune responses. While laparoscopic cystectomy is common, techniques like CO2 laser ablation and plasma energy are considered more tissue-sparing, potentially minimizing ovarian damage.
  • Other Localizations (Anterior Compartment/Bladder, Peritoneal, Parametrial):
    • Bladder Endometriosis: Laparoscopic excision has shown encouraging results in improving fertility, with a significant proportion of spontaneous pregnancies post-surgery.
    • Peritoneal Endometriosis: Its role in infertility is linked to a chronic inflammatory state. The efficacy of surgery is debated; some suggest IVF as first-line for infertility related to PE, reserving surgery for severe symptoms. Surgery is generally not recommended for asymptomatic women with infertility.
    • Parametrial Endometriosis: This is a severe form of DIE, often associated with urinary dysfunctions. While surgery for DIE may improve IVF outcomes, the specific impact of parametrial endometriosis surgery on fertility is not well-studied, and no superiority between surgery and IVF has been established.

Assisted Reproductive Technologies (ART) for Endometriosis-Related Infertility

ART, particularly IVF, is a well-established treatment for endometriosis-related infertility. It is often considered the first-line approach in cases of ovarian endometriomas to avoid potential surgical damage to ovarian reserve.

  • Indications for ART: ART is generally preferred for asymptomatic infertile patients over 35 years old or those with decreased ovarian reserve, other associated infertility factors, bilateral endometriomas, endometrioma recurrence, a history of previous endometriosis surgery, or failure of natural conception after surgery. IVF should also be considered first in cases of male infertility or advanced age with reduced ovarian reserve, to minimize the time to pregnancy and the depletion of ovarian function.
  • Ovarian Stimulation: Ovarian stimulation with GnRH agonists or antagonists can be performed safely in endometriosis patients, as it does not appear to increase the risk of disease progression or recurrence. While endometriosis patients may require higher doses of gonadotropins and may yield fewer oocytes, they can still achieve similar live birth rates compared to women without endometriosis if a sufficient number of high-quality embryos are obtained.
  • Pelvic Infection Risk: While the overall risk is low (0.12%), ovarian endometriomas may slightly increase the risk of pelvic infection and abscess formation after oocyte retrieval. Careful aseptic technique and antibiotics are recommended.

The Debate and Personalized Management

Choosing the optimal treatment for infertility in patients with endometriosis is still a challenge, with surgeons and reproductive physicians often advocating for their respective approaches.

  • Conflicting Evidence: There is conflicting data regarding whether the presence of endometriotic lesions negatively affects ART outcomes. Some meta-analyses report no influence, while others suggest a negative impact dependent on disease stage, with lower success rates for severe cases (stage III or IV).
  • Similar Outcomes: Medical centers treating endometriosis-related infertility should offer both surgical and IVF strategies, as a similar live birth rate of around 25% is seen with both approaches.
  • Individualized Approach: The decision must be carefully considered and individualized based on several factors, including the patient’s symptoms, age, ovarian reserve, duration of infertility, concomitant male infertility, extent of the disease, previous pelvic surgery, and their personal reproductive goals and preferences. Shared decision-making with the patient is essential.
  • Timing of Intervention: If surgery is performed for fertility purposes, it is important to note that the best time to conceive is often within the first year after surgery. Repeated ovarian surgery has a detrimental effect on ovarian function and reduces the chances of pregnancy; therefore, it should be avoided when possible.

Current Challenges and Future Directions

Despite increasing data, there is a lack of international consensus and updated, evidence-based guidelines from scientific societies for managing endometriosis-related infertility, particularly regarding the size threshold for surgery prior to IVF and specific indications for fertility preservation. This leads to significant variability in current practices, often influenced by individual practitioner expertise and training rather than solely by institutional setting.

There is a clear and strong need for future well-designed randomized controlled trials to compare surgical and medical treatment options, including the timing of interventions, to optimize fertility outcomes for women with endometriosis. Furthermore, the development of reliable, non-invasive diagnostic tools for endometriosis, such as salivary microRNA signatures, could revolutionize patient management by allowing earlier diagnosis and more tailored interventions, potentially reducing the need for invasive diagnostic laparoscopies. Ultimately, a personalized, multidisciplinary approach, carefully considering the patient’s symptoms, age, ovarian reserve, and reproductive goals, is essential to optimize outcomes.

Endometriosis is frequently observed in women experiencing conception delays, with affected women being nearly twice as likely to suffer from infertility. The condition is hypothesized to negatively influence natural conception by causing mechanical distortion of pelvic anatomy, impairing gamete and embryo transport, reducing oocyte and embryo quality, diminishing ovarian reserve, altering immune and endocrine functions, dysregulating hormonal and cell-mediated endometrial receptivity, and affecting the ability to have regular intercourse. IVF is an established treatment option for managing infertility in endometriosis patients, as it is thought to counteract the toxic effects of the endometriotic pelvic environment by allowing fertilization and preimplantation embryo development to occur outside the body.

Impact of Endometriosis on IVF Outcomes Early meta-analyses, published before 2000, indicated that women with ASRM (American Society for Reproductive Medicine) stage I/II endometriosis and tubal factor infertility had lower fertilization and implantation rates compared to those with tubal factor infertility alone. These analyses also suggested that endometriosis of any stage negatively impacted oocyte yield and fertilization rate, concluding that endometriosis could affect oocyte and embryo quality, as well as endometrial receptivity.

More recent analyses, however, present a nuanced picture:

  • Fertilization and Live Birth Rates A meta-analysis in 2013 reported lower fertilization rates for ASRM stage I/II endometriosis, but no significant differences in implantation, clinical pregnancy, or live birth rates. For stage III/IV endometriosis, reduced implantation and clinical pregnancy rates were observed, but no difference in live birth rates. Hamdan and colleagues found that women with stage III/IV disease had significantly lower clinical pregnancy and live birth rates, alongside a lower number of oocytes retrieved, when compared to controls. However, a large data analysis from the Latin American Data Registry indicated that while women with endometriosis undergoing IVF had lower oocyte yield and higher cycle cancellation rates, these findings did not translate into a difference in live birth rates. Similar results have been corroborated by several other meta-analyses.
  • Oocyte/Embryo Quality Successful IVF hinges on oocyte quality, which influences embryo development and, subsequently, endometrial receptivity for implantation.
    • A large 2022 study analyzing over 13,000 IVF cycles reported no significant difference in live birth rates in fresh or frozen embryo transfer cycles, suggesting minimal to no impact of endometriosis on oocyte quality.
    • Studies on euploidy and aneuploidy rates showed equivalent rates between women with endometriosis and age-matched controls.
    • While some studies have suggested reduced oocyte quality due to altered morphology (cortical granule loss, spindle disruption, zona pellucida hardening), failure in in vitro maturation, and lower cytoplasmic mitochondrial content, others found oocyte quality unaffected, with normal morphology and equivalent fertilization rates.
    • Similarly, some research pointed to reduced embryo quality with increased aberrant development, nuclear and cytoplasmic impairment, and altered blastomere division. Yet, other systematic reviews and studies found no difference in total or top-quality embryos, euploidy rates, clinical pregnancy rates, implantation rates, or live birth rates.
    • Overall, despite suggestions of impact on oocyte and embryo quality, a clear clinical effect on IVF outcomes is not consistently confirmed.
  • Endometrial Receptivity The eutopic endometrium in women with endometriosis can exhibit progesterone resistance and aberrant cell signaling, which might alter receptivity. However, studies using endometrial receptivity array (ERA) tests showed no difference in the gene signature during the implantation window compared to healthy controls. Sibling oocyte studies and randomized controlled trials on endometrial scratching also did not find a negative impact of endometriosis on implantation rates or improved outcomes from scratching. Recent evidence from euploid frozen embryo transfer cycles suggests no marked defect in endometrial receptivity when high-quality embryos are transferred in a medicated frozen embryo transfer cycle.
  • Ovarian Endometriomas (OMAs) Present in up to 50% of women with endometriosis, OMAs can reduce ovarian reserve through damage to healthy ovarian tissue. Meta-analyses consistently show a significant reduction in the number of mature oocytes retrieved in women with endometrioma, but no difference in gonadotropin dose, total embryos, high-quality embryos, clinical pregnancy rate, or live birth rate. The reduction in oocytes is more pronounced with larger or bilateral endometriomas. Surgical removal of endometriomas can negatively affect ovarian reserve, leading to a 30% reduction in AMH levels for unilateral and 44% for bilateral cases, with a reported 2.4% risk of premature ovarian insufficiency following bilateral removal. Younger women are particularly susceptible to recurrence and repeated surgeries, further compounding ovarian reserve insult.

Management Strategies in Women with Endometriosis Undergoing IVF

  • Pre-Treatment Strategies
    • GnRH Analogues (GnRHa): Prolonged GnRHa use (minimum 3 months) before ovarian stimulation has been proposed to improve pregnancy outcomes by mitigating inflammatory effects. However, a Cochrane review found the benefit uncertain regarding clinical pregnancy, miscarriage, and live birth, and concerns exist about pituitary over-suppression leading to poor ovarian response. Extended downregulation, with or without prior surgery, does not seem to improve IVF outcomes.
    • Letrozole: One retrospective study on 126 women with endometriomas suggested improved reproductive outcomes when Letrozole (an aromatase inhibitor) was used with GnRH analogues, but further studies are needed.
    • Dienogest: A systematic review and meta-analysis of long-term dienogest therapy showed no significant difference in clinical pregnancy rate, live birth rate, miscarriage rate, or oocyte retrieval.
    • Elagolix: An ongoing trial is evaluating Elagolix, an oral GnRH receptor antagonist, for pre-IVF treatment.
  • Ovarian Stimulation There is limited research on specific gonadotropin preparations or dosages for women with endometriosis. While low-quality evidence suggests a higher dose of gonadotrophins may be needed due to lower ovarian response, IVF itself does not appear to increase disease progression or recurrence in deep endometriosis patients.
  • GnRH Agonist vs. Antagonist Protocols A randomized controlled trial showed equivalent implantation and clinical pregnancy rates with both GnRH agonist and antagonist protocols for minimal/mild endometriosis and endometrioma. A systematic review suggested higher clinical pregnancy rates with the long GnRH agonist protocol for moderate/severe endometriosis, though subgroup analyses did not find significant differences in reproductive outcomes across durations. Current evidence indicates no significant difference in outcomes, but a longer agonist protocol could be considered, especially after surgery for symptomatic endometriosis.
  • Pelvic Infection The risk of pelvic infection and abscess post-oocyte retrieval is slightly increased in the presence of an ovarian endometrioma, though the overall risk remains low. Aseptic technique and routine broad-spectrum antibiotics are recommended to minimize infection rates. Careful positioning of the aspiration needle can help avoid contamination with endometrioma fluid.
  • Method of Fertilization Limited data exist comparing IVF and ICSI for endometriosis. One study found no significant difference in fertilization rates using IVF in women with endometriosis compared to other infertility causes.
  • Elective Embryo Freezing This approach aims to mitigate the adverse effects of supraphysiological estradiol levels during ovarian stimulation on endometrial receptivity. Retrospective studies and meta-analyses have shown higher cumulative or live birth rates with frozen embryo transfer compared to fresh embryo transfer. However, further studies are needed to confirm the definitive benefit.
  • Surgical Treatment of Endometriosis
    • Ovarian Endometrioma: Multiple systematic reviews and meta-analyses conclude that ovarian cystectomy for endometrioma prior to IVF does not improve clinical pregnancy or live birth rates. It may even lead to higher rates of cycle cancellation due to poor ovarian response. Surgery for endometrioma before ART is primarily considered for pain control or to improve follicular accessibility for oocyte retrieval, not to enhance IVF outcomes or prevent disease progression.
    • Deep Infiltrative Endometriosis (DIE): One meta-analysis suggested that surgery prior to IVF for DIE might offer benefits, but noted concerns regarding analytical accuracy and loss to follow-up. Surgery for DIE can be complex, with an 18.5% risk of post-operative complications.
    • Minimal and Mild Endometriosis: One study indicated that complete surgical removal of visible ASRM stage I and II lesions before IVF improved implantation, pregnancy, and live birth rates, and reduced time to pregnancy. However, a more recent systematic review and meta-analysis reported that surgery prior to IVF does not improve IVF/ICSI outcomes, with higher quality studies even suggesting lower outcomes after previous surgery.

Conclusion Endometriosis may negatively affect ovarian reserve, oocyte/embryo quality, response to ovarian stimulation, and oocyte retrieval accessibility during IVF treatment. Despite these challenges, analyses of large registries and meta-analyses show that women with endometriosis maintain similar live birth rates to those without endometriosis, even with lower oocyte yields. Routine surgical removal of ovarian endometriomas before IVF is not recommended due to its detrimental effect on ovarian reserve and lack of improvement in live birth rates; however, it may be considered for symptom control or to improve follicle access. IVF does not appear to worsen disease progression or recurrence in deep endometriosis patients. Further well-designed randomized controlled trials are needed to fully evaluate the role of surgical and medical treatments in endometriosis patients undergoing assisted conception.

Endometriosis is a complex, chronic inflammatory disease affecting approximately 5–10% of women of reproductive age and is a major cause of pelvic pain and infertility. It is estimated that 30–50% of patients with endometriosis experience infertility, and this condition accounts for about 10% of all patients undergoing Assisted Reproductive Technologies (ART) treatments.

The management of infertility in patients with endometriosis is not straightforward, as the optimal approach – whether surgical intervention or In Vitro Fertilization (IVF) – remains a subject of ongoing debate. This document synthesizes key information regarding endometriosis-related infertility, the role of surgery and ART, and the increasing importance of fertility preservation strategies.

Endometriosis and Its Impact on Fertility

Endometriosis is characterized by the presence of endometrial glands and stroma outside the uterine cavity. The mechanisms contributing to infertility in affected women are multifactorial:

  • Ovarian Endometriomas (OMAs): Found in 17–44% of patients, OMAs contain fluid rich in free iron, reactive oxygen species (ROS), proteolytic enzymes, and inflammatory molecules. This toxic environment can lead to the replacement of normal ovarian cortical tissue with fibrous tissue, resulting in a reduction of the primordial follicle pool. Women with endometriomas often exhibit lower Anti-Müllerian Hormone (AMH) levels and a more rapid decline in ovarian reserve compared to age-matched controls.
  • Pelvic Anatomical Distortion: Adhesion formation caused by endometriosis can distort pelvic anatomy, disrupting normal tubal function and impairing gamete and embryo transport.
  • Chronic Inflammation: An exacerbated inflammatory state in the peritoneal fluid due to inflammatory mediators, cytokines, and growth factors can affect oocyte release, oocyte quality, and endometrial receptivity.
  • Altered Endometrial Receptivity: The eutopic endometrium in women with endometriosis may exhibit progesterone resistance and aberrant cell signaling, which can impair embryo implantation.
  • Dyspareunia: Chronic pelvic pain and dyspareunia can hinder regular intercourse, further complicating conception.
  • Iatrogenic Damage from Surgery: Surgical interventions, particularly on the ovaries, carry the risk of inadvertently removing healthy ovarian tissue, leading to a diminished ovarian reserve.

While some studies suggest a reduced oocyte quality and altered embryo morphology in women with endometriosis, other meta-analyses indicate that embryo aneuploidy rates and subsequent pregnancy, live birth, and miscarriage rates are similar to those in patients undergoing IVF for other reasons, provided an adequate number of oocytes are retrieved.

Surgical Management of Endometriosis for Infertility

The role of surgery in improving fertility for endometriosis patients is highly debated.

  • For Minimal/Mild Endometriosis (ASRM Stage I/II): Some randomized controlled trials suggest that excision or ablation of endometriotic lesions and lysis of adhesions during laparoscopy can increase natural pregnancy rates compared to diagnostic laparoscopy alone. Guidelines from various societies, including ASRM and ESHRE, support operative laparoscopy as an option to improve natural, ongoing pregnancy rates in these cases. However, the number needed to treat (NNT) to achieve an additional pregnancy is high (at least 12), and some studies show no significant benefit in terms of fecundity.
  • For Deep Infiltrating Endometriosis (DIE): The efficacy of surgery for improving fertility in ASRM stage III/IV endometriosis is less clear. Some studies indicate that surgical treatment of DIE may improve pregnancy rates after IVF, while others report conflicting results, with some experts suggesting IVF as a first-line treatment for asymptomatic patients prioritizing fertility. Surgery for DIE is often considered when patients experience severe pain, bowel or urinary obstruction, or subocclusion.
  • For Ovarian Endometriomas (OMAs): Surgical removal of OMAs can improve natural conception rates. The stripping technique is generally recommended due to lower recurrence risk and higher natural pregnancy probability compared to drainage/electrocoagulation. However, surgical excision of endometriomas significantly reduces ovarian reserve, with AMH levels dropping by 30-44% after unilateral and bilateral cystectomies, respectively. There’s a reported 2.4-13% risk of premature ovarian failure post-surgery.

Impact of Surgery on Ovarian Reserve and IVF Outcomes

Surgical interventions for endometriomas can damage ovarian parenchyma through several mechanisms, including the accidental removal of healthy ovarian tissue, vascular damage from electrocoagulation, and autoimmune responses triggered by inflammation. While laparoscopic cystectomy is common, techniques like CO2 laser ablation and plasma energy are considered more tissue-sparing, potentially minimizing ovarian damage.

Despite the potential for natural conception, solid evidence from multiple meta-analyses indicates that surgical treatment of endometriomas generally does not improve IVF outcomes in terms of live birth rates or clinical pregnancy rates. In fact, it may lead to a higher cycle cancellation rate due to poor ovarian response. The most recent ESHRE guidelines do not routinely recommend surgery prior to ART solely to enhance live birth rates.

Assisted Reproductive Technologies (ART) for Endometriosis-Related Infertility

ART, particularly IVF, is a well-established treatment for endometriosis-related infertility. It is often considered the first-line approach in cases of ovarian endometriomas to avoid potential surgical damage to ovarian reserve.

  • Indications for ART: ART is generally preferred for asymptomatic infertile patients over 35 years old or those with decreased ovarian reserve, other associated infertility factors, bilateral endometriomas, endometrioma recurrence, a history of previous endometriosis surgery, or failure of natural conception after surgery.
  • Ovarian Stimulation: Ovarian stimulation with GnRH agonists or antagonists can be performed safely in endometriosis patients, as it does not appear to increase the risk of disease progression or recurrence. While endometriosis patients may require higher doses of gonadotropins and may yield fewer oocytes, they can still achieve similar live birth rates compared to women without endometriosis if a sufficient number of high-quality embryos are obtained.
  • Elective Embryo Freezing: Some evidence suggests that elective embryo freezing and deferred frozen embryo transfer may improve cumulative pregnancy and live birth rates by mitigating the adverse effects of high estradiol levels during ovarian stimulation on endometrial receptivity.
  • Pelvic Infection Risk: While the overall risk is low, ovarian endometriomas may slightly increase the risk of pelvic infection and abscess formation after oocyte retrieval. Careful aseptic technique and antibiotics are recommended.

Fertility Preservation in Women with Endometriosis

Given the chronic nature of endometriosis and the potential for disease progression or surgical damage to ovarian reserve, fertility preservation (FP) strategies, particularly oocyte cryopreservation, have gained significant attention.

  • Feasibility and Effectiveness: Oocyte cryopreservation has proven feasible and successful for endometriosis patients, with comparable IVF outcomes (e.g., live birth rates) to those undergoing FP for other indications, provided an optimal number of oocytes are retrieved.
  • Key Factors for Success: Age and ovarian reserve are critical predictors of FP success. Younger patients and those with better ovarian reserve tend to have better outcomes.
  • Multiple Cycles: Due to potentially reduced ovarian reserve in endometriosis patients, multiple ovarian stimulation cycles may be required to obtain an adequate number of oocytes (at least 10 MII oocytes) for cryopreservation.
  • Surgical History Impact: Patients with a history of prior ovarian surgery for endometrioma tend to have fewer retrieved oocytes compared to those without previous surgery. However, the stage of endometriosis (I-IV) does not seem to significantly influence the number of cryopreserved oocytes.
  • Indications for FP: While no universal guidelines exist, proposed indications for FP in endometriosis patients include: age over 35, bilateral endometriomas (before surgery), history or risk of multiple surgeries, reduced preoperative ovarian reserve, ovarian endometrioma combined with reduced ovarian reserve, previous unilateral endometrioma surgery with contralateral recurrence, severe endometriosis diagnosis, or large endometriomas (>4 cm).
  • Preferred Method: Oocyte cryopreservation is considered the most suitable FP technique for post-pubertal endometriosis patients, as it does not require a male partner and has a low associated morbidity. Embryo cryopreservation requires a partner and raises ethical concerns. Ovarian tissue cryopreservation is not typically recommended for this benign condition, as it involves removing normal cortical tissue, but could be considered in very specific, severe cases.

Current Challenges and Future Directions

Despite increasing data, there is still a lack of international consensus and updated, evidence-based guidelines from scientific societies for managing endometriosis, particularly regarding the size threshold for surgery prior to IVF and specific indications for fertility preservation. This leads to significant variability in current practices, often influenced by individual practitioner expertise and training rather than solely by institutional setting.

There is a clear and strong need for future well-designed randomized controlled trials to compare surgical and medical treatment options, including the timing of interventions, to optimize fertility outcomes for women with endometriosis. Furthermore, the development of reliable, non-invasive diagnostic tools for endometriosis, such as salivary microRNA signatures, could revolutionize patient management by allowing earlier diagnosis and more tailored interventions. Ultimately, a personalized, multidisciplinary approach, carefully considering the patient’s symptoms, age, ovarian reserve, and reproductive goals, is essential to optimize outcomes.

General Considerations on Endometriosis and Infertility Endometriosis is a chronic, estrogen-dependent disease that affects approximately 10% of women of reproductive age globally and is associated with significant health costs. Common symptoms linked to endometriosis include pelvic inflammation, adhesions, chronic pain, dysmenorrhea, dyspareunia, and infertility. The underlying mechanisms by which endometriosis causes infertility, and how surgical intervention might improve IVF outcomes, are not yet fully understood. It is hypothesized that endometriosis:

  • Elevates inflammatory cytokines in the pelvic cavity, potentially impacting oocyte production, ovulation, fertilization, and implantation.
  • Increases oxidative stress, which could hinder IVF success.
  • Surgical intervention may restore normal pelvic anatomy, improving ovarian access during oocyte retrieval.
  • In some cases, pre-IVF surgery is essential to address hematosalpinx (blood in the fallopian tube), as tubal fluid entering the endometrial cavity can disrupt the local environment and affect embryo implantation.

Establishing a definitive link between endometriosis surgery and IVF outcomes is challenging due to the lack of randomized controlled trials (RCTs) specifically investigating this impact. Different manifestations of endometriosis (ovarian endometrioma, deep endometriosis, superficial endometriosis) often co-exist and are addressed concurrently during surgery, further complicating research.

Surgery for infertile women with endometriosis is indicated in specific scenarios:

  • When bowel nodules cause intestinal lumen stenosis and occlusive symptoms.
  • When ureteral stenosis due to endometriosis leads to hydronephrosis.
  • When ovarian endometriomas exhibit ultrasonographic features suggestive of malignancy.
  • When patients experience intolerable pain symptoms that cannot be managed by hormonal therapies, as these therapies are often contraceptive or interfere with conception.

Surgery is also frequently offered as an alternative to IVF, particularly for women who decline assisted reproductive techniques (ART). The decision for surgical excision as an infertility treatment should be individualized based on patient factors such as the intensity of pain symptoms, history of previous surgery, woman’s age, ovarian reserve, presence of large endometriomas, tubal patency, and semen analysis.

Surgery for Superficial/Peritoneal Endometriosis Superficial/peritoneal endometriosis involves endometrium-like tissue lesions exclusively on the peritoneal surface. Treatment typically involves excision or ablation.

  • The impact of surgery for superficial endometriosis on IVF outcomes is not clearly established.
  • Only one retrospective study (Opoien et al.) investigated this, suggesting that surgical eradication of minimal and mild endometriosis prior to IVF improved implantation, pregnancy, and live birth rates, and shortened the time to first pregnancy.
  • However, more data are needed to confirm the benefits of surgery for peritoneal disease in improving ART outcomes and to recommend it in routine practice.
  • The review concludes that it is unlikely that surgical treatment of peritoneal endometriosis can improve IVF outcomes.

Surgery for Ovarian Endometriomas (OMAs) The effect of endometriomas on ovarian function and female fertility is not fully elucidated, although the presence of an endometrioma does not appear to impair spontaneous ovulation in the affected ovary.

  • Surgical excision of ovarian endometriomas carries a significant risk of diminishing ovarian reserve. A meta-analysis showed a substantial 38% decline in Anti-Müllerian Hormone (AMH) levels postoperatively (from 3 ng/mL to 1.87 ng/mL). This decline was observed as 30% for unilateral cystectomy and 44% for bilateral cystectomy. While AMH levels may progressively recover, the damage occurs due to the mechanical removal of healthy ovarian cortex, coagulation of residual ovarian tissue, and inflammation/edema caused by surgery.
  • Compelling evidence from multiple systematic reviews and meta-analyses demonstrates that surgical treatment of endometriomas does not improve IVF outcomes, including live birth rates and clinical pregnancy rates.
  • Studies have shown similar live birth and clinical pregnancy rates in women with or without surgical treatment for endometriomas before IVF. However, some analyses indicated a lower total number of oocytes retrieved in the surgery group.
  • Therefore, the review emphasizes that surgical treatment of ovarian endometriosis may decrease ovarian reserve, especially with bilateral endometriomas or repeated surgical procedures, and it does not improve IVF outcomes. Pre-operative assessment by an expert sonographer is recommended to exclude malignancy risk.

Surgery for Deep Endometriosis (DE) Surgical excision of DE can be offered to infertile women to alleviate endometriosis-related pain and prevent rare complications like bowel occlusion or subocclusion and hydroureter/hydronephrosis during ovarian stimulation for IVF and pregnancy.

  • The impact of laparoscopic excision of DE on IVF outcomes remains controversial, and no randomized controlled trials have been conducted on this specific topic.
  • Studies on the time interval between surgery and IVF have shown no significant impact on outcomes whether surgery was performed within 6 months or between 6 and 60 months of oocyte retrieval.
  • Conflicting evidence from observational studies:
    • A Brazilian prospective study observed significantly higher implantation and pregnancy rates in patients who underwent extensive DE excision before IVF, despite a lower number of oocytes retrieved.
    • Conversely, a French cohort study found no significant differences in pregnancy and delivery rates among groups with complete excision, incomplete excision, or no surgery for DE.
    • Another French study indicated that prior colorectal surgery for endometriosis-associated infertility improved ICSI-IVF outcomes, with 55.5% of women with previous IVF failure achieving pregnancy after colorectal surgery.
    • However, other studies suggested that bowel infiltration negatively influences reproductive outcomes after IVF, with colorectal segmental resection linked to a lower conception rate.
    • A retrospective study on DE without digestive involvement concluded that surgery did not impact IVF outcomes.
    • One meta-analysis (Casals et al.) indicated that patients undergoing surgery before IVF for DE (with or without digestive involvement) had significantly higher pregnancy rates per patient, pregnancy rates per cycle, and live birth rates per patient.
    • However, another recent systematic review and meta-analysis (Bourdon et al.) found no statistically significant differences in ongoing pregnancy or live birth rates per cycle. After excluding high-bias studies, the live birth rate per cycle was significantly reduced in cases of surgical treatment before IVF/ICSI.

Conclusion on Deep Endometriosis Surgery and IVF

  • The literature on the role of DE surgery before IVF is scarce, with no randomized controlled trials available.
  • Based on current evidence, surgical excision of DE should not be offered as the first-line treatment for asymptomatic patients solely to improve IVF outcomes. This is due to the potential for severe complications (e.g., ureteral damage, pelvic abscess, intestinal suture leakage) that could delay subsequent infertility treatment.
  • Surgical treatment for DE may be necessary before IVF for patients who experience intolerable pain despite hormonal therapies, those at risk of bowel occlusion or subocclusion, or hydroureter/hydronephrosis during IVF and pregnancy. It may also be a suitable option for women who have failed prior multiple IVF treatments.
  • Future randomized controlled trials with adequate power and follow-up are required to define the role of DE surgery before IVF.

Practice Points and Research Agenda

  • For deep endometriosis, surgical excision is not recommended for asymptomatic patients to improve IVF outcomes, but it may be necessary for pain management or to prevent complications.
  • The impact of surgical excision of peritoneal endometriosis on IVF outcomes has not been thoroughly investigated.
  • There is solid evidence that surgical treatment of ovarian endometriomas does not improve IVF outcomes.
  • Future research should include randomized studies on DE and peritoneal endometriosis, differentiating outcomes by disease form.

Endometriosis and Infertility: A Complex Landscape Endometriosis is characterized as a systemic inflammatory disease commonly associated with pelvic pain and infertility. Its prevalence ranges from 2% to 10% in the general female population and extends to as high as 50% in women experiencing infertility. The mechanisms linking endometriosis to infertility are multifaceted, including:

  • An exacerbated inflammatory state in the uterus and ovaries.
  • Altered endometrial receptivity, ovarian reserve, and oocyte quality.
  • Mechanical distortion of pelvic anatomy due to adhesions and bilateral tubal blockage.
  • Progesterone resistance in the eutopic endometrium, leading to an estrogenic state that impairs implantation.

Historically, diagnostic laparoscopy was routinely performed for diagnosis and treatment in patients with suspected endometriosis and infertility. However, its use has declined due to mounting evidence suggesting that surgery for endometriosis does not consistently improve ART outcomes and carries the risk of further ovarian reserve impairment. Conversely, ART itself does not appear to worsen endometriosis symptoms or impact ovarian endometriomas or deep infiltrating endometriosis (DIE). Given this ongoing debate, determining which patients benefit from laparoscopic treatment to improve natural conception chances remains a challenge.

Study Design and Participants This retrospective observational study analyzed data from 200 patients who underwent laparoscopic surgery for endometriosis-related infertility between 2014 and 2020, with a follow-up period of up to two years. All included patients were aged 25 to 43 years, had symptoms and/or imaging findings consistent with endometriosis, and received a laparoscopic diagnosis of the condition. Exclusion criteria included other laparoscopic diagnoses, prior endometriosis surgeries, bilateral negative tubal patency, thrombophilia, recurrent abortion, and moderate/severe male factor infertility.

Patients were categorized into groups based on their fertility management strategy:

  • ART-p (ART immediately): 16.5% of patients opted for ART immediately after laparoscopic treatment.
  • Wait for Spontaneous Pregnancy: 83.5% of patients chose to wait for spontaneous conception. This group was further subdivided:
    • SP-p (Spontaneous Pregnancy): 71.8% of these patients achieved spontaneous pregnancy within 12 months of surgery.
    • NSP-p (Non-Spontaneous Pregnancy, requiring ART): 28.2% of these patients were unable to conceive spontaneously and subsequently required ART.

The revised American Society for Reproductive Medicine (rASRM) classification system was used to stage endometriosis based on direct visualization during laparoscopy, considering lesion depth, size, and adhesion type/extent. The Endometriosis Fertility Index (EFI) score, which predicts non-IVF pregnancy rates post-surgery, was also calculated.

Key Findings on Pregnancy Outcomes and Influencing Factors

  • Overall Spontaneous Pregnancy Rate: A significant finding was that, after surgery, 71.8% of patients who waited for spontaneous pregnancy successfully conceived naturally. This supports the notion that surgical treatment can increase spontaneous pregnancy rates.
  • Age and ART: Patients in the ART-p group were disproportionately older, especially those over 39 years. This suggests that factors associated with advanced age, such as lower ovarian reserve, likely influenced the decision for immediate ART.
  • Endometriosis Fertility Index (EFI) Score: Patients who underwent immediate ART (ART-p) had significantly lower EFI scores compared to both groups that waited for spontaneous pregnancy (SP-p and NSP-p). This indicates that other underlying factors, beyond endometriosis, might be at play in decisions for immediate ART. Interestingly, no significant difference in EFI scores was observed between the SP-p and NSP-p groups. The average EFI score in the study’s model was 7.27, ranging from 4 to 10.
  • Time to Achieve Pregnancy:
    • For those who achieved spontaneous pregnancy (SP-p), the average time to conception was 5.7 months.
    • The group that eventually required ART (NSP-p) took 1.8 times longer to achieve pregnancy since surgery (10.2 ± 3.7 months) compared to the SP-p group.
    • However, once ART was initiated for the NSP-p group, the time to pregnancy was similar to that of the SP-p group (4.9 ± 3.7 months). This suggests that earlier identification of patients who would ultimately need ART could significantly reduce their waiting time to conception.
  • ASRM Score and Tubal Quality: While no significant difference in ASRM scores was found between SP-p and NSP-p, the ART-p group tended to have higher ASRM scores (Stages III and IV). Tubal quality was the only studied variable that showed a significant difference between the SP-p and NSP-p groups, with a higher percentage of “regular” quality in the NSP-p group (22.8% vs. 8.5%, p<0.05).

Identifying Patients Who Need ART: The Decision Tree Model Recognizing that no single clinical variable could effectively predict which patients would require ART, the study developed a multivariate decision tree algorithm. This algorithm is specifically designed for patients under 40 years old, as they are most likely to benefit from ART. The model achieved 81.3% accuracy and 53.3% sensitivity on the study’s dataset.

The decision tree incorporates four key parameters:

  1. Time of infertility.
  2. Tubal quality.
  3. Age.
  4. ASRM score.

This algorithm offers a practical, clinic-friendly tool that can be used quickly without complex calculations. It complements the existing EFI score system, which is valuable for patients with poor prognoses, by specifically identifying those with good EFI scores who may still benefit from ART.

Implications and Future Directions The study’s findings support the role of surgical treatment for endometriosis in improving spontaneous pregnancy rates. However, it also highlights that laparoscopic surgery for endometriosis is not a definitive cure, with recurrence rates of 40-45% potentially interfering with future fertility. Therefore, early identification of patients who are likely to require ART after surgery is crucial to minimize the time to pregnancy and improve overall outcomes. The proposed decision tree algorithm could be a valuable tool in achieving this goal.

Further studies with larger patient cohorts and additional variables are recommended to refine and improve the accuracy of the decision tree. The ongoing discussion regarding the optimal management of endometriosis-associated infertility emphasizes the need for individualized treatment approaches based on patient characteristics and clinical factors.

Materials and Methods

  • Study Design and Setting This was a retrospective cross-sectional controlled study conducted at Bunda General Hospital and Morula IVF Jakarta Clinic, Indonesia, from January 2018 to December 2022.
  • Participants and Grouping
    • A total of 279 patients diagnosed with endometriosis underwent removal surgery at Bunda General Hospital.
    • Among these, 86 couples with histologically confirmed endometrioma proceeded with an IVF program.
    • These 86 women were divided into two main groups based on the timing of surgery relative to IVF:
      • IVF-OPS (IVF prior to endometrioma removal surgery): 48 women. In this group, all embryos from IVF cycles were cryopreserved, followed by surgery, and then embryo transfer in frozen cycles.
      • OPS-IVF (Endometrioma removal surgery followed by an IVF program): 38 women.
    • Control Group: An additional group of patients diagnosed with endometriosis and endometrioma, who underwent IVF without a history of surgical removal, was included for comparison. For the control group, endometriosis diagnosis was confirmed through ultrasound by a certified fertility specialist, while for IVF-OPS and OPS-IVF groups, it was confirmed via pathology histological report.
  • Inclusion/Exclusion Criteria (Implicit in study parameters) The study focused on patients with confirmed endometrioma undergoing IVF. Data was retrieved from clinic databases.
  • IVF Protocols and Procedures
    • Participants underwent various ovarian stimulation protocols: antagonist, agonist long protocol, and mild stimulation.
    • Gonadotropins (Gonal-F, Pergoveris, Menopur) were used, with starting doses from 150 to 375 IU.
    • Ovum pick-up (OPU) was performed 36–38 hours after maturation injection.
    • All retrieved mature oocytes were fertilized via intracytoplasmic sperm injection (ICSI) or intra-morphologically selected sperm injection (IMSI).
    • Embryo culture was performed in a time-lapse incubator, and embryo transfer occurred at either the cleavage or blastocyst stage.
  • Endometriosis Surgery Procedures
    • Surgeries were conducted by fertility specialists certified in advanced laparoscopy and robotic minimally invasive surgeries, with over 10 years of experience.
    • Laparoscopic and robotic surgeries were performed under general anesthesia.
    • Adhesiolysis and peritoneal endometriosis were completely excised using electrocautery or Harmonic ultrasonic instruments.
    • Endometriosis cysts were removed using the stripping technique. All removed samples were sent for histopathology.
  • Outcomes Measurement and Statistical Analysis
    • The primary outcome measured was the clinical pregnancy rate, defined as the detection of at least a single fetal heartbeat via ultrasound.
    • Clinical pregnancy for OPS-IVF and control groups was calculated in fresh embryo transfer cycles, while for IVF-OPS, it was from frozen cycles as most embryos were frozen.
    • Statistical analysis utilized SPSS software (version 26.0) using Mann–Whitney or Kruskal–Wallis for numerical data, and Chi-Square for categorical data, with a significance level set at p < 0.05.

Key Findings

  • Baseline Characteristics
    • Female age, infertility duration, and proportion of infertility types were comparable across the three groups.
    • Body Mass Index (BMI) was significantly lower in the OPS-IVF group compared to the control group (p = 0.038).
    • Basal hormone levels (FSH, LH, estradiol, progesterone), antral follicle count (AFC), ovarian stimulation protocol, starting gonadotropin dosage, total gonadotropin usage, and endometrial thickness were comparable among groups.
    • Ovarian stimulation duration significantly differed among the groups. The OPS-IVF group had a longer stimulation duration compared to the IVF-OPS group.
    • Anti-Müllerian Hormone (AMH) levels significantly differed: OPS-IVF showed lower levels compared to IVF-OPS and the control group when measured after removal surgery (p < 0.05).
    • The median size of endometrioma in the control group was significantly smaller than in both surgery groups, explaining why surgery was not prioritized for controls.
  • Clinical Pregnancy Rate
    • The overall clinical pregnancy rate did not significantly differ among the three groups (IVF-OPS: 50%; OPS-IVF: 26.3%; Control: 34.7%; p = 0.068).
    • However, a subgroup analysis showed a noteworthy clinical pregnancy rate difference between IVF-OPS (50%) and OPS-IVF (26.3%) groups (p = 0.029).
    • After adjusting for AMH levels, the difference between IVF-OPS and OPS-IVF remained significant (p = 0.041, OR 2.73, 95% CI 1.04–7.17).
  • Laboratory Outcomes
    • The study found no overall differences in the number of retrieved oocytes or total embryos transferred among all groups.
    • However, significant differences were observed in:
      • Number of injected and fertilized oocytes.
      • Number of embryos at both cleavage and blastocyst stages.
      • Number of top-quality cleavage and blastocyst stages.
    • Overall, IVF laboratory outcomes were comparable between the IVF-OPS and control groups, but favorable for IVF-OPS compared to the OPS-IVF group (p < 0.05).
    • Specifically, the number of cleavages and blastocysts, as well as top-quality cleavages and blastocysts, was significantly higher in the IVF-OPS group compared to both OPS-IVF and control groups.

Discussion and Implications

  • Favorable Timing for Surgery The study suggests that performing IVF before endometrioma removal surgery (IVF-OPS) yields more favorable IVF outcomes, including a significantly better clinical pregnancy rate compared to surgery first (OPS-IVF). The IVF-OPS strategy involved cryopreserving all embryos from IVF cycles, followed by surgery, and then frozen embryo transfer after approximately three months.
  • Impact on Ovarian Reserve and Oocyte Quality
    • Endometriosis is known to reduce ovarian reserve due to the toxic inflammatory microenvironment within endometriotic cysts, which can damage ovarian tissue and follicles.
    • Surgical removal of endometriomas, while theoretically beneficial by creating a more favorable environment, was consistently associated with reduced ovarian reserve, as reflected by lower AMH levels after surgery in the OPS-IVF group. This reduction is attributed to the inadvertent removal of healthy ovarian tissue, thermal damage during hemostasis, and vascular compromise.
    • Lower AMH levels were presumed to lead to a downregulation of growth differentiation factor-9 (GDF9) and bone morphogenetic protein-15 (BMP15), crucial for oocyte maturation, potentially explaining the lower number of injected and fertilized oocytes in the OPS-IVF group.
  • Controversy of Surgery for IVF Outcomes The benefit of surgical intervention for endometriosis in improving IVF outcomes remains debated. While some reports indicate that endometrioma removal does not enhance IVF results, this study’s findings suggest a benefit of timing the surgery after oocyte retrieval.
  • Higher Embryo Quality in IVF-OPS The significantly higher number of top-quality cleavages and blastocysts in the IVF-OPS group is attributed to the unaltered AMH level in this group during oocyte retrieval, as their surgery occurred after IVF stimulation and oocyte collection.
  • Overall Recommendation The study concludes that opting for IVF prior to endometrioma removal surgery results in a more favorable IVF outcome compared to endometrioma removal followed by an IVF program. This is particularly important for women with already diminished ovarian reserve.

Limitations The study acknowledges several limitations, including:

  • The retrospective cross-sectional design.
  • The non-exclusion of women with irregular menstruation or hydrosalpinx, which could influence results due to coexisting conditions.
  • AMH levels in the OPS-IVF group were measured after surgery, so their pre-surgical levels were unknown, making it difficult to fully assess the surgical impact on ovarian reserve compared to baseline.

What this study adds to clinical work:

  • Performing surgery after the IVF program (IVF-OPS) yields better outcomes, highlighting the importance of timing in surgical intervention for endometrioma patients undergoing IVF.
  • Surgery before IVF (OPS-IVF) results in poorer embryology lab outcomes, suggesting it may be less effective for improving fertility outcomes.

Overview of Minimal/Mild Endometriosis (MME) and Infertility:

  • Definition and Prevalence: Endometriosis is a common gynecological disease affecting approximately 1 in 10 reproductive-aged women, characterized by ectopic endometrium-like tissue leading to chronic inflammation. It’s often linked with pelvic pain and/or infertility. MME (rASRM stage I/II) is believed to be present in 15% to 50% of endometriosis patients. Fecundity rates in couples with untreated endometriosis range from 2% to 10%, compared to 15-20% in those without documented infertility.
  • Diagnosis: Despite advances in non-invasive tests, diagnostic laparoscopy remains the gold standard for MME diagnosis, offering histological confirmation.
  • Mechanisms of Infertility: Reduced fecundity in MME may stem from various mechanisms:
    • Pain: Increased risk of deep dyspareunia, leading to reduced coital frequency.
    • Inflammatory Microenvironment: MME lesions increase production of chemokines, cytokines, and prostaglandins, causing chronic inflammation and oxidative stress. This negatively impacts oocyte quality and ovarian reserve (“oocyte aging”), and impairs implantation and early embryonic development. High levels of activated macrophages and growth factors also exert toxic effects on sperm.
    • Uterine Dysfunction: Uterine dysperistalsis may compromise rapid sperm transport.
    • Ovarian/Follicular Abnormalities: MME can lead to prolonged follicular phases, reduced follicular growth, impaired LH surge, altered hormone secretion, and luteinized unruptured follicles (LUF). There’s also a suggested risk of aneuploid gamete formation.
    • Endometrial Receptivity: Women with endometriosis may have reduced endometrial receptivity, evidenced by decreased expression of implantation markers (e.g., αvβ3 integrin, glycodelin A) and altered gene expression leading to progesterone resistance. Chronic endometritis has also been linked to lower pregnancy rates in MME patients.

Role of Laparoscopic Surgery in MME-Related Infertility:

  • Rationale: Surgical management of MME aims to minimize the deleterious effects of peritoneal implants by removing or destroying them, thereby reducing local and systemic inflammation. If adhesions are present, adhesiolysis is performed to restore normal pelvic anatomy, which can also negatively impact fertility. Laparoscopy is preferred over laparotomy due to better visualization and minimal access benefits.
  • Evidence on Spontaneous Conception:
    • The European Society of Human Reproduction and Embryology (ESHRE) weakly recommends operative laparoscopy for rASRM stage I/II endometriosis as it improves natural, ongoing pregnancy rates, despite limited data on live birth rates or comparison with medically assisted reproduction (MAR).
    • Some randomized controlled trials (RCTs) showed that laparoscopic surgery for MME significantly increased cumulative pregnancy rates (e.g., ENDOCAN study: 30.7% vs. 17.7% in diagnostic laparoscopy group), though overall rates remained low. Other studies found no significant difference in post-operative natural conception rates.
    • The Number Needed to Treat (NNT) for MME laparoscopy to achieve an additional pregnancy is at least 12, potentially increasing to 40 if undiagnosed cases of MME in unexplained infertility are included. In contrast, IVF has an NNT of around 4.
    • The Endometriosis Treatment Italian Club (ETIC) strongly recommends not performing surgery solely for diagnosing and treating superficial endometriosis in asymptomatic infertile patients. However, if pelvic pain co-exists with infertility, operative laparoscopy is justified for both symptom alleviation and fertility enhancement.
    • Some guidelines (CNGOF, NICE, WES, S2k, ACOG, ASRM) suggest considering surgical management for suspected MME and infertility.
    • Regarding surgical technique, there is no robust evidence favoring ablation over excision of MME lesions for enhancing fertility, though radical excision by a skilled surgeon may yield high pregnancy rates. Post-operative recurrence is a concern, with rates estimated up to 21.5% at 2 years and 40-50% at 5 years.
  • Medical Therapy in relation to Surgery:
    • Pre-operative hormonal treatment to suppress inflammation is theoretically appealing but carries a risk of making lesions invisible. Its clinical benefit is not demonstrated, and ESHRE guidelines do not recommend it for conception purposes.
    • Post-operative GnRH agonists have not consistently shown beneficial effects on spontaneous or IVF pregnancy rates.
    • Post-operative Controlled Ovarian Stimulation (COS) with Intrauterine Insemination (IUI) may be considered within 6 months after surgical management of stage I/II endometriosis, as it might improve pregnancy rates.

Laparoscopy vs. Other Fertility Modalities for MME:

  • Expectant Management: About 50% of MME patients may conceive spontaneously without intervention. However, some studies suggest MME patients have a lower probability of pregnancy than those with unexplained infertility and normal pelvis.
  • COS with IUI: ESHRE weakly recommends COS with IUI over expectant management or IUI alone for infertile women with rASRM stage I/II endometriosis, as it increases pregnancy rates.
  • Laparoscopy vs. Medical Management: One prospective study found no significant difference in cumulative pregnancy rates between MME patients undergoing surgical ablation/resection and those receiving diagnostic laparoscopy followed by GnRH agonist treatment, but both groups had higher rates than diagnostic laparoscopy alone.

Impact of MME on IVF Outcomes:

  • Fertilization and Implantation: Meta-analyses show MME is associated with a reduction in fertilization rate (7-21%) and early implantation processes, but may not significantly impact clinical pregnancy or live birth rates. In contrast, severe endometriosis negatively affects all reproductive stages.
  • Oocyte/Embryo Quality: When high-quality euploid embryos are transferred in medicated frozen embryo transfer cycles, women with endometriosis generally do not show marked defects in endometrial receptivity.
  • Pre-IVF Medical Treatments: ESHRE guidance does not recommend prolonged GnRH agonist or combined contraceptive/progestogen use before planned IVF for MME, as evidence for increased live birth rates is lacking.

Role of Laparoscopic Management of MME Prior to ART (IVF):

  • General Recommendation: The most recent ESHRE guideline does not recommend routine surgery prior to ART for MME to enhance live birth rates, due to a lack of high-quality evidence.
  • Conflicting Evidence: While one retrospective study linked surgical ablation of MME prior to ART with improved reproductive outcomes (e.g., higher implantation, pregnancy, and live birth rates, shorter time to first pregnancy), a very recent meta-analysis indicated that surgery for endometriosis before IVF does not impact ongoing pregnancy or early pregnancy loss rates, and may even result in lower live birth rates in higher quality studies.

Future Role of Non-Invasive Diagnosis:

  • The development of reliable, widely available, and inexpensive non-invasive tests for MME diagnosis is crucial to reduce the need for diagnostic laparoscopies.
  • Given the high prevalence of MME in patients with unexplained infertility and the positive impact of laparoscopic management on fecundity, such tools could revolutionize the management of unexplained infertility, allowing for targeted laparoscopic intervention and potentially reducing the reliance on medically-assisted reproduction.

Conclusion of the Source:

  • Laparoscopic management of MME can enhance fecundity and spontaneous conception rates in appropriately selected cases.
  • However, routine laparoscopy for asymptomatic, infertile women solely to diagnose and manage MME is not recommended due to lack of strong evidence.
  • Similarly, laparoscopic management of MME cannot be routinely recommended prior to ART to solely enhance fertility outcomes, as strong beneficial evidence is lacking.
  • Treatment decisions should be individualized, considering patient preference, age, symptoms, ovarian reserve, and past surgical history.
  • If surgery is performed, it should be done by appropriately trained clinicians to fully eradicate the disease while minimizing trauma.
  • Future research needs to provide solid evidence on the impact of MME and its surgical management on fertility outcomes, with clear differentiation between disease stages and phenotypes. The development of reliable non-invasive diagnostic tools for MME is anticipated to significantly impact decision-making for these patients.

This investigation was motivated by the ongoing debate and the absence of international consensus on the optimal approach for these patients. Large endometriomas pose unique challenges due to associated pain and potential interference with follicle accessibility during oocyte retrieval, while surgery to remove them can unfortunately diminish ovarian reserve and responsiveness to gonadotropins.

Methodology The study was designed as a cross-sectional online survey.

  • Distribution and Participants: The survey was disseminated via email to an estimated 410 gynecologists through professional societies in various European countries (France, Switzerland, Italy), as well as through the European Endometriosis League (EEL). A total of 111 specialists completed the survey, resulting in a 27.8% response rate. Importantly, all participants who accessed the survey link completed it in full, indicating a 100% completion rate for analyzed responses.
  • Participant Characteristics:
    • The majority of respondents (73%) practiced in academic settings, with 13.5% in private practice and 13.5% in public hospitals.
    • A significant proportion (61%) had more than 15 years of clinical experience, with 29.7% having over 25 years.
    • Clinical activities varied: 14.4% focused solely on IVF, 47.7% on surgery only, and 31.5% performed both IVF and endometrioma surgery.
  • Survey Content: The survey consisted of 18 multiple-choice questions. These questions covered:
    • Clinical experience and type of prevalent medical practice.
    • Geographic location and institutional affiliation.
    • Prevailing practices concerning the evaluation of Anti-Müllerian Hormone (AMH) levels (both before and after surgery).
    • Whether management strategies are modified based on AMH levels (e.g., more conservative methods for very low AMH).
    • The use of hormonal treatment before and after surgery.
    • The threshold size (diameter in mm) of endometrioma for which surgery is typically recommended prior to IVF.
    • Specific management approaches for very large endometriomas (>10 cm) before IVF.
    • The type of surgical procedure commonly performed or advised, and interest in adopting new technologies like CO2 laser or plasma energy devices.
    • The time span between surgery and the initiation of the first ovarian stimulation for IVF.
    • Perceived need for updated guidelines from scientific societies to improve management in this specific clinical scenario.
  • Data Collection and Analysis: Responses were collected anonymously using SurveyMonkey and analyzed using SPSS version 29.0.2.0. Statistical methods included median and interquartile range (IQR) for continuous variables, frequencies and percentages for categorical variables, Mann-Whitney U tests for non-normally distributed group comparisons, and multivariable linear/logistic regression models to examine associations.
  • Ethical Considerations: The IRB Board (CER-VD) determined that the data collection was outside the scope of the Swiss Human Research Act (HRA) and did not require authorization, as the study involved no human subjects and was solely a survey of practices.

Key Findings on Management Practices

  1. Threshold Size for Surgery:
    • The median threshold size for recommending surgery prior to IVF was 50 mm (interquartile range [IQR] 40–60 mm). Responses for this threshold ranged widely, from 20 mm to 101 mm.
    • Surgeons who primarily perform laparoscopic surgery tended to recommend intervention for significantly smaller endometriomas. Their distribution of thresholds was notably narrower (IQR 40–60 mm) compared to practitioners not primarily performing such surgery (IQR 47–89 mm), indicating a significant effect (β = −15.72, 95% CI = −27.95 to −3.49, p = 0.006). This suggests that training background and clinical focus significantly influence decision-making.
    • The practice setting (academic vs. private) did not significantly impact these decisions, with similar median thresholds observed (52 mm vs. 50 mm, p = 0.479).
    • Practitioners using ultrasound-guided cyst drainage showed a non-significant tendency toward a higher threshold size (median 55 mm, IQR 33–85).
  1. Types of Surgery Performed/Advised:
    • Laparoscopic cystectomy remained the most common procedure, accounting for 48.2% of all reported interventions. This is despite its known risks of significant ovarian tissue loss and reduced ovarian reserve.
    • Other methods included laparoscopic combination of cystectomy and ablation using CO2 laser or plasma energy devices (12.5%), laparoscopic alcohol sclerotherapy (3.6%), and ultrasound-guided cyst drainage (2.7%).
    • While laparoscopic cystectomy was predominant, IVF experts tended to perform fewer cystectomies (39.1% vs. 48.9%, p = 0.046) and opted more for other techniques, such as ultrasound-guided cyst drainage (10.9%).
    • A notable 40.5% of participants indicated they would change their practice if a CO2 laser or plasma energy device were available in their surgical armamentarium. These advanced techniques are seen as promising alternatives due to their potential to minimize ovarian damage and maintain comparable recurrence rates.
  1. Management of Large Endometriomas (>10 cm):
    • For endometriomas larger than 10 cm, 41.4% of specialists perform a laparoscopic cystectomy.
    • Other approaches include laparoscopy with alcohol sclerotherapy (9.9%).
    • 8.1% of specialists preferred not to intervene at all, believing that IVF could be performed without prior size-reducing surgery for such large endometriomas. This finding indicates significant variability in practice for extremely large cysts.
  1. Perioperative Hormonal Treatment:
    • The majority of participants (53.2%) typically do not administer hormonal treatment before endometrioma surgery. Among those who do, progestins are the most common choice (65.4%).
    • However, a large majority (86.5% would initiate hormonal treatment after surgery). Progestins were again the most commonly prescribed (48.4%), followed by combined estrogen-progestin contraceptives (22.6%). A significant number (29%) also used other forms, including GnRH agonists.
  1. Perioperative Measurement and Influence of AMH Levels:
    • Most participants (80.2% measured AMH before surgery, and 61.3% measured it after surgery).
    • A significant majority of participants (67.9%) modified their management strategy based on preoperative AMH levels. This often involved considering more conservative methods or even no surgery for patients with very low AMH levels.
    • Measuring AMH before surgery was significantly associated with a higher likelihood of performing both IVF and laparoscopy, with respondents who measure AMH being about 5 times more likely to perform both procedures (OR=5.09, 95% CI: 1.1–23.2, p < 0.05). This indicates the perceived importance of AMH in guiding combined management decisions.
  1. Timing of Ovarian Stimulation Post-Surgery:
    • The median timing for initiating ovarian stimulation for IVF after endometrioma management was 6 weeks (IQR 4–8 weeks).
    • Despite this median, the timing showed wide variability, which the authors suggest highlights the need for individualized treatment plans based on patient response and recovery, and is influenced by personal experience in the absence of solid evidence on ovarian recovery principles.
  1. Need for Updated Guidelines:
    • A large majority of surveyed gynecologists (88.3%) expressed that updated guidelines from scientific societies are necessary to improve the management of endometriomas before IVF.
    • More experienced practitioners (those with more years of Ob/Gyn clinical experience) were significantly more likely to emphasize this need (OR = 2.00, 95% CI [1.16–3.44], p = 0.012).
    • There was no significant association found between the belief in the necessity of updated guidelines and specific clinical practices, such as the use of advanced surgical tools, hormonal treatment protocols, or AMH testing. This highlights a broad recognition of knowledge gaps and the desire for clear, evidence-based recommendations.

Conclusion of the Survey Document The study concludes that the management of large endometriomas prior to IVF involves a delicate balance between the potential benefits of surgery and the inherent risks to ovarian reserve. The survey highlights significant variability in current practices, which are influenced more by individual practitioner expertise and training than by the institutional setting (academic vs. private). While laparoscopic cystectomy remains the predominant surgical procedure, despite its documented association with ovarian tissue loss, there is a clear interest in adopting advanced, potentially less damaging techniques such as CO2 laser ablation and plasma energy devices. The findings collectively underscore a clear and strong need for updated, evidence-based guidelines from scientific societies to standardize and improve management practices, ultimately aiming to optimize fertility preservation and clinical outcomes for women with large endometriomas undergoing IVF.

Limitations of the Study The authors acknowledge several limitations, including:

  • Its survey-based design, which relies on self-reported practices and may therefore introduce response bias, potentially not fully reflecting actual clinical behavior.
  • A response rate of 27.8%, which, while within acceptable ranges for survey studies, might limit the generalizability of the findings, as non-respondents could hold different practices or perspectives.
  • Its primarily descriptive nature, aiming to provide an overview of current practices rather than establishing causal relationships or evaluating clinical outcomes.
  • Potential for incomplete capture of regional or institutional variability, as the majority of respondents practiced in academic settings.

Podcast

Course outline :
Does Pre-IVF Surgery Improve Outcomes in Women with Endometriosis?

  • What is Endometriosis?
    • A chronic, estrogen-dependent inflammatory disease characterized by the presence of endometrial tissue outside the uterus.
    • Affects approximately 5–10% of reproductive-aged women worldwide.
    • Commonly associated with pelvic pain, dysmenorrhea, dyspareunia, and infertility.
  • Endometriosis and Infertility:
    • Infertility is a major concern, affecting 30–50% of women with endometriosis.
    • Endometriosis accounts for about 10% of patients undergoing ART (Assisted Reproductive Technology) treatments.
  • The Core Question: The choice between surgical treatment and In Vitro Fertilization (IVF) for endometriosis-related infertility is complex and often debated, with limited clear guidance.
  • Session Objectives: By the end of this session, participants will be able to:
    • Understand the complex relationship between endometriosis, infertility, and IVF.
    • Differentiate the impact of pre-IVF surgery on outcomes based on endometriosis type (Ovarian Endometriomas, Deep Infiltrating Endometriosis, Minimal/Mild Endometriosis).
    • Identify the risks and benefits associated with surgical intervention before IVF.
    • Recognize the importance of individualized patient management and counseling in decision-making.
    • Discuss current guidelines and areas of ongoing debate regarding pre-IVF surgery.
  • Multifactorial Mechanisms Contributing to Infertility:
    • Inflammatory Mediators in Peritoneal Fluid: Can affect oocyte release and quality. An altered peritoneal microenvironment also impacts tubal ciliary beat frequency.
    • Adhesions: Disrupt pelvic anatomy and tubal function, hindering gamete and embryo transport.
    • Ovarian Endometriomas (OMAs): Directly affect folliculogenesis, reducing ovarian function and reserve. Cyst fluid contains toxic substances like free iron and reactive oxygen species (ROS), leading to oxidative stress, fibrosis, and follicular damage.
    • Impaired Endometrial Receptivity: Altered hormonal and cell-mediated functions in the eutopic endometrium, including progesterone resistance, can compromise embryo implantation.
    • Altered Oocyte/Embryo Quality: Some studies suggest reduced oocyte quality and abnormal embryo morphology in women with endometriosis, although conflicting data exist.
    • Dyspareunia: Chronic pelvic pain and dyspareunia can make intercourse difficult, directly affecting conception attempts.
    • Diminished Ovarian Reserve (DOR): Clinically evaluated by Anti-Müllerian Hormone (AMH) levels and Antral Follicle Count (AFC). Endometriosis itself can reduce AMH levels and accelerate their decline.
  • Prevalence: OMAs are found in up to 44% of women with endometriosis.
  • Impact of OMAs on Ovarian Function and IVF:
    • OMAs can reduce the number of mature oocytes retrieved during IVF. The reduction is greater with large or bilateral endometriomas.
    • However, meta-analyses consistently show no significant difference in clinical pregnancy rates or live birth rates in women with OMAs undergoing IVF compared to controls or women with untreated OMAs.
  • Impact of Surgical Intervention on Ovarian Reserve:
    • Surgical removal of OMAs (cystectomy) carries a significant risk of diminishing ovarian reserve.
    • A meta-analysis reported a 38% decline in AMH levels post-operatively, with a 30% reduction for unilateral and 44% for bilateral cystectomies.
    • There is a reported risk of premature ovarian insufficiency (POI) of 2.4–13% following endometrioma removal.
    • Damage mechanisms include inadvertent removal of healthy ovarian tissue, thermal damage during hemostasis or ablation, and vascular compromise.
    • Repeated ovarian surgery has a detrimental effect on ovarian function and reduces pregnancy chances.
  • Indications for Pre-IVF Surgery for OMAs (Limited):
    • Current guidelines primarily recommend surgery for OMAs prior to ART only for pain management, to address potential malignancy, or to improve the accessibility of follicles for oocyte retrieval.
    • Surgery is not routinely recommended to improve IVF outcomes or prevent disease progression.
  • Timing of IVF and Surgery:
    • A recent study suggests that performing IVF before surgery (IVF-OPS) may yield better clinical pregnancy outcomes and embryology laboratory outcomes (e.g., higher number of top-quality blastocysts) compared to surgery before IVF (OPS-IVF).
    • This is potentially because OPS-IVF is associated with lower AMH levels after surgery.
  • Surgical Techniques and Practices:
    • Laparoscopic cystectomy is the most common procedure (48.2% of surveyed specialists). However, it is associated with significant ovarian tissue loss.
    • Techniques like CO2 laser ablation and plasma energy are being explored to minimize ovarian damage.
    • The median threshold size for surgery among specialists is 50 mm. There is significant variability in practices and a high demand for updated guidelines.
  • Prevalence and Locations: The posterior compartment (e.g., uterosacral ligaments, cul-de-sac, rectovaginal septum, rectum) is most frequently affected by DIE.
  • Does Surgery Improve IVF Outcomes?
    • The evidence regarding the benefit of surgical excision of DIE on IVF outcomes is conflicting.
    • Some meta-analyses suggest that surgery for DIE prior to IVF may offer benefit in terms of higher pregnancy rates per patient, pregnancy rates per cycle, and live birth rates per patient, including for DIE with and without digestive involvement.
    • However, other high-quality studies and meta-analyses found no significant difference or even lower live birth rates in women who underwent surgery before IVF compared to those who did not.
  • Indications for Surgery (primarily symptoms/complications):
    • Surgery for DIE is primarily indicated for intolerable pain symptoms (e.g., chronic pelvic pain, dyspareunia), to address the risk of organ obstruction (e.g., bowel occlusion, hydronephrosis), or after repeated IVF failures.
    • It is not generally recommended as a first-line treatment for asymptomatic patients solely to improve IVF outcomes due to insufficient evidence and the potential for severe complications.
  • Complications: Surgery for DIE can be complex and carries a significant risk of post-operative complications (e.g., ureteral damage, pelvic abscess, intestinal leakage), which can delay subsequent infertility treatment.
  • Research Gap: There is a lack of randomized controlled trials (RCTs) directly comparing surgery for DIE before IVF with IVF alone. Two ongoing clinical trials (ENDO-FERT and SVIDOE) aim to address this.
  • Mechanisms of Infertility: MME can reduce fertility through inflammation, oxidative stress, uterine dysperistalsis, altered ovarian follicular development, and reduced endometrial receptivity.
  • Impact on Natural Conception:
    • Some randomized controlled trials indicate that laparoscopic excision or ablation of MME lesions can increase natural pregnancy rates compared to diagnostic laparoscopy alone.
    • However, the “number needed to treat” (NNT) to achieve an additional pregnancy is high (estimated at 12–40).
  • Impact on IVF Outcomes:
    • While some early meta-analyses suggested MME might reduce fertilization rates or affect early implantation processes, later studies and meta-analyses found no significant difference in implantation, clinical pregnancy, or live birth rates compared to controls or women with other causes of infertility.
    • A single retrospective study by Opøien et al. found improved IVF outcomes when surgical removal of MME preceded IVF. However, this finding has not been consistently replicated by higher-quality studies, and some recent meta-analyses suggest no benefit or even lower live birth rates after surgery for MME prior to IVF.
  • Recommendations for Surgery:
    • Routine laparoscopy is not recommended in asymptomatic infertile women solely to diagnose and manage MME due to lack of robust evidence for improving ART outcomes and the invasiveness of the procedure.
    • However, if pelvic pain coexists with infertility, operative laparoscopy may be considered for symptom alleviation and potential fertility enhancement.
    • The sources indicate that no previous study has investigated the direct impact of surgical excision of peritoneal endometriosis on the outcomes of IVF.
  • Individualized Approach: There is no universal guideline for combining surgery and IVF in endometriosis-related infertility. Treatment strategies must be individualized based on:
    • Patient’s wishes and preferences.
    • Age (older patients might prefer IVF for quicker conception).
    • Symptomatology (presence and severity of pain, dyspareunia).
    • Type and extent of endometriosis lesions (e.g., OMA size, DIE involvement).
    • Ovarian reserve (AMH, AFC).
    • Previous surgical history (repeated surgery is detrimental).
    • Other infertility factors (e.g., tubal patency, male factor, adenomyosis).
    • Duration of infertility.
    • Endometriosis Fertility Index (EFI).
  • Fertility Preservation (Oocyte Cryopreservation):
    • Is a feasible and successful option for women with endometriosis.
    • Crucial before surgery that might damage ovarian reserve, especially in cases of bilateral endometriomas or recurrent surgery.
    • Multiple ovarian stimulation cycles may be required due to reduced ovarian reserve in these patients.
    • Age and ovarian reserve are key predictors of success. If an adequate number of oocytes are retrieved, IVF outcomes are comparable to those in patients without endometriosis.
  • Non-Surgical Management:
    • IVF itself does not appear to increase disease progression or recurrence in deep endometriosis patients.
    • Pre-treatment with GnRH analogues or aromatase inhibitors before IVF has been investigated, but their benefit on IVF outcomes is not consistently proven and can carry concerns.
    • Elective embryo freezing and deferred frozen embryo transfer may improve cumulative pregnancy rates by mitigating adverse effects of high estradiol levels during ovarian stimulation.
  • Emotional and Psychological Impact: Endometriosis-related infertility imposes significant emotional and financial stress. Patient counseling and shared decision-making are vital, acknowledging the patient’s lived experience and perceptions.
  • Surgeon Expertise: The experience of a “dedicated endometriosis” surgeon plays a critical role in preserving ovarian function and optimizing outcomes.
  • Key Takeaways:
    • For Ovarian Endometriomas (OMAs), pre-IVF surgery is not routinely recommended to improve IVF outcomes and carries a significant risk of damaging ovarian reserve. It is reserved for pain management, malignancy concerns, or improving follicular accessibility. IVF before surgery may be preferable for outcomes.
    • For Deep Infiltrating Endometriosis (DIE), the evidence for improving IVF outcomes with surgery is conflicting. Surgery is primarily indicated for symptom relief or to prevent complications (e.g., organ obstruction) rather than solely for fertility enhancement.
    • For Minimal/Mild Endometriosis (MME)/Superficial Peritoneal Endometriosis (SPE), while surgery can improve natural conception rates in selected cases, there is no strong evidence to support routine surgery prior to ART to improve IVF outcomes.
    • Individualized management is paramount, considering patient age, symptoms, ovarian reserve, previous surgical history, and other infertility factors.
    • Fertility preservation (oocyte cryopreservation) is a viable and important option for many women with endometriosis, especially those with high risk of ovarian reserve damage or prior to surgery.
  • Future Research: More high-quality, randomized controlled trials are needed across all endometriosis phenotypes to provide definitive answers on the role of surgery before IVF.
  • Questions & Discussion

Slides for the Powerpoint Presentation

Slide 1: Combine Surgery and In Vitro Fertilization (IVF) in Endometriosis-Related Infertility: When and Why

    • Exploring the complex interplay between endometriosis, infertility, and treatment strategies.
    • A review of current evidence to guide tailored management in clinical practice.

Slide 2: Endometriosis: A Chronic Inflammatory Disease

    • Endometriosis is a chronic, estrogen-dependent inflammatory disease characterized by the presence of endometrial tissue outside the uterus.
    • It affects approximately 5–10% of reproductive-aged women, with a prevalence up to 10% in the general population.
    • Common symptoms include pelvic pain and infertility.
    • The pathogenesis is multifactorial, involving retrograde menstruation, coelomic metaplasia, lymphatic/vascular spread, immune system dysfunction, genetic factors, and environmental influences.
    • Characterized by local hypoestrogenism, progesterone resistance, and an enhanced proinflammatory microenvironment.
    • Recognized phenotypes include superficial peritoneal endometriosis (SUP), deep endometriosis (DE), and ovarian endometrioma (OMA).

Slide 3: How Endometriosis Compromises Fertility

    • Inflammatory mediators in the peritoneal fluid affect oocyte release and quality.
    • Development of adhesions disrupts pelvic anatomy and tubal function.
    • Endometriomas (OMAs) detrimentally affect folliculogenesis and ovarian function, potentially through mechanical stretching or toxic effects of cyst fluid (rich in free iron, reactive oxygen species leading to oxidative stress, fibrosis, follicular damage).
    • Impaired endometrial receptivity due to altered hormonal response, gene expression, and chronic inflammation.
    • Chronic pelvic pain and dyspareunia (superficial and deep) complicate intercourse, affecting desire, frequency, arousal, and orgasm.
    • Diminished ovarian reserve (clinically evaluated by Antral Follicle Count [AFC] and Anti-Müllerian Hormone [AMH] levels) is a pivotal factor, exacerbated by endometriosis itself and advancing age.
    • The average delay of 7 years to diagnosis is critical for women facing infertility, as combined effects severely compromise pregnancy chances.

Slide 4: Identifying Endometriosis: Current Diagnostic Tools

    • Transvaginal ultrasound (TVS) is widely accepted as the first-line diagnostic imaging technique for pelvic endometriosis.
    • Patients should be systematically evaluated according to the International Deep Endometriosis Analysis (IDEA) group.
    • Diagnosis can be tricky due to diverse lesion appearances (cystic ovarian, blurry hypoechoic, fallopian tube distortion, parametrial involvement).
    • A thorough history and accurate TVS are crucial to map the disease, as endometriosis rarely confines to a single site and often involves multiple structures.
    • Magnetic Resonance Imaging (MRI) can also accurately study parametrial disease localization.
    • While non-invasive tests are being explored (e.g., blood, urine, salivary microRNA signature), no definitive biomarker has yet been identified for routine clinical use.
    • Diagnostic laparoscopy remains the gold standard for minimal/mild endometriosis (MME), offering histological confirmation.

Slide 5: Staging Systems for Endometriosis and Fertility Prediction

    • The 1996 revised American Society for Reproductive Medicine (rASRM) classification system categorizes endometriosis into four stages: minimal (I), mild (II), moderate (III), and severe (IV).
    • Staging is based on changes involving the peritoneum, fallopian tubes, and ovaries, assigning points for deep/superficial lesions, size, and adhesions.
    • However, the correlation between rASRM stage and reproductive outcome is often poor.
    • The Endometriosis Fertility Index (EFI) is another tool designed to forecast non-IVF pregnancy rates after surgical staging and treatment.
    • The EFI score system has been validated as particularly useful for patients with a poor prognosis.
    • A decision tree algorithm, using parameters like time of infertility, tubal quality, age, and ASRM score, has been proposed to identify patients who might benefit from early ART even with a good EFI score.

Slide 6: Navigating Treatment Pathways: Surgery vs. IVF

    • Laparoscopic surgical excision of endometriotic lesions and in vitro fertilization (IVF) are the two primary management options.
    • Current data provide limited guidance on when to prefer one approach over the other.
    • Treatment strategies must be individualized based on the patient’s wishes, symptomatology, age, and couple’s preferences.
    • Timely intervention and structured follow-up may maximize conception rates post-surgery, while minimizing repeated interventions.
    • First-line IVF is particularly viable for unoperated deep infiltrating endometriosis in asymptomatic women, or for those ineligible for or opposed to surgery.
    • Medical centers should ideally offer both surgical and IVF strategies, as similar live birth rates (around 25%) have been observed with both approaches.

Slide 7: Surgical Strategy: Restoring Pelvic Anatomy and Maximizing Potential

    • The primary goal of surgical excision is to remove or destroy endometriotic implants to minimize their deleterious effects.
    • In cases of co-existing adhesions, adhesiolysis should be performed to restore normal pelvic anatomy and improve fallopian tube/ovarian mobility, which can be limited by adhesions and negatively impact fertility.
    • The laparoscopic route (traditional or robot-assisted) is generally preferred over laparotomy due to improved lesion visualization, better recovery, less pain, and improved cosmetic outcomes.
    • An experienced “dedicated endometriosis” surgeon is crucial to assess the radicality of treatment, restore pelvic anatomy, and avoid ovarian or tubal injury.
    • Repeated ovarian surgery has a detrimental effect on ovarian function and reduces pregnancy chances, thus should be avoided if possible.
    • If surgery is performed, the best time to conceive is within the first year after surgery, emphasizing the importance of tailored treatment timing based on reproductive desire.

Slide 8: Bladder Endometriosis: Surgical Benefits for Fertility

    • The bladder is the most common anterior compartment localization, occurring in 84–90% of cases.
    • Treatment of choice is laparoscopic excision due to extrinsic growth infiltrating the detrusor muscle.
    • Studies show bladder nodules have a negative effect on fertility.
    • After bladder surgery, 47.2% of patients conceived within 2 years, with 65.4% spontaneously.
    • Surgical treatment also achieved complete symptom resolution in 84.2% of cases.
    • Improved fertility may be due to changes in the intraperitoneal milieu and reduced anatomical distortion (fixation of uterus).
    • In a subgroup with previous IVF failure, surgery showed a positive role: 6 out of 11 patients had subsequent IVF pregnancies, and 2 conceived spontaneously.
    • Similar high pregnancy rates were observed in patients with isolated bladder endometriosis (67%) and those with associated deep infiltrating endometriosis (DIE) (62-68%) after surgery.

Slide 9: Deep Infiltrating Endometriosis (DIE): Surgical Outcomes

    • The posterior compartment is the most frequently affected by endometriotic implants.
    • Anatomical distribution often includes uterosacral ligaments (67.08%), cul-de-sac (12.02%), rectovaginal septum (12.66%), rectum, rectosigmoid junction, and ureter.
    • Among infertile women treated laparoscopically for DIE, 62.07% achieved pregnancy after surgery, with the majority conceiving spontaneously.
    • Surgical excision of lesions in ASRM stage III–IV endometriosis significantly increased spontaneous pregnancy rates from 4% preoperatively to 43% postoperatively.
    • The removal of inflammatory mediators and the restoration of pelvic anatomy by surgery are thought to contribute to improved fertility.
    • However, some studies present conflicting data regarding IVF outcomes after prior DIE surgery, with some suggesting no improvement in ART success rates.
    • The ENDORE RCT demonstrated that overall pregnancy rates after deep endometriosis surgery exceeded 80%, with spontaneous pregnancy rates over 50%, suggesting surgery may eliminate the need for ART in many cases.

Slide 10: Current Recommendations for DIE Surgical Intervention

    • The ESHRE 2022 guidelines recommend operative laparoscopy as a therapeutic option for symptomatic women desiring pregnancy.
    • Surgery is deemed necessary if there is bowel or urinary obstruction or severe pain persisting despite medical treatment.
    • However, surgery can cause lifelong complications and adhesions that might impair natural or assisted pregnancy success.
    • The decision for surgery considers patient symptoms, prior surgery history, age, preferences, ovarian reserve, other infertility factors, duration of infertility, and the endometriosis fertility index (EFI).
    • For asymptomatic patients primarily concerned with fertility, first-line IVF without surgery is increasingly accepted as a valid choice.
    • The approach of first-line surgery followed by IVF remains a possible option, especially for persistent infertility or when symptoms significantly affect quality of life, including sexual dysfunction.

Slide 11: Ovarian Endometriomas (OMAs): Impact and Surgical Considerations

    • OMAs are found in up to 44% of women with endometriosis and can cause infertility through anatomical damage and immunological alterations.
    • Severe endometriosis with OMAs may lead to significantly lower pregnancy rates following IVF compared to severe endometriosis without OMAs.
    • OMAs reduce ovarian reserve due to damage to healthy ovarian tissue and mechanical stretch, leading to a progressive reduction in primordial follicles.
    • Ovarian cyst fluid is rich in free iron and reactive oxygen species (ROS), causing oxidative stress, fibrosis, inhibition of angiogenesis, and follicular damage.
    • Surgical excision of OMAs traditionally aimed to improve natural conception rates.
    • However, current evidence shows no benefit of OMA treatment for associated infertility.
    • Surgery for OMAs prior to ART does not improve clinical pregnancy or live birth rates and may increase cycle cancellation rates due to poor ovarian response.

Slide 12: Balancing OMA Surgery: Techniques and Ovarian Reserve

    • Cystectomy (stripping) is associated with lower reoperation risk and improved pain symptoms but has concerns about ovarian damage and is generally associated with the accidental removal of healthy ovarian tissue.
    • Various studies and meta-analyses show that AMH levels decrease after endometrioma excision, with a significant decline of up to 38%. Bilateral cystectomy can lead to a 44% reduction in AMH levels.
    • Ablative techniques include laser, plasma energy, or bipolar diathermy. Laser and plasma energy appear more tissue-sparing than bipolar diathermy.
    • Sclerotherapy with ethanol involves draining the cyst and exposing the wall to alcohol.
    • The expertise of the surgeon plays a critical role in preserving ovarian function.
    • Repeated ovarian surgery has a detrimental effect on ovarian function and AMH levels, often more severe than the initial surgery.
    • Current guidelines recommend surgery for OMA prior to ART only to improve endometriosis-associated pain or accessibility of follicles.

Slide 13: Peritoneal Endometriosis: Surgical Role and Fertility

    • PE is characterized by endometrial-like tissue on the peritoneal surface, often not macroscopically visible.
    • It’s linked to infertility due to an inflammatory state affecting spontaneous fertility and ovulation.
    • The peritoneal environment in PE can lead to continuous leukocyte recruitment and chronic inflammation, affecting tubal ciliary beat frequency and embryo implantation.
    • The role of surgical treatment for PE remains debated.
    • Some advocate for IVF as first-line treatment for PE-related infertility, reserving surgery for debilitating symptoms, neoplastic risk, or organ obstruction.
    • ASRM, ESHRE, and SGOC consider surgery an option for women with infertility and suspected mild or moderate endometriosis, after careful evaluation of patient age, symptoms, and fertility treatment options.
    • However, societies emphasize surgery should not be performed in asymptomatic women solely to search for endometriosis signs.
    • Laparoscopy can remove tubal adhesions in mild cases, but IVF-ET may be equally valid as it is not influenced by adhesions.
    • For PE, personalization of treatment is essential, resorting to surgery only when strictly necessary.

Slide 14: Parametrial Endometriosis (PaE): A Less Studied Localization

    • PaE involves connective tissue surrounding hypogastric vessels, typically identified above the ureter.
    • It is encountered in advanced disease scenarios, often causing ureter stenosis, dilatation, and voiding dysfunctions due to nerve involvement.
    • Diagnosis can be accurately studied using transvaginal ultrasound (TVS) or magnetic resonance imaging (MRI).
    • The efficacy of medical therapy for PaE is largely unknown.
    • Surgical treatment (parametrectomy) is challenging, with significant impact on operative time and morbidity due to potential damage to pelvic autonomic nerves, leading to neurogenic pelvic dysfunctions.
    • Studies highlight higher rates of postoperative adverse events, particularly voiding dysfunctions, in patients undergoing parametrectomy.
    • The presence of PaE did not affect infertility outcomes in one study.
    • Currently, no studies primarily evaluate the impact of PaE on fertility, but given it’s a severe DIE form, it could negatively impact reproductive processes due to inflammation.
    • Superiority between surgical treatment and IVF for PaE-associated infertility cannot be established.

Slide 15: In Vitro Fertilization (IVF): A Key Fertility Intervention

    • IVF is an established treatment option for infertility in endometriosis patients, aiming to mitigate the toxic effects of the endometriotic pelvic environment by performing fertilization and preimplantation embryo development outside the body.
    • First-line IVF is particularly viable in cases of unoperated deep infiltrating endometriosis in asymptomatic women, or for those ineligible for or opposed to surgery.
    • It is recommended as a first intention treatment for infertile patients with ovarian endometriomas to avoid surgical damage to ovarian reserve.
    • Widely agreed indications include asymptomatic infertile patients over 35 years old or with decreased ovarian reserve, other associated infertility factors, bilateral endometriomas, endometrioma recurrence, previous history of surgery for endometriosis, or failure of natural conception after surgery.
    • IVF should be considered first in cases of male infertility or advanced age with reduced ovarian reserve to minimize time to pregnancy and ovarian function depletion.
    • Performing IVF does not increase disease progression or recurrence in deep endometriosis patients.

Slide 16: Endometriosis and IVF Success Rates: A Complex Picture

    • Early meta-analyses suggested endometriosis negatively impacts oocyte and embryo quality and endometrial receptivity, with lower fertilization and implantation rates for stage I/II, and reduced implantation/clinical pregnancy rates for stage III/IV.
    • More recent large data analyses and meta-analyses show that while women with endometriosis undergoing IVF may have a lower oocyte yield and higher cycle cancellation rates, these findings do not always translate to a difference in live birth rates.
    • One meta-analysis reported similar clinical pregnancy and live birth rates for stage I/II endometriosis compared to other infertility causes or stage III/IV endometriosis.
    • However, others found that stage I/II endometriosis was associated with a 7% reduction in fertilization rate and impaired implantation, while severe endometriosis negatively impacted all reproduction stages.
    • Conflicting data exists regarding the overall influence of endometriotic lesions on ART results, with some meta-analyses reporting no influence and others reporting a negative influence dependent on disease stage (e.g., up to 30% reduction in clinical pregnancy rate and 40% in live birth rate for severe stage III or IV).

Slide 17: Oocyte/Embryo Quality and Endometrial Receptivity

    • Success in IVF depends on oocyte quality (impacting embryo creation) and endometrial receptivity for implantation.
    • Studies on euploidy and aneuploidy rates in women with endometriosis compared to age-matched controls report equivalent euploidy rates.
    • Despite some studies suggesting reduced oocyte quality (e.g., altered morphology, lower in vitro maturation rates, lower fertilization rates), overall clinical impact on IVF outcomes is not consistently confirmed.
    • The eutopic endometrium in endometriosis may exhibit progesterone resistance and aberrant cell signaling, potentially altering endometrial receptivity.
    • However, studies using endometrial receptivity array (ERA) tests and sibling oocyte studies found no significant difference in endometrial receptivity gene signature or implantation rates in women with endometriosis compared to controls.
    • Current evidence suggests that with known high-quality embryos in a medicated frozen embryo transfer cycle, women with endometriosis do not show marked defects in endometrial receptivity.

Slide 18: Endometriomas (OMAs) in IVF: Impact on Oocyte Retrieval and Outcomes

    • OMAs are prevalent in almost 50% of women with endometriosis and reduce ovarian reserve due to damage to healthy ovarian tissue.
    • Meta-analyses show a significant reduction in the number of mature oocytes retrieved in women with endometrioma versus controls.
    • The reduction in oocytes is greater in large endometriomas and bilateral cases.
    • Despite fewer oocytes, these studies generally report no significant difference in clinical pregnancy rate or live birth rate between women with and without ovarian endometriomas when undergoing IVF/ICSI.
    • This suggests that while OMAs affect the quantity of retrieved oocytes, they may not severely compromise the overall IVF success rate if enough good quality oocytes are obtained.
    • Medical management of endometrioma is evolving, with Dienogest and other oral combined estrogen-progestogen therapies showing potential to reduce the need for surgery before IVF.

Slide 19: Optimizing IVF Protocols for Endometriosis Patients

    • Pre-treatment with GnRH analogues: Prolonged use (minimum 3 months) prior to ovarian stimulation to mitigate inflammatory effects; however, benefit for clinical pregnancy, miscarriage, and live birth is uncertain. Concerns exist regarding pituitary over-suppression. Post-operative use of GnRH analogues does not seem to benefit embryo quality or clinical pregnancy rates before IVF.
    • Letrozole (aromatase inhibitor): One retrospective study suggests improved outcomes when used with GnRH analogues, but further studies are needed.
    • Dienogest: Long-term therapy shows no significant difference in clinical pregnancy rate, live birth rate, miscarriage rate, or oocytes retrieved.
    • Oral GnRH receptor antagonists (e.g., Elagolix): An ongoing trial is evaluating their use prior to IVF.
    • Ovarian Stimulation: Women with endometriosis may require a higher dose of gonadotrophins due to lower ovarian response. No specific approach for stimulation is universally recommended.
    • Pelvic Infection: Risk of pelvic infection/abscess post-oocyte retrieval is increased with ovarian endometrioma, though overall risk is low (0.12%); careful aspiration and extended antibiotics if puncture occurs are recommended.
    • Elective Embryo Freezing: Supraphysiological estradiol during stimulation may affect endometrial receptivity; elective freezing and deferred transfer have shown higher cumulative pregnancy rates and live birth rates in some studies, but true benefit remains uncertain.

Slide 20: The Role of Surgery Prior to IVF: Conflicting Evidence

    • Ovarian Endometriomas (OMAs): Several systematic reviews and meta-analyses conclude that ovarian cystectomy for endometrioma prior to IVF does not improve clinical pregnancy or live birth rates. It can even lead to higher cycle cancellation rates due to poor ovarian response. Surgery for OMAs is primarily considered for pain control or to improve follicular accessibility.
    • Deep Infiltrating Endometriosis (DIE): Meta-analyses yield conflicting results. Some suggest surgery prior to IVF for DIE may offer benefit in pregnancy rates. Others argue that surgery does not improve ART outcomes and may lead to complications. No randomized controlled trials exist on surgical excision of DE before IVF. Surgical excision of DE is not recommended as first-line treatment for asymptomatic patients to improve IVF outcomes due to potential severe complications and delay in treatment.
    • Minimal/Mild Endometriosis (MME): One retrospective study (Opoien et al.) linked surgical removal of MME before IVF with improved implantation, pregnancy, and live birth rates. However, most guidelines do not routinely recommend surgery prior to ART for MME due to lack of robust evidence.

Slide 21: A Promising Approach: IVF Before Endometrioma Surgery

    • A recent retrospective cross-sectional study compared IVF outcomes in patients who underwent IVF prior to endometrioma removal surgery (IVF-OPS) versus surgery followed by IVF (OPS-IVF).
    • The study found a comparable clinical pregnancy rate across IVF-OPS, OPS-IVF, and a control group (no surgery).
    • However, sub-group analysis showed IVF-OPS resulted in a significantly better clinical pregnancy rate (50%) compared to OPS-IVF (26.3%).
    • IVF-OPS also led to an improved number of top-quality blastocysts compared to both control and OPS-IVF groups.
    • The OPS-IVF group showed lower AMH levels measured after surgery, consistent with previous research on ovarian reserve reduction post-surgery.
    • Lower AMH levels in the OPS-IVF group were associated with a lower number of retrieved, injected, and fertilized oocytes, and fewer quality embryos (cleavage and blastocyst stages).
    • This suggests that performing surgery after IVF programs may preserve ovarian reserve and enhance embryo quality.

Slide 22: Tailoring Management: A Patient-Centered Approach

    • Given the heterogeneity of endometriosis, treatment decisions must be highly individualized.
    • Key factors to consider include:
      • Patient’s wishes and preferences.
      • Symptomatology (presence and intensity of pain, dyspareunia).
      • Age and its impact on ovarian reserve.
      • Ovarian reserve status (AMH, AFC).
      • Location and extent of lesions (DIE, OMA, PE, PaE).
      • Previous surgical history and risk of repeated interventions.
      • Other infertility factors (e.g., male factor, tubal patency).
      • Duration of infertility.
      • Endometriosis Fertility Index (EFI) score.
    • Counseling is fundamental for women to understand that the best time to conceive is often within the first year after surgery, and to tailor treatment to their reproductive desire.
    • A shared and informed decision between patient and physician is essential to achieve the best outcome.

Slide 23: Tools for Guiding Treatment Decisions and Timing

    • The Endometriosis Fertility Index (EFI) is a validated system that predicts non-IVF pregnancy rates following surgical endometriosis staging and treatment.
    • It helps to evaluate chances of natural conception and guide decisions on surgical intervention vs. ART.
    • A decision tree algorithm has been developed to predict which patients will require ART after laparoscopic surgery for endometriosis-related infertility.
    • This algorithm, using parameters like time of infertility, tubal quality, age, and ASRM score, achieved 81.3% accuracy and 53.3% sensitivity in identifying patients who might need ART.
    • Such a tool can lead to shorter waiting times until pregnancy for a significant portion of patients by enabling earlier identification of ART needs.
    • This approach complements the EFI by identifying patients who, even with a good EFI score, may still require ART.

Slide 24: Preserving Future Fertility: Indications in Endometriosis

    • Endometriosis can compromise fertility, and some patients are eligible for fertility preservation strategies.
    • Oocyte cryopreservation (oocyte vitrification) is the most frequently proposed and suitable technique for young patients with endometriosis, particularly those with preserved menstrual cycles.
    • Key indications for fertility preservation include:
      • Age over 35 years.
      • Bilateral endometriomas (especially before surgery).
      • History or risk of multiple surgeries.
      • Reduced preoperative ovarian reserve.
      • Ovarian endometrioma combined with reduced ovarian reserve.
      • Previous unilateral endometrioma surgery with contralateral recurrence.
      • Severe endometriosis diagnosis (Stage III-IV).
      • Large ovarian endometriomas (>4 cm) if not aiming for immediate pregnancy.
      • Unlikely postoperative natural conception.
    • Fertility preservation should be discussed in pre-surgical counseling for women at reproductive age with negative prognostic fertility factors.

Slide 25: Maximizing Success in Fertility Preservation for Endometriosis

    • Multiple ovarian stimulation cycles may be needed to retrieve an optimal number of oocytes (at least 10) due to reduced ovarian reserve in endometriosis patients.
    • Age and ovarian reserve are critical predictors of success: better outcomes (higher cumulative live birth rates) are observed in younger women (≤35 years old) and with a higher number of cryopreserved oocytes.
    • Surgical history influences oocyte retrieval: Patients with prior ovarian surgery tend to have fewer oocytes retrieved than those without a surgical history.
    • However, the stage of the disease does not significantly influence the number of cryopreserved oocytes.
    • When an adequate number of oocytes is cryopreserved, IVF outcomes (live birth rates) are comparable to those in patients who underwent fertility preservation for other indications, suggesting a quantitative, not qualitative, effect on IVF outcomes.
    • Fertility preservation before surgery can protect ovarian reserve from the detrimental effects of surgical interventions.
    • Embryo cryopreservation requires a male partner and raises ethical concerns. Ovarian tissue cryopreservation is not typically suitable for endometriosis due to the conservative nature of most surgeries, but may be applied in selected severe cases.