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.

Ovarian Endometrioma: To Resect or Not Before IVF?

Dr Cécile François

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Dr François durand

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ovarian endometrioma (OMA): overview

The decision of whether to surgically resect an ovarian endometrioma (OMA) before In Vitro Fertilization (IVF) treatment is a complex and long-standing debate in reproductive medicine, with current evidence not offering a robust consensus for firm recommendations. Endometriosis, a chronic estrogen-dependent inflammatory disease, affects up to 50% of infertile women, with OMAs being a common manifestation. The primary goal of managing OMAs in infertile women is to enhance pregnancy chances while minimizing harm to ovarian function.

The mere presence of an OMA is debated to negatively influence ovarian reserve.

  • Ovarian Reserve Markers: Some studies indicate that women with intact OMAs have significantly lower Anti-MMüllerian Hormone (AMH) levels and Antral Follicle Count (AFC) compared to healthy controls or those with non-endometriotic cysts. This reduction is attributed to potential mechanisms such as mechanical stretching, toxic elements (e.g., free iron radicals, reactive oxygen species) causing follicular damage and atresia, and local inflammation. Some evidence suggests a faster decline in AMH levels in women with OMAs managed expectantly. Conversely, other studies report inconsistent findings regarding the relationship between OMA size and ovarian reserve. One systematic review found no significant difference in pre-operative AMH levels between unilateral and bilateral endometriomas, challenging the concept that an intact endometrioma reduces functional ovarian reserve per se based on severity.
  • Oocyte Quantity and Quality: Women with intact endometriomas generally require higher doses of gonadotropins for ovarian stimulation and exhibit a lower number of oocytes retrieved, fewer mature oocytes (MII), and a lower number of viable and top-quality embryos. This is thought to be due to impaired folliculogenesis and altered follicular fluid composition. However, some studies on patients with diminished ovarian reserve (DOR) found that the presence of OMA did not reduce ovarian response or the number of oocytes retrieved.
  • IVF/ICSI Pregnancy Outcomes: Despite the impact on ovarian reserve and oocyte yield, most studies, including retrospective analyses and meta-analyses, consistently report that clinical pregnancy rates (CPR) and live birth rates (LBR) in IVF/ICSI cycles are comparable between women with and without intact endometriomas. This suggests that while OMA may affect the quantity of oocytes and embryos, it does not necessarily compromise the quality of those successfully retrieved and fertilized, nor the overall chance of pregnancy per cycle. The lower cumulative live birth rate (CLBR) observed in some studies in endometrioma groups is often attributed to the decreased number of available embryos rather than compromised quality.
  • Complications during ART: While theoretical risks such as difficult oocyte retrieval, infection, or follicular fluid contamination exist, studies indicate that accidental endometrioma punctures are generally not accompanied by an increased risk of pelvic infection, especially when followed by total aspiration and washing of the cyst. Complications during ART with an intact endometrioma are infrequent.

Surgical excision, particularly laparoscopic cystectomy using the stripping technique, has long been a common approach for OMAs.

  • Reasons for Surgery: Surgery is considered for significant pain unresponsive to medical treatment, large cysts (e.g., > 3-4 cm or ≥ 6 cm), suspicious features suggesting malignancy, or when ovarian accessibility for oocyte retrieval is difficult.
  • Detrimental Effect on Ovarian Reserve: Surgical excision of endometriomas is commonly associated with significant and often permanent reduction in ovarian reserve, as indicated by AMH levels. This iatrogenic damage is believed to result from the inadvertent removal of normal ovarian follicles adjacent to the cyst wall and potential thermal damage from coagulation during hemostasis. The decline can be substantial (e.g., 39% to 57% decrease in AMH after unilateral and bilateral cystectomy, respectively) and may not fully recover, with AMH levels remaining irrevocably reduced at 9-18 months post-operatively. Bipolar coagulation is considered more detrimental than non-thermal hemostatic methods. While AMH is a sensitive marker of this damage, AFC may be less affected or show inconsistent changes. Surgical damage is more severe after bilateral procedures and may lead to premature ovarian insufficiency (POI) in a small percentage of cases, especially in older women or with repeat surgeries.
  • Oocyte Quantity and Quality Post-Surgery: Women who underwent previous laparoscopic cystectomy for endometrioma typically need higher doses of gonadotrophins for ovarian stimulation and have a lower number of retrieved oocytes. While surgical intervention can partly improve oocyte maturation and fertilization rates, it generally results in fewer oocytes retrieved.
  • IVF/ICSI Pregnancy Outcomes Post-Surgery: Most systematic reviews and meta-analyses consistently report that surgical management of endometrioma prior to IVF/ICSI treatment does not significantly improve pregnancy rates (CPR or LBR) compared to conservative management or women with intact endometriomas. This suggests that despite the potential for improved oocyte quality or accessibility, the reduction in ovarian reserve negates any potential benefit to overall IVF success. For DOR patients, surgical excision is often not recommended due to the pre-existing compromised ovarian reserve.
  • Role of Medical Therapy: Medical treatments are primarily used for pain associated with endometriosis and generally inhibit ovarian function, making them unsuitable as a primary fertility treatment. However, they may be considered as an adjunct to IVF or as a conservative strategy to delay surgery.
  • Impact on OMA Size and Ovarian Reserve: Some progestins like Dienogest (DNG) have shown effectiveness in reducing OMA size and may have a positive effect on ovarian reserve markers like AFC, appearing to preserve ovarian reserve, though more confirmatory studies are needed. GnRH agonists (GnRHa) may reduce the proinflammatory environment and stabilize AMH/FSH levels, but their effect on OMA size is inconsistent. Newer GnRH antagonists (GnRHant) are effective for pain but their impact on ovarian reserve markers is not well-documented. Aromatase inhibitors (AIs) have shown promise in improving AFC and mature oocyte yield in some studies when combined with GnRHa.
  • Conservative Management Preferred: Current evidence and guidelines often suggest that routine surgical removal of endometriomas before ART is generally not indicated. This stance is based on the significant and often permanent detrimental effect of surgery on ovarian reserve, without a consistent improvement in IVF outcomes. Conservative management is encouraged unless there is a considerable risk of complications, severe pain, or difficulty with oocyte retrieval.
  • Individualized Counseling: The decision about management should be individualized and shared with the patient, considering factors such as OMA size, associated symptoms (especially pain), patient’s age, ovarian reserve, previous failed ART cycles, and accessibility for oocyte retrieval.
  • Evolving Techniques: While stripping remains the gold standard for recurrence rates and pain relief, newer tissue-sparing surgical techniques (e.g., ablation with CO2 laser or plasma energy, combined techniques, sclerotherapy) are being investigated to minimize ovarian damage, with some showing promising results on ovarian reserve preservation, but more robust data on long-term fertility outcomes are needed.
  • Limitations and Future Research: A significant limitation across many studies is their retrospective nature, which may affect the robustness of conclusions. There is a call for larger, prospective, randomized controlled trials to clarify the impact of OMA size, specific surgical techniques, medical management, and long-term follow-up on ovarian reserve and fertility outcomes, and to refine risk estimates. Fertility preservation strategies, such as oocyte cryopreservation, should also be discussed with women, especially if surgery is unavoidable or ovarian reserve is already compromised.

FAQ

The impact of an intact endometrioma on ovarian reserve is a controversial topic. Some studies indicate that women with intact OMAs have significantly lower Anti-Müllerian Hormone (AMH) levels and Antral Follicle Count (AFC) compared to healthy controls or those with non-endometriotic cysts, suggesting a damaging effect. This reduction is attributed to factors like mechanical compression, impaired circulation, follicular damage, and local inflammation from toxic elements such as free iron radicals and reactive oxygen species. Conversely, one meta-analysis found no significant difference in pre-operative AMH levels between unilateral and bilateral endometriomas, challenging the idea that an intact endometrioma per se reduces functional ovarian reserve based on disease severity.

Limited data suggest that AMH levels in women with OMAs can decrease significantly faster than in healthy women (e.g., a median 26% decline over 6 months in OMA patients versus 7% in healthy controls). This suggests that expectant management may not be as safe as commonly thought regarding ovarian reserve, although further confirmatory studies are needed.

Women with intact endometriomas generally have a significantly lower number of oocytes retrieved, fewer mature oocytes (MII), and a lower number of viable and top-quality embryos compared to controls. This is primarily attributed to impaired folliculogenesis and altered follicular fluid composition caused by local inflammation. However, some studies on patients with diminished ovarian reserve (DOR) found that the presence of OMA did not reduce ovarian response or the number of oocytes retrieved, suggesting that ovarian reserve status may be a more important factor than the endometrioma itself in these cases.

Most studies consistently report that clinical pregnancy rates (CPR) and live birth rates (LBR) in IVF/ICSI cycles are comparable between women with and without intact endometriomas. While the cumulative live birth rate (CLBR) per patient may be lower in women with endometrioma, this is mainly attributed to a decreased number of available embryos rather than compromised embryo quality or endometrial receptivity.

The presence of an endometrioma can make ultrasound monitoring of follicular growth difficult and ovum pick-up more problematic due to poor ovarian accessibility. However, studies indicate that accidental or voluntary endometrioma punctures during oocyte retrieval are generally not accompanied by an increased risk of pelvic infection, especially when followed by total aspiration and washing of the cyst. Complications during ART with an intact endometrioma are infrequent.

Most systematic reviews and meta-analyses consistently report that surgical management of endometrioma prior to IVF/ICSI treatment does not significantly improve pregnancy rates (CPR or LBR) compared to conservative management or women with intact endometriomas. This suggests that despite potential benefits like improved oocyte accessibility, the reduction in ovarian reserve may negate any overall IVF success benefit.

Surgical excision, particularly laparoscopic cystectomy using the stripping technique, is commonly associated with a significant and often permanent reduction in ovarian reserve. This iatrogenic damage is believed to result from the inadvertent removal of normal ovarian follicles adjacent to the cyst wall and potential thermal damage from coagulation during hemostasis. AMH levels can drop substantially (e.g., 39% to 57% decrease after unilateral and bilateral cystectomy, respectively) and may remain irrevocably reduced at 9-18 months post-operatively.

Histological studies and long-term follow-up of AMH levels suggest that the impact on ovarian reserve is not reversible. AMH concentrations have been reported to remain irrevocably reduced by an estimated 40-53% at 9-18 months post-operatively, consistent with a permanent impact on ovarian reserve and reproductive lifespan.

While uncommon (affecting up to 2.4% of women), POI can occur in the immediate and late post-surgical period and is associated with an increased risk of earlier menopause. The risk is higher after bilateral endometriotic cystectomy or with repeat surgeries, and is further modified by age, with older women facing a greater risk.

The stripping technique, while recommended for lower recurrence rates and better fecundability, is associated with inadvertent removal of healthy ovarian tissue and coagulation damage. Bipolar coagulation is considered more detrimental than non-thermal hemostatic methods (e.g., sutures, hemostatic sealants), leading to a greater decline in AMH levels. Newer tissue-sparing techniques like ablation with CO2 laser or plasma energy, or combined techniques, are being investigated to minimize ovarian damage, with some showing promise in ovarian reserve preservation. However, more robust data on long-term fertility outcomes are needed for these newer techniques.

No, surgical excision of endometriomas is often not recommended for DOR patients due to the pre-existing compromised ovarian reserve. Studies suggest that in DOR women, the presence of endometrioma did not affect IVF outcomes, and ovarian reserve status appears to be a more important factor than the endometrioma itself.

While some studies indicate that bilateral OMAs may have a higher negative impact on ovarian reserve compared to unilateral OMAs, and larger endometriomas (e.g., ≥ 6 cm) are associated with significantly lower AFC and fewer retrieved oocytes/embryos, these effects on ovarian reserve and oocyte quantity generally do not translate into significant differences in clinical pregnancy or live birth rates. One study reported that cysts over 6 cm were associated with higher AMH levels.

Medical treatments (e.g., oral contraceptives, progestins, GnRH analogs, aromatase inhibitors) are primarily used for pain associated with endometriosis and generally inhibit ovarian function, making them unsuitable as primary fertility treatments. However, they may be considered as an adjunct to IVF. Dienogest (DNG) has shown effectiveness in reducing OMA size and may have a positive effect on ovarian reserve markers like AFC, appearing to preserve ovarian reserve.

Current guidelines, such as those from ESHRE (European Society of Human Reproduction and Embryology), often suggest that routine surgical removal of endometriomas before ART is generally not indicated. This stance prioritizes avoiding the significant detrimental effect of surgery on ovarian reserve without a consistent improvement in IVF outcomes.

Surgery is primarily considered for:

  • Significant pain unresponsive to medical treatment.
  • Large cysts that pose a considerable risk of complications.
  • Suspicious features suggesting malignancy.
  • When ovarian accessibility for oocyte retrieval is difficult.
  • After repeated failed ART cycles, although robust evidence is lacking.

Low-quality evidence suggests that deep invasive endometriosis may progress with controlled ovarian stimulation. However, there is moderate evidence indicating that IVF-ET itself does not worsen pain related to endometriosis nor increase the risk of endometriosis recurrence.

The likelihood of developing ovarian cancer within an endometrioma is rare at reproductive age. While women with endometriosis have a slightly higher lifetime ovarian cancer risk compared to the general population (1.80% vs. 1.31%), these cancers are often diagnosed synchronously with endometriosis after the average menopausal age, suggesting a need for long-term follow-up. Surgery is considered for suspicious features or fast-growing cysts to rule out malignancy.

A significant limitation across many studies is their retrospective nature, which may affect the robustness of conclusions. Other limitations include difficulty in precisely defining operators’ manual skills, potential local biases, limited sample sizes for subgroup analyses, and the inclusion of only infertile women which may introduce selection bias. There is also a lack of consistent evaluation of AMH levels before and after surgery in some studies.

The current evidence supports conservative management of endometrioma until reproductive aspirations are realized. Routine surgical excision is generally discouraged due to its significant and often permanent detrimental effect on ovarian reserve, without consistently improving IVF outcomes. The decision should be individualized, considering factors like pain, cyst size, ovarian reserve, and accessibility for oocyte retrieval. There is a strong call for larger, prospective, randomized controlled trials to refine risk estimates and clarify the impact of different management strategies on long-term fertility outcomes. Fertility preservation strategies, such as oocyte cryopreservation, should also be discussed if surgery is unavoidable or ovarian reserve is already compromised.

Bibliography

Baldini, G. M., Laganà, A. S., Mastrorocco, A., Malvasi, A., et al. (2024).
Can the endometrioma be an obstacle to complete oocyte retrieval in IVF cycles? A retrospective study. European Review for Medical and Pharmacological Sciences, 28, 2827–2836.

Ban Frangež, H., Vrtacnik Bokal, E., Štimpfel, M., Divjak Budihna, T., Gulino, F. A., Garzon, S., Ghezzi, F., Alkatout, I., Gitas, G., & Laganà, A. S. (2022).
Reproductive outcomes after laparoscopic surgery in infertile women affected by ovarian endometriomas, with or without in vitro fertilisation: results from the SAFE (surgery and ART for endometriomas) trial. Journal of Obstetrics and Gynaecology, 42(5), 1293–1300. DOI: 10.1080/01443615.2021.1959536.

Wu, Y., Yang, R., Lan, J., Lin, H., Jiao, X., & Zhang, Q. (2021).
Ovarian Endometrioma Negatively Impacts Oocyte Quality and Quantity But Not Pregnancy Outcomes in Women Undergoing IVF/ICSI Treatment: A Retrospective Cohort Study. Frontiers in Endocrinology, 12, 739228. DOI: 10.3389/fendo.2021.739228.

Younis, J. S., & Nelson, S. M. (2022).
What is the recommended management of a young woman with an intact endometrioma desiring future fertility? Frontiers in Endocrinology, 13, 1005597. DOI: 10.3389/fendo.2022.1005597.

Muzii, L., Galati, G., Mattei, G., Chinè, A., Perniola, G., Di Donato, V., Di Tucci, C., & Palaia, I. (2023).
Expectant, Medical, and Surgical Management of Ovarian Endometriomas. Journal of Clinical Medicine, 12(5), 1858. DOI: 10.3390/jcm12051858.

Invernici, D., Fornelli, G., Reschini, M., La Vecchia, I., Vigano’, P., Somigliana, E., Vercellini, P., & Benaglia, L. (2025).
Ovarian damage following surgery for endometriomas, 20 years later: did awareness improve the situation? Archives of Gynecology and Obstetrics. DOI: 10.1007/s00404-025-08039-x.

Deng, Y., Ou, Z., Yin, M., Chen, Z., Chen, S., & Sun, L. (2022).
Does current ovarian endometrioma increase the time for DOR patients to reach live birth in IVF? BMC Pregnancy and Childbirth, 22, 324. DOI: 10.1186/s12884-022-04670-7.

Zeng, C., Lu, R., Li, X., Kuai, Y., Wang, S., & Xue, Q. (2022).
The presence of ovarian endometrioma adversely affect ovarian reserve and response to stimulation but not oocyte quality or IVF/ICSI outcomes: a retrospective cohort study. Journal of Ovarian Research, 15, 116. DOI: 10.1186/s13048-022-01042-9.

 

Endometriosis is a chronic, common, and estrogen-dependent inflammatory gynecologic disease characterized by the presence of endometrial-like tissue outside the uterus. It affects up to 50% of sub- and infertile women and can negatively impact pregnancy chances, leading to reduced ovarian reserve and worse fecundity rates due to altered follicular fluid composition and poor follicular and oocyte development. Ovarian endometriomas, cysts in the ovarian tissues, are diagnosed in about 17-44% of women with endometriosis and are a common reason for IVF treatment among those with endometrioma-related infertility.

Background on Endometrioma and IVF The presence of an endometrioma can make ultrasound monitoring of follicular growth difficult, lead to inadequate ovarian response to hyperstimulation, and make ovum pick-up more problematic by interfering with ovarian accessibility. This can result in incomplete oocyte recovery and low competence of retrieved oocytes. Concerns also exist about accidental cyst rupture leading to inflammatory diseases and pelvic sepsis. However, some publications suggest that endometriomas do not significantly affect embryo development and pregnancy rates. Many studies indicate that surgery for endometriomas does not increase IVF success rates and may even harm Assisted Reproductive Techniques (ART) by reducing ovarian response to controlled ovarian stimulation. Surgical excision has been reported to reduce anti-Müllerian hormone (AMH) levels, likely due to the removal of healthy ovarian tissue.

Study Design and Methods This retrospective study analyzed 251 women with ovarian endometriomas undergoing IVF at an infertility unit between January 2012 and December 2023, comparing their outcomes to an age-matched control group of 251 women without endometriomas who underwent uncomplicated oocyte retrieval. From a total of 6,204 IVF cycles performed, 861 patients (20.7%) had a primary or secondary diagnosis of endometriosis. Patients with previous pelvic/abdominal surgery, endometriosis removal surgery, pelvic inflammatory disease, non-endometriosis ovarian cysts, BMI > 30, concomitant male infertility, adenomyosis, or deep endometriosis were excluded. Endometrioma diagnosis was based on transvaginal ultrasound, identifying a cystic mass of round shape, with a minimum diameter of 10 mm, thick walls, regular margins, low homogeneous exogenous fluid content with scattered internal echoes, and without papillary projections.

All women underwent a baseline evaluation including transvaginal ultrasound, antral follicle count (AFC), and hormone analysis (AMH, FSH, estradiol) two months before starting the ART cycle. Controlled ovarian stimulation (COS) was performed using the GnRH antagonist protocol, with gonadotropin dosage determined by age, AMH, and AFC. Follicular maturation was monitored via serum estradiol and progesterone levels, and transvaginal follicular ultrasound. Ovulation was induced with hCG when three or more follicles reached > 18 mm diameter.

Oocyte Collection Procedures and Ancillary Maneuvers Oocyte aspiration was performed using a 17-gauge aspiration needle connected to a transvaginal ultrasound device, with intravenous anesthetic drugs. The standard procedure involved minimal insertion of the needle and aspiration of all present follicles, including a needle spinning maneuver during the final stage. If all follicles could not be aspirated with a single insertion, a new introduction of the needle was made.

Ancillary maneuvers were specifically employed for endometriomas or misplaced ovaries. These maneuvers included:

  • 1st Maneuver: Bimanual abdominal pressure and vaginal probe pressure.
  • 2nd Maneuver: Anti-Trendelenburg position.
  • 3rd Maneuver: Cervical clamp traction.
  • 4th Maneuver: Trans-abdominal oocyte retrieval.
  • 5th Maneuver: Trans-myometrial oocyte retrieval.

If these manipulations were insufficient for complete follicle aspiration, endometrioma transfixion was performed. This involved passing the needle through the endometrioma without aspirating it, to reach follicles behind the cysts. After follicle aspiration with transfixion, the cysts were completely aspirated and washed with physiological solution, and the cyst fluid was discarded. Follicle retrieval was considered complete upon aspiration of all follicles > 11-12 mm. Accidental endometrioma aspiration was confirmed by the presence of cloudy, dark brown fluid with fine black particles under a stereomicroscope. Post-procedure, patients were evaluated after 24 hours for side effects and complications, and contaminated oocytes were treated similarly to uncontaminated ones.

Insemination and Transfer Procedures Semen preparation for conventional IVF involved density gradient and swim-up procedures, followed by insemination in drops containing oocytes. For ICSI, cumulus-oocyte complexes were processed to select metaphase II (MII) oocytes, and the ICSI procedure was performed under an inverted microscope. Fertilized oocytes and embryos were cultured for up to 6 days. Fresh embryos were transferred as single embryo transfers (SET) on day 3 or 5, based on embryo number and patient age. Pregnancy was confirmed by serum beta-hCG levels and intrauterine gestational sac identification.

Statistical Analysis Data were analyzed using Prism 8 software. Continuous variables were presented as mean ± standard deviation, and categorical variables as percentages. Statistical comparisons between groups used Student’s t-test or Chi-square test, with p-value < 0.005 considered statistically significant.

Results The two groups were homogeneous in baseline characteristics, except for antral follicle count (AFC), which was lower in the endometrioma group. No statistically significant differences were observed between the endometrioma and control groups for fertilization rate, number of embryos, pregnancy rate, or live birth rate. The only significant difference was that the number of oocytes retrieved was higher in the control group compared to women with endometrioma.

Surgical complications were infrequent and similar in both groups, both immediately and after 24 hours, with no serious complications reported. Accidental or voluntary endometrioma punctures were not associated with an increased risk of pelvic infection. In fact, the study reported two cases of pelvic infections, both in the control group, unrelated to endometrioma presence or transfixion. The study found that ancillary maneuvers successfully helped reach the ovary and collect oocytes, and that complete ovum pick-up was possible in patients with endometrioma, with no significant differences in incomplete pick-ups between groups. The location of the endometrioma did not affect retrieval parameters.

Conclusions The study concluded that patients with endometrioma can undergo high-performance oocyte recovery procedures safely, thanks to accessory maneuvers during ovum pick-up. While endometrioma can be an obstacle to complete oocyte recovery in some cases, accessory maneuvers, including endometrioma transfixion when necessary, can be safely practiced to aspirate all follicles. The study’s results suggest that complete oocyte pick-up is possible in endometrioma patients, especially when performed by experienced gynecologists. The findings challenge previous publications by showing that accidental or voluntary endometrioma punctures, when accompanied by total aspiration and washing, do not increase the risk of pelvic infection. A limitation noted was the retrospective nature of the study and the difficulty in precisely defining operator manual skills for statistical purposes. Further studies with larger samples are suggested to clarify the impact of endometrioma size on oocyte recovery.

Endometriosis is a common, chronic inflammatory gynecological disease characterized by the presence of endometrial-like tissue outside the uterus. It affects up to 50% of sub- and infertile women and can negatively impact pregnancy chances. Ovarian endometriomas, which are cysts in the ovarian tissues, are frequently diagnosed in 17–44% of women with endometriosis. These cysts are a common reason for IVF treatment among those with endometrioma-related infertility.

Background and Clinical Debate The presence of an endometrioma can complicate ultrasound monitoring of follicular growth, lead to an inadequate ovarian response to hyperstimulation, and make oocyte retrieval more problematic due to interference with ovarian accessibility. This can potentially result in incomplete oocyte recovery and low competence of retrieved oocytes. Historically, a long-standing debate exists on whether endometriomas should be surgically removed before IVF. On one hand, surgical enucleation of endometriomas may facilitate subsequent oocyte retrieval, reduce follicular fluid contamination or infection, and allow for histological diagnosis of potential malignancy. On the other hand, surgery carries risks of complications, even with minimally invasive approaches, and may cause an iatrogenic reduction in ovarian reserve, thereby decreasing the success rate of assisted reproductive technology (ART). Studies have reported a reduction in anti-Müllerian hormone (AMH) levels after endometriosis surgery, likely due to the removal of healthy ovarian tissue. This decline in AMH levels can be faster in women with endometrioma than in healthy women, even without surgery, suggesting a detrimental role of endometriomas themselves on ovarian reserve. Current evidence has not provided robust recommendations on this matter, making individualized decisions crucial, based on factors such as endometrioma size, other symptoms (e.g., pain), failed medical therapies, previous failed ART, and the patient’s age and ovarian reserve.

Study Design and Methods (SAFE Trial) This study was a retrospective cohort study, known as the “Surgery and ART for Endometriomas” (SAFE) trial (Clinical Trial ID: NCT03717870). It included women who underwent laparoscopic cystectomy for endometrioma prior to their first IVF cycle. The data for this study were collected from medical records, including surgical procedures and IVF databases, between January 2011 and December 2016. The study compared the reproductive outcomes of 256 women with endometrioma who had undergone previous laparoscopic cystectomy (Group 1) to three control groups: 180 women with unexplained infertility (Group 2), 319 women with male factor infertility (Group 3), and 290 women with tubal factor infertility (Group 4). In the control groups, endometriosis was ruled out by ultrasound followed by laparoscopy and visual inspection of the pelvic cavity.

Exclusion criteria for the study included previous pelvic and abdominal surgery, prior endometriosis removal surgery, pelvic inflammatory disease history, non-endometriosis ovarian cysts, BMI greater than 30, concomitant male infertility, adenomyosis, or deep endometriosis for the primary source. For the SAFE trial, specific exclusion criteria for controls were not detailed as much as the primary source, but the general methodology focused on isolating the impact of endometrioma vs. other infertility factors. In Group 1, 158 women had unilateral endometrioma and 98 had bilateral endometriomas, with a mean size of 3.669 cm ± 1.518 cm. Most patients (253) in Group 1 were surgically treated for the first time, with only 3 cases of recurrent endometrioma.

All women in the study group had a history of infertility of at least two years. After surgical procedures, patients were followed for 0–12 months. IVF-ET procedures were offered to women who failed to conceive spontaneously within 6 to 12 months after laparoscopic surgery. The IVF protocols used were short antagonist cetrorelix or long desensitization buserelin protocols. One or two embryos were transferred on day 3 or 5 after oocyte retrieval. IVF procedures were performed by skilled senior gynecologists with over five years of experience.

The main outcomes measured included:

  • Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels between the 2nd and 5th day of the cycle before IVF.
  • Total gonadotropin dose required for ovarian stimulation.
  • Number of oocytes retrieved.
  • Number of developed embryos.
  • Pregnancy rate per embryo transfer (ET).
  • Delivery rate. Statistical analysis was performed using t-tests for continuous variables and chi-square analysis for dichotomous variables, with a significance level set at p < .05.

Results The study found several key differences and similarities across the groups:

  • Hormone Levels and Gonadotropin Doses: Average FSH and LH levels (between days 2-5 of the cycle before IVF) were significantly higher in women who underwent previous laparoscopic cystectomy for endometrioma (Group 1) compared to all other infertility groups (Groups 2, 3, and 4). Similarly, Group 1 required significantly higher doses of gonadotropins for ovarian stimulation. However, this effect became non-significant when considering women over 40 years of age.
  • Oocyte Retrieval and Embryo Development: The number of oocytes retrieved was lower in Group 1 compared to male factor and tubal factor infertility groups. This difference also tended to attenuate in women over 40 years of age. Conversely, the study did not find significant differences in the number of developed embryos between women with previous endometriomas and other types of infertility, except for a small significance in women under 35 years old compared to tubal factor infertility.
  • Fertilization and Blastocyst Rates: The fertilization rate, considering all cycles, was significantly higher in women who underwent previous laparoscopic cystectomy for endometrioma (Group 1) compared to unexplained infertility (Group 2) and male factor infertility (Group 3). No significant differences were observed in the blastocyst rate per embryo cultured until day 5/6 when considering all cycles.
  • Pregnancy and Delivery Rates: Crucially, the study found no significant differences between the endometrioma group (Group 1) and the other infertility groups (unexplained, male factor, tubal) regarding embryo utilization, pregnancy rates per embryo transfer, or delivery rates, irrespective of the patient’s age.

Discussion and Implications The findings from the SAFE trial contribute significantly to the ongoing debate about the management of endometriomas in infertile women. The study acknowledges that endometriosis has a major impact on female health and reproductive capacity, and that surgery for endometrioma can result in a progressive loss of follicular heritage. While previous studies indicated that surgery for endometriomas often does not increase IVF success rates and may even harm ART by reducing ovarian response, the present study demonstrates that despite requiring higher doses of gonadotropins and yielding a lower number of retrieved oocytes, women with previous laparoscopic cystectomy for endometrioma achieve comparable pregnancy and delivery rates to women with other causes of infertility.

This suggests that while endometrioma or its surgical removal might impact ovarian stimulation parameters (e.g., higher FSH/LH, higher gonadotropin dose, fewer oocytes), it does not necessarily translate into a worse ultimate reproductive outcome in terms of successful pregnancies and live births. The study also notes that the differences in ovarian stimulation parameters between the endometrioma group and other infertility types diminished with increasing age, particularly for women over 35 years. This implies that in older women, the challenge of ovarian stimulation and lower oocyte yield becomes a common background regardless of endometriosis.

The authors highlight that the study’s findings provide useful information for adequate counseling about reproductive outcomes for infertile women with ovarian endometriomas, allowing for a proper, shared decision-making approach with the patient. This suggests that surgery might not be universally necessary for improving IVF outcomes, particularly if the main goal is pregnancy. However, if symptoms like chronic pelvic pain, dysmenorrhea, or dyspareunia are significant, surgery may still be indicated.

Limitations The study acknowledges several limitations. It is a retrospective study, which inherently carries certain limitations regarding data accuracy and confounding factors. Another important limitation is that the study did not evaluate AMH levels before and after surgery, which could have provided more direct insights into the impact of cystectomy on ovarian reserve. Additionally, FSH levels were not compared before and after surgery. The authors call for further investigations with larger cohorts to confirm their findings.

In conclusion, the SAFE trial provides evidence that even after laparoscopic cystectomy for endometrioma, infertile women can achieve comparable pregnancy and delivery rates via IVF to those with other infertility factors, despite requiring more intensive ovarian stimulation and yielding fewer oocytes. This reinforces the idea that while endometriomas and their treatment can affect ovarian response, they do not necessarily negatively impact the ultimate IVF success rates, guiding clinicians towards a more conservative approach regarding pre-IVF surgery unless other symptoms necessitate intervention.

Background and Clinical Debate The influence of endometriomas on ovarian function and assisted reproductive technology (ART) outcomes has been a subject of ongoing debate. Some studies suggest that endometriomas negatively affect oocyte quality and quantity due to mechanical stress, impaired blood supply, local inflammation, and toxic cyst content. The presence of inflammatory mediators, reactive oxygen species, and iron within OMA fluid is thought to disrupt normal folliculogenesis and lead to oocyte apoptosis. Conversely, other research indicates that endometriomas do not significantly impact embryo development or pregnancy rates. Historically, surgical interventions like laparoscopic cystectomy have been performed, but concerns persist about potential reductions in ovarian reserve and responsiveness, and the possibility that surgery may not improve IVF success rates. This study sought to clarify these effects by comparing women with endometriomas to a matched control group without the condition.

Study Design and Methods This retrospective cohort study included 862 infertile women with ovarian endometriomas (the endometrioma group) and a matched control group of 862 women without endometriomas. The control group had infertility due to other factors, such as tubal or incretion factors, and was carefully matched to the endometrioma group based on maternal age, body mass index (BMI), and infertility duration. Endometrioma diagnoses were made by expert sonographers, or via magnetic resonance imaging (MRI), or confirmed by abdominopelvic surgery.

Key exclusion criteria for both groups included polycystic ovarian syndrome (PCOS), adenomyosis, systemic lupus erythematosus, prior pelvic inflammatory disease, non-endometriosis ovarian cysts, BMI over 30, concomitant male infertility, or deep endometriosis. This meticulous selection aimed to isolate the impact of endometrioma itself. For women in the endometrioma group, those who had undergone surgical intervention (laparoscopic ovarian cystectomy) prior to IVF/ICSI treatment were included, and the endometrioma group was further subdivided based on their history of ovarian surgery to evaluate its impact on outcomes.

All patients in the study underwent their first IVF/ICSI cycle with autologous oocytes. Ovarian stimulation typically followed flexible gonadotropin-releasing hormone (GnRH) agonist or antagonist protocols. Follicle growth was regularly monitored by transvaginal ultrasound and serum hormone levels (estradiol, progesterone, luteinizing hormone). Oocyte retrieval was performed 34–36 hours after human chorionic gonadotropin (hCG) administration. Fresh embryo transfers occurred on Day 3 or Day 5, with no more than three embryos transferred. Luteal phase support was provided by vaginal progesterone.

The main outcomes measured included:

  • Ovarian reserve markers: Antral Follicle Count (AFC) and Anti-Müllerian Hormone (AMH) levels.
  • Ovarian response parameters: Total gonadotropin units used, duration of stimulation, number of follicles ≥14 mm, number of oocytes retrieved, number of metaphase stage II (MII) oocytes, and Ovarian Sensitivity Index (OSI).
  • Oocyte and embryo quality: Oocyte maturation and fertilization rates, blastocyst rate, and number of available and top-quality embryos.
  • Pregnancy outcomes: Clinical pregnancy rate, live birth rate (LBR) per oocyte pickup cycle, and cumulative live birth rate (CLBR) per patient.

Statistical analysis included t-tests for continuous variables, chi-square tests for categorical variables, and multivariate logistic regression (MLR) to identify factors associated with live birth.

Results The study revealed several significant findings regarding the impact of endometrioma:

  • Ovarian Reserve: Women with endometrioma showed significantly lower AMH levels (3.02 ± 3.04 ng/ml vs. 5.74 ± 4.53 ng/ml, P < 0.001) and lower AFC (10.95 ± 7.22 vs. 17.74 ± 10.57, P < 0.001) compared to the non-endometrioma control group. They also had higher FSH levels. This indicates that ovarian endometrioma per se is associated with diminished ovarian reserve.
  • Ovarian Response and Oocyte Quantity: The endometrioma group required longer durations of stimulation and greater doses of FSH. They also had a lower number of large follicles, oocytes retrieved (8.39 ± 6.07 vs. 11.75 ± 7.10, P < 0.001), and mature oocytes. The OSI was significantly lower in endometrioma women, suggesting a poorer ovarian response.
  • Oocyte and Embryo Quality: Women with endometrioma had a lower blastocyst rate (49.36% vs. 65.32%, P < 0.001) and fewer available embryos (3.88 ± 3.18 vs. 4.39 ± 3.12, P = 0.001) and top-quality embryos (1.54 ± 2.01 vs. 2.70 ± 2.72, P < 0.001). While the number of normal fertilized oocytes was lower, the fertilization rate itself did not show a significant difference between the two main groups.
  • Pregnancy and Live Birth Outcomes:
    • The clinical pregnancy rate (49.88% vs. 50.30%) and LBR per oocyte pickup cycle (37.08% vs. 39.88%) showed no significant differences between the endometrioma and non-endometrioma groups.
    • The CLBR per patient was lower in women with endometrioma (39.32% vs. 46.87%, P = 0.002).
    • However, importantly, multivariate logistic regression (MLR) analysis revealed no correlation between endometrioma per se and live birth after adjusting for the number of top-quality embryos transferred and the stage of embryo transfer. This suggests that while endometrioma affects the quantity of embryos, it does not independently affect the likelihood of a live birth when considering the quality of embryos available for transfer.
  • Impact of Prior Surgery: When comparing endometrioma women with and without prior ovarian surgery:
    • Women with prior surgery had a lower number of large follicles, oocytes retrieved (8.01 ± 5.70 vs. 9.12 ± 6.69, P = 0.013), and mature oocytes.
    • However, they had higher maturation (86.03% vs. 83.42%, P = 0.003) and fertilization rates (78.16% vs. 74.93%, P = 0.004).
    • Live birth rates were comparable between women with endometrioma who underwent surgery and those who did not, both in fresh and frozen embryo transfer cycles. The study found no statistical difference in the impact of surgery on AMH and AFC in patients with endometrioma.

Discussion and Implications The study’s findings indicate that while ovarian endometrioma significantly negatively impacts ovarian reserve and the quantity of oocytes and embryos, it does not negatively impact overall pregnancy outcomes (LBR and CLBR) in women undergoing IVF/ICSI treatment. The lower CLBR observed in the endometrioma group was mainly attributed to the decreased number of available embryos, rather than a reduction in the quality or implantation potential of the embryos that were formed.

The authors discuss the mechanisms behind reduced ovarian reserve, including mechanical stress, altered blood supply, and local inflammation from the endometrioma’s toxic contents, leading to oocyte loss and poor embryo quality. However, the study’s crucial insight is that even with fewer oocytes and embryos, the successful pregnancy rates remain comparable, suggesting that the remaining oocytes and embryos maintain their competence.

Regarding surgery, the study found that prior laparoscopic cystectomy in women with endometrioma improved oocyte maturation and fertilization rates, suggesting that surgery might positively influence the microenvironment of the surrounding follicles. However, this improvement in oocyte/embryo quality did not translate into a statistically significant improvement in live birth rates compared to those without surgery. The study’s observation that surgery did not statistically impact AMH or AFC in endometrioma patients contrasts with some previous literature suggesting a post-surgical decline in ovarian reserve. This difference might be influenced by factors like the size of the cyst and the time elapsed between surgery and IVF treatment.

The study emphasizes that the presence of endometrioma did not worsen IVF outcomes for women with diminished ovarian reserve (DOR); rather, ovarian reserve status itself appeared to be the more critical factor for oocyte numbers. This supports a more conservative approach for DOR patients, suggesting that endometrioma cystectomy prior to IVF may not be necessary, especially for those already facing compromised ovarian reserve.

Limitations The authors acknowledge several limitations, including the retrospective nature of the study, which inherently carries potential for confounding factors and inaccuracies. It was a monocentric study, which may limit the generalizability of the findings. Additionally, while propensity score matching was used, the reduction in sample size after matching could have unforeseen effects. The study also notes that the control group, defined by the absence of ovarian cysts, might not entirely exclude the presence of peritoneal endometriosis, which could be a confounding factor. The authors call for future prospective randomized controlled trials with larger cohorts to confirm these findings and further investigate the nuances of endometrioma management.

Conclusion In conclusion, the study provides evidence that ovarian endometrioma negatively impacts oocyte quality and quantity by affecting ovarian reserve and response to stimulation. However, despite these negative effects on quantitative parameters, the overall pregnancy outcomes, including clinical pregnancy rates and live birth rates, remain comparable in women undergoing IVF/ICSI treatment, regardless of the presence of endometrioma or a history of prior surgery. This suggests that while endometrioma affects the number of embryos, it does not necessarily diminish their quality or the ultimate chance of a successful live birth. Therefore, the decision for surgical intervention before IVF/ICSI for endometriomas should be carefully individualized, particularly considering a patient’s existing ovarian reserve.

Background and Clinical Dilemma

Endometriosis is a common, chronic inflammatory gynecologic disease, with endometrioma being a distinct and advanced manifestation found in up to 44% of affected women. It is associated with reproductive dysfunction and infertility, often necessitating ART treatment. Despite its prevalence, the optimal management strategy for OMAs in women desiring future fertility remains unstandardized, with surgery frequently advised pre-conceptually and before in vitro fertilization (IVF) treatment. However, recent guidelines suggest that routine endometrioma removal before ART is generally not indicated, prompting a re-evaluation of this practice within a critical framework.

Impact of Endometrioma on Ovarian Reserve

The question of whether an intact endometrioma per se affects ovarian reserve is a highly controversial topic. Several mechanisms have been proposed to explain a potential adverse effect on early folliculogenesis and ovarian reserve:

  • Mechanical stretching: The physical presence of the endometrioma can mechanically stretch the surrounding cortical tissue.
  • Toxic microenvironment: Endometriomas contain various toxic elements, such as free iron radicals, reactive oxygen species, proteolytic enzymes, and inflammatory molecules, which can create a hostile local environment, mediated by macrophages, cytokines, and vasoactive substances, leading to inflammation and fibrosis.
  • Accelerated follicular atresia: The local pelvic inflammation triggered by endometrioma may enhance follicular recruitment and subsequent atresia of early follicles, leading to a “burnout” effect.

Despite these proposed mechanisms, the evidence clarifying the negative impact of endometrioma on adjacent ovarian cortical tissue and early folliculogenesis is still far from conclusive at the molecular and cellular level. Clinically, studies offer conflicting views: one prospective study reported a median serum anti-Müllerian hormone (AMH) decline of 26.4% over six months in women with intact endometrioma compared to 7.4% in controls. Conversely, another retrospective study found no significant difference in ovarian responsiveness to controlled ovarian stimulation. A recent meta-analysis, encompassing 17 studies, indicated that AMH levels were significantly reduced in patients with ovarian endometriomas compared to women with healthy ovaries or other benign ovarian cysts, suggesting a damaging effect of the endometrioma per se. However, a more recent systematic review and meta-analysis found no significant difference in pre-operative AMH levels between unilateral and bilateral endometriomas, which challenges the notion that an intact endometrioma inherently reduces functional ovarian reserve, even in more advanced disease.

Impact of Endometrioma Surgery on Ovarian Reserve

Surgical excision of endometriomas, particularly the stripping technique, is frequently complicated by the inadvertent removal of healthy ovarian follicles adjacent to the pseudo-capsule, which appears unavoidable even for experienced surgeons. This iatrogenic damage can result from tissue manipulation, tearing, and coagulation-induced thermal injury.

  • AMH Reduction: Laparoscopic stripping cystectomy has been consistently shown to have an adverse impact on serum AMH levels. A systematic review and meta-analysis revealed that AMH levels dropped significantly by 1.65 ng/mL (39%) for unilateral and 2.03 ng/mL (57%) for bilateral endometriotic cystectomy at 9-12 months post-operatively compared to basal levels.
  • Hemostatic Methods: Different hemostasis methods used during cystectomy can also affect ovarian reserve. Bipolar coagulation has been found to be more detrimental than non-thermal methods (such as sutures or hemostatic sealants), with non-thermal methods leading to approximately 7% less AMH decline. However, these meta-analyses were often retrospective, involved a modest number of women, and evaluated AMH only once post-surgery.

Reversibility of Surgical Impact and Premature Ovarian Insufficiency (POI)

Histological studies suggest that the impact of endometrioma cystectomy on ovarian reserve may not be reversible, as they show a loss of normal primordial follicles adjacent to the removed endometrioma specimens. Two recent systematic reviews and meta-analyses of prospective studies reported that AMH concentrations remained irrevocably reduced by an estimated 40-53% at 9-18 months post-operatively, indicating a permanent impact on ovarian reserve and reproductive lifespan.

While POI is a serious concern, it is an uncommon complication, affecting up to 2.4% of women after endometriotic cystectomy. It is primarily associated with bilateral endometriotic cystectomy or repeat surgery, and the risk increases with older maternal age at the time of surgery.

Reliability of Ovarian Reserve Tests: AMH vs. AFC

The use of Antral Follicle Count (AFC) or AMH to evaluate ovarian reserve in endometrioma cases has yielded discordant outcomes. A recent meta-analysis that evaluated repeat, concomitant, and parallel measures of AMH and AFC in the same women found a significant reduction in serum AMH but not in AFC after endometriotic cystectomy. This suggests that AMH is a more sensitive biomarker of ovarian reserve than AFC and should be routinely incorporated into pre- and post-operative counseling for women considering endometriotic surgery.

Impact on IVF Outcomes

The central question of whether endometrioma cystectomy improves IVF results has been consistently addressed by several systematic reviews and meta-analyses. These studies have found that the number of retrieved oocytes, clinical pregnancy rates, and live birth rates were comparable in women who underwent endometriotic cystectomy versus those with intact endometriomas. Specifically, a meta-analysis by Hamdan et al. showed that women undergoing cystectomy before IVF had similar clinical pregnancy rates (OR 0.97) and live birth rates (OR 0.90) compared to those without surgical intervention. This evidence suggests that surgery should not be routinely undertaken to improve IVF success, though it may be appropriate in specific cases to improve follicle accessibility or enhance quality of life during assisted conception.

Similarly, for women with intact endometriomas, studies have found that while the number of retrieved oocytes may be reduced, clinical pregnancy and live birth rates were comparable to controls without endometriomas. Hamdan et al. also reported similar clinical pregnancy (OR 1.17) and live birth (OR 0.98) rates in women with intact endometriomas compared to controls. The authors highlight that most published meta-analyses on ART outcomes in women with endometrioma are retrospective, which may affect the reliability of the estimates.

Risks of Conservative Management During ART

Conservative management (i.e., not performing surgery) of endometriomas during ART cycles carries potential risks, including:

  • Abnormal oocyte competence.
  • Technical difficulties during oocyte retrieval.
  • Endometrioma rupture.
  • Injury to adjacent organs.
  • Infection, with an incidence of 0.6%.
  • Follicular fluid contamination with endometrioma content.

While cystectomy might theoretically reduce these risks, the most expected risk without surgery is infection, for which routine antibiotic administration should be considered at the time of oocyte retrieval.

Endometriosis Progression and Ovarian Cancer Risk

Regarding disease progression, low-quality evidence suggests that deep infiltrating endometriosis might progress with controlled ovarian stimulation, although moderate evidence indicates that IVF-ET does not worsen endometriosis-related pain or increase the risk of recurrence.

The likelihood of developing ovarian cancer within an endometrioma is rare at reproductive age. The lifetime ovarian cancer risk is estimated at 1.31% in the general population, rising to 1.80% in women with endometriosis, with a low relative risk of 1.42%. However, a Dutch study found a higher incidence of specific ovarian cancer subtypes (clear-cell and endometrioid) in women with histologically proven endometriosis, with many diagnoses occurring synchronously after average menopausal age, suggesting the need for long-term follow-up.

Conclusion and Clinical Management Strategy

The authors conclude that the available data supports conservative management of endometriomas until reproductive aspirations are realized. They recommend avoiding routine endometriotic cystectomy due to its documented deleterious and sustained effects on ovarian reserve and the limited upside in terms of improving pregnancy probability. Conservative management is encouraged even when ART is performed, unless there is a considerable risk of endometrioma-related complications.

However, there are specific situations where surgical intervention should still be considered:

  • Women with endometriosis-associated pelvic pain that has failed medical therapy.
  • Cases where developing follicles cannot be reached during oocyte retrieval due to the endometrioma’s presence.
  • In patients with endometrioma showing manifestations of endometriosis-associated ovarian cancer, though rare at reproductive age, surgery and histological evaluation become inevitable for diagnosis and treatment.

The authors acknowledge the retrospective nature of many studies, emphasizing the need for future prospective studies to refine risk estimates. They also suggest exploring other advanced (non-conservative) modalities like ultrasound-guided sclerotherapy or laser vaporization, and highlight the importance of discussing fertility preservation in cases where surgery is unavoidable or ovarian reserve is a priori impaired.

Introduction to Endometriosis and Ovarian Endometriomas Endometriosis is a common, chronic, estrogen-dependent gynecological disease affecting approximately 10% of women of reproductive age worldwide, impacting an estimated 176 million women. It is defined by the presence of endometrial glands and stroma outside the uterine cavity, most commonly in the ovaries and pelvic peritoneum. Women with endometriosis may experience symptoms like dysmenorrhea, chronic pelvic pain, and dyspareunia, or they may be asymptomatic, with endometriosis found incidentally during surgery for other indications. Endometriosis is classified into three subtypes: superficial peritoneal endometriosis, ovarian endometrioma (OMA), and deep infiltrating endometriosis. Superficial ovarian endometriosis is typically diagnosed during surgery, with current guidelines supporting surgical treatment for associated infertility or pain, preferably by excision for histological samples.

OMAs, which are cysts in the ovarian tissues, are a distinct and advanced manifestation of endometriosis. They are present in 17–44% of young women with endometriosis and can be accurately diagnosed via transvaginal sonography. The management options for OMAs include expectant management, medical treatment, surgical treatment, in vitro fertilization (IVF) for infertility-associated cases, or a combination thereof. The choice of management largely depends on the main presenting symptoms and the OMA size. Historically, surgery was considered the gold standard for OMAs, especially for cysts larger than 3 cm. However, accumulating evidence suggests a potential detrimental role of surgical excision on ovarian reserve, leading to a shift towards more conservative approaches, including increased referral to medical therapy. Clinicians now face a dilemma when discussing management options, with ovarian reserve preservation becoming a pivotal consideration.

Ovarian Reserve in the Presence of Endometrioma The impact of an intact endometrioma on ovarian reserve is a highly debated topic. Several mechanisms are proposed for its adverse effect on early folliculogenesis and ovarian reserve: mechanical stretching of surrounding cortical tissue, the presence of toxic elements like free iron radicals, reactive oxygen species, proteolytic enzymes, and inflammatory molecules within the endometrioma, which create a hostile microenvironment leading to inflammation and fibrosis. Additionally, endometrioma-triggered local pelvic inflammation may lead to accelerated follicular recruitment and atresia, a “burnout” effect. While molecular, histological, and morphological clues support these mechanisms, conclusive evidence is still lacking.

In clinical settings, studies present conflicting findings. Some indicate a negative impact of intact endometrioma on functional ovarian reserve, with one prospective study showing a 26% median serum AMH decline over six months in women with intact endometrioma compared to 7.4% in controls. A meta-analysis involving 17 studies also found significantly reduced AMH levels in patients with OMAs compared to healthy ovaries or other benign cysts. Conversely, other studies found no significant difference in ovarian responsiveness to controlled ovarian stimulation in women with intact endometrioma compared to controls. A recent systematic review and meta-analysis found no significant difference in pre-operative AMH levels between unilateral and bilateral endometriomas, challenging the idea that intact endometrioma inherently reduces functional ovarian reserve, even in more advanced disease.

The progression of ovarian reserve decline in women with endometriosis remains unclear. While some studies suggest a correlation between OMA size and ovarian reserve damage, others do not. For instance, Karadag et al. reported a significant negative correlation between larger OMA size and lower AMH levels. However, Roman et al. found large OMAs (over 6 cm) associated with higher AMH levels. Limited longitudinal data exist, but one prospective study by Kasapoglu et al. suggested AMH levels decline significantly faster in women with OMAs (26% over 6 months) than in healthy controls (7%). This suggests that expectant management might not be as safe as commonly perceived, though further confirmatory studies are needed.

Medical Therapy and Ovarian Reserve The effect of medical therapy on ovarian reserve in the presence of OMAs is not extensively studied. Medical treatments, including oral contraceptives (COCs), progestins, gonadotropin-releasing hormone agonists (GnRHa), antagonists (GnRHant), and aromatase inhibitors (AIs), primarily inhibit ovarian function and are generally not recommended for infertile patients. Their role in infertility treatment is largely limited to adjuncts to IVF, such as long-term GnRHa therapy before IVF, though this role is questioned.

  • Oral Contraceptives (COCs): While frequently prescribed for endometriosis-related pain, there is limited data on their effect on OMA diameter and ovarian reserve. One study showed a slight decrease in OMA diameter with COC treatment but provided no information on ovarian reserve changes.
  • Dienogest (DNG): A fourth-generation progestin, DNG is effective in reducing endometriosis-related pain and cyst size due to its anti-inflammatory and anti-angiogenic properties. Angioni et al. reported a significant OMA diameter reduction with DNG treatment over 6 months, while COCs showed no change, but ovarian reserve markers were not assessed. Some studies suggest DNG pretreatment may improve AFC and retrieved oocytes during IVF cycles, or positively impact IVF outcomes after OMA excision. However, one study by Tamura et al. reported lower retrieved oocytes and pregnancy/live birth rates after DNG treatment before IVF. A prospective study by Muzii et al. indicated that DNG treatment for 6 months significantly reduced OMA diameter and pain while preserving ovarian reserve, with improved AFC and no significant AMH change. This suggests DNG could be a safe option to delay surgery and preserve ovarian reserve in asymptomatic OMA cases, but further confirmation is needed.
  • GnRH Agonists (GnRHa): GnRHa primarily reduce the impact of endometriotic lesions by inhibiting FSH secretion and creating a hypoestrogenic state, potentially reversing a proinflammatory peritoneal environment. However, their effectiveness in consistently reducing OMA size is debated. While one study reported OMA size reduction with GnRHa, another found no significant change in cyst diameter or AFC. Importantly, some studies suggest that GnRHa treatment does not reduce ovarian reserve or primordial/primary follicle function.
  • GnRH Antagonists (GnRHant): Newer GnRHant like elagolix, relugolix, and linzagolix have shown efficacy in reducing endometriosis-associated pain. However, these studies primarily included patients with a previous surgical diagnosis of endometriosis and did not report on ovarian reserve markers.
  • Aromatase Inhibitors (AIs): AIs, such as letrozole, suppress locally produced estradiol by endometriotic deposits. One study combining GnRHa with letrozole showed higher AFC and decreased OMA diameter, leading to more mature oocytes and blastocysts.

Overall, current data on medical therapy and ovarian reserve in OMAs are scarce but suggest DNG may be a promising option for preservation, particularly for asymptomatic cases.

Surgery and Ovarian Reserve ESHRE guidelines recommend medical therapy as first-line for endometriosis-associated pain and suggest surgery only for non-response or when OPU is technically difficult due to OMA presence. There is no mandate for surgery based on cyst diameter. Surgery for histology to rule out malignancy should be considered for non-reassuring sonographic features or fast-growing cysts, as unexpected malignancy can be found in about 0.9% of cases.

Surgical techniques for endometriotic cysts include cystectomy (stripping), electrocoagulation, laser ablation, plasma-energy ablation, and combined techniques. The stripping technique is the recommended treatment, associated with lower recurrence rates and better post-surgical fecundability. However, it often leads to inadvertent removal of healthy ovarian tissue adjacent to the pseudo-capsule, even by experienced surgeons, and causes coagulation-induced thermal damage. Laparoscopic stripping cystectomy consistently reduces serum AMH levels; a meta-analysis showed a 39-57% decline 9-12 months post-operatively. The impact of cystectomy on ovarian reserve is largely not reversible, with AMH concentrations remaining reduced by an estimated 40-53% at 9-18 months post-operatively. While premature ovarian insufficiency (POI) is a serious concern, it is an uncommon complication (up to 2.4%), mainly associated with bilateral or repeat surgery, and increases with age.

Different hemostasis methods can affect ovarian reserve. Bipolar coagulation is consistently more detrimental than non-thermal methods (sutures or hemostatic sealants), leading to about 7% less AMH decline with non-thermal methods. The use of bipolar coagulation should be limited.

While AMH consistently shows reduction after cystectomy, Antral Follicle Count (AFC) does not always. A meta-analysis comparing AMH and AFC in the same women found a significant reduction in serum AMH but not AFC after endometriotic cystectomy, suggesting AMH is a more sensitive biomarker for post-surgical ovarian reserve. Clinicians should routinely incorporate AMH into pre- and post-operative counseling.

Non-excisional techniques, such as ablation with bipolar coagulation, plasma energy, or CO2 laser, preserve ovarian cortex by not removing the cyst wall. Studies on plasma energy ablation and CO2 laser vaporization have shown promising results in terms of pregnancy rates comparable to cystectomy, with some indicating better ovarian reserve preservation (AFC and AMH). However, a meta-analysis by Zhang et al. found both cystectomy and ablation reduced AMH, but ablation was more respectful of ovarian reserve when evaluated by AFC. Ultrasound (US)-guided aspiration and sclerotherapy are also being used; they may preserve ovarian reserve but are associated with higher recurrence rates.

A combined surgical technique (partial stripping + ablation of remaining capsule) aims to combine radical removal with tissue preservation. An RCT has confirmed its non-inferiority to stripping regarding recurrences and ovarian reserve preservation.

Damage to ovarian reserve is more severe in bilateral OMAs compared to unilateral procedures. A study showed AMH levels were significantly lower in bilateral groups at early, intermediate, and late terms post-surgery. The decline in AMH levels post-surgery may not be temporary; some studies report irreversible reduction beyond 12 months, especially for bilateral and larger endometriomas.

Impact on IVF Outcomes Several systematic reviews and meta-analyses consistently show that endometrioma cystectomy does not improve IVF results in terms of retrieved oocytes, clinical pregnancy rates, or live birth rates, compared to women with intact endometriomas. Therefore, surgery should not be routinely undertaken to improve IVF success.

Similarly, for women with intact endometriomas, while the number of retrieved oocytes may be reduced, clinical pregnancy and live birth rates are comparable to controls without endometriomas. Hamdan et al. reported similar clinical pregnancy and live birth rates in women with intact endometriomas compared to controls. However, most published meta-analyses on ART outcomes in women with endometrioma are retrospective, which may affect the reliability of the estimates.

Risks of Conservative Management During ART Conservative management during ART carries potential risks, including abnormal oocyte competence, technical difficulties during oocyte retrieval, endometrioma rupture, injury to adjacent organs, infection, and follicular fluid contamination. The most expected risk without surgery is infection, with an incidence of 0.6%, suggesting routine antibiotic administration should be considered during oocyte retrieval. Importantly, accidental or voluntary endometrioma punctures were not associated with increased pelvic infection risk in one study, especially when punctures were followed by total aspiration and washing of the cysts.

Disease Progression and Ovarian Cancer Risk Low-quality evidence suggests deep infiltrating endometriosis might progress with controlled ovarian stimulation, but moderate evidence indicates IVF-ET does not worsen pain or increase recurrence risk. The likelihood of developing ovarian cancer within an endometrioma is rare at reproductive age. While general lifetime ovarian cancer risk is 1.31%, it rises to 1.80% in women with endometriosis (relative risk 1.42%). However, a Dutch study found higher incidence of clear-cell and endometrioid ovarian cancer in women with histologically proven endometriosis, with many diagnoses occurring synchronously after average menopausal age, suggesting a need for long-term follow-up.

Conclusion and Clinical Management Strategy The authors conclude that current data support conservative management of endometriomas until reproductive aspirations are realized, advocating against routine endometriotic cystectomy due to its deleterious and sustained effects on ovarian reserve and its limited benefit for pregnancy probability. Conservative management is encouraged even with ART, unless there’s significant risk of endometrioma complications.

Surgical intervention should be considered in specific scenarios:

  • Women with endometriosis-associated pelvic pain unresponsive to medical therapy.
  • Cases where developing follicles are inaccessible during oocyte retrieval due to the endometrioma’s presence.
  • In patients with endometrioma showing manifestations of endometriosis-associated ovarian cancer, despite its rarity at reproductive age, surgery and histological evaluation are necessary for diagnosis and treatment.

The authors acknowledge the retrospective nature of many studies and call for future prospective studies to refine risk estimates. They also suggest exploring other advanced non-conservative modalities like ultrasound-guided sclerotherapy or laser vaporization. Finally, fertility preservation should be discussed when surgery is unavoidable or ovarian reserve is a priori impaired.

Introduction to the Problem Endometriosis is a common, chronic, inflammatory gynecological disease characterized by endometrial-like tissue growing outside the uterus, affecting up to 50% of infertile women. Ovarian endometrioma (OMA), or ovarian chocolate cysts, are a frequent manifestation, found in approximately 17-44% of women with endometriosis. The impact of OMAs on ovarian function and fertility, and the optimal management strategy, particularly concerning surgery before assisted reproductive technology (ART) such as in vitro fertilization (IVF), has been a subject of extensive debate. Early reports from the beginning of the 21st century highlighted significant ovarian damage following laparoscopic stripping of endometriomas, leading to concerns about diminished ovarian reserve. Despite increased awareness among surgeons about the potential detrimental effects of surgery and efforts to refine techniques, it remained unclear whether this heightened consciousness has led to a reduction in surgically-related ovarian damage in real-life clinical practice. This study aimed to answer this crucial question by evaluating ovarian response during IVF stimulation in women who had previously undergone unilateral endometrioma surgery, using an intra-patient comparison design that allows for direct comparison with findings from two decades prior.

Background: Ovarian Damage and Evolving Surgical Practices Initial studies confirmed that surgical excision of endometriomas, especially via laparoscopic stripping, significantly reduces ovarian reserve, notably indicated by a decrease in serum Anti-Müllerian Hormone (AMH) levels. In ART settings, the responsiveness of operated ovaries to stimulation was found to be halved, with a concerning rate of complete non-response in approximately one in eight cases. Damage was also found to be more severe after surgery for bilateral endometriomas, and in rare instances, led to post-surgical ovarian failure.

In response to these findings, there has been a push to modify surgical indications and techniques. Current guidelines suggest that surgery for endometriomas should primarily be considered for larger cysts (over 4 cm in diameter), for pain that is refractory to hormonal treatments, or when ultrasound findings raise suspicion of malignancy. Routine surgical removal of endometriomas before IVF treatment is generally not indicated, as publications show surgery does not increase IVF success rates and may even harm ART by reducing ovarian response.

Efforts to limit ovarian damage during surgery have included:

  • Employing more careful and meticulous surgical techniques with reduced use of electric diathermy coagulation.
  • Exploring alternative ablative methods such as drainage and laser vaporization of the inner cyst layer.
  • Using hemostatic sutures or sealants instead of diathermy coagulation for hemostasis.
  • Developing combined techniques of stripping and vaporization.
  • Utilizing drainage of cyst content with or without local injection of sclerotic agents.

However, the efficacy and robustness of these alternative techniques remain inconclusive, and laparoscopic stripping continues to be considered the gold standard for its established benefits in terms of pain reduction, natural fertility enhancement, and lower recurrence rates.

Study Design and Methodology This study was a retrospective review of IVF-ICSI cycles conducted between January 2014 and December 2022. It specifically focused on women who had undergone previous laparoscopic excision of unilateral endometriotic ovarian cysts. A key strength of the study’s design was its use of intra-patient comparisons, evaluating the response to ovarian stimulation between the previously operated ovary and the contralateral intact gonad within the same individual. This approach minimizes inter-individual variability and strengthens statistical power, allowing for a more reliable assessment of surgical impact.

Inclusion criteria for patients were:

  • Previous laparoscopic excision of one or more unilateral endometriotic ovarian cysts.
  • Availability of a detailed description of the surgical intervention.
  • Age ≤ 42 years at the time of ovarian stimulation.
  • More than 3 developed follicles (> 11 mm) in the non-operated ovary, to exclude women with low ovarian reserve unrelated to endometriosis surgery.

Exclusion criteria included previous surgery for non-endometriotic ovarian cysts, the presence of non-endometriotic ovarian cysts at the time of the procedure, previous surgery for bilateral endometriomas, two or more previous surgeries for ovarian endometriomas, or surgery performed prior to 2010. Patients were included regardless of the time elapsed between their surgery and the IVF cycle.

During IVF cycles, follicular growth was monitored by serial transvaginal ultrasonography, and the number and diameter of all follicles greater than or equal to 11 mm were routinely recorded separately for each ovary. The primary outcome measure was the rate of operated ovaries that did not show any developed follicles. The secondary outcome was the number of follicles with a mean diameter of 11 mm or greater at the time of triggering. Statistical analysis involved non-parametric Wilcoxon tests for paired data and Chi-square tests for proportions.

Key Findings of the Study Out of 861 women with endometriosis who underwent IVF during the study period, 107 were deemed eligible for this specific analysis.

  • The mean age of the women at the time of their endometrioma surgery was 31 ± 5 years, with an average of 4.6 ± 3.6 years between surgery and the IVF cycle.
  • The mean diameter of the excised endometriomas was 47 ± 20 mm, with 59% of cases involving cysts 4 cm or larger.
  • The vast majority (97%) underwent cyst stripping, while only a small minority (3%) received cyst wall ablation.
  • The study found a markedly lower response in operated gonads: the median number of developed follicles was 3 [interquartile range, IQR 1–5] in the operated gonads compared to 7 [IQR 5–9] in the contralateral intact gonads (p < 0.001).
  • Crucially, absence of follicular growth was observed in 19 (18%) of the operated ovaries (95% Confidence Interval, CI 12–26%). This rate was not lower than previously observed more than a decade ago (13%, 95% CI 7–21%).
  • Subgroup analyses based on the surgical unit (internal vs. external hospital), the diameter of the removed cyst (<4 cm vs. ≥4 cm), or the presence of endometrioma recurrence did not identify a subgroup with a markedly increased risk of ovarian damage. Due to the low number of ablation cases, subgroup analysis by surgical technique was not possible.
  • The cumulative live birth rate for the IVF cycles in this cohort was 33%.

Discussion and Implications The study’s findings are disappointing, indicating that the rate of severe ovarian damage following surgery for endometriomas has not improved over the years. Despite heightened awareness among surgeons and efforts towards more meticulous techniques, the prevalence of non-responsive ovaries remains substantial. The continued reliance on the stripping technique, even with presumed careful use of electrodiathermy, suggests that the underlying mechanisms causing ovarian damage are not yet fully understood or effectively mitigated. The debate regarding surgical techniques persists; while ablation might be less harmful to ovarian reserve, it has not shown superior outcomes in natural conceptions or IVF results.

The increased awareness has, however, led to restricted indications for surgery. The study cohort itself reflects this shift, with only a minority of infertile women having undergone prior endometrioma surgery, and a tendency towards operating on larger cysts. This implies a more conservative management approach is being adopted, potentially delaying surgery until more significant clinical indications arise. However, the study notes that even larger cysts may inherently be detrimental to ovarian reserve before surgery, complicating the inference of surgical impact.

The study acknowledges several limitations, including its retrospective nature and the potential for findings to reflect local rather than general practices, especially given the low number of ablation cases. The exclusive focus on infertile women introduces a selection bias, as ovarian reserve’s importance differs between IVF success and natural conception. Furthermore, the wide time interval between surgery and IVF and the reliance solely on ovarian response as a surrogate for ovarian reserve (given AMH’s inability to differentiate individual ovary contribution and AFC’s unreliability in operated ovaries) are points for consideration.

Conclusion and Future Directions In conclusion, despite increased awareness regarding the detrimental impact of surgery on ovarian reserve, leading to more restricted surgical indications, women undergoing surgery for endometriomas still face a relevant and seemingly unmitigated degree of ovarian damage. This highlights an urgent need for further research to clarify the precise pathogenetic mechanisms responsible for this damage. A deeper understanding of these mechanisms is a crucial preliminary step for designing large randomized controlled trials to investigate whether modifications in surgical techniques can indeed improve outcomes. Future studies should not only assess ovarian reserve but also focus on key clinical outcomes relevant to patients, such as pain relief, spontaneous pregnancy rates, and disease recurrence.

Background: Endometrioma, Ovarian Reserve, and IVF Endometriosis is a common, chronic, estrogen-dependent inflammatory gynecological disease characterized by endometrial-like tissue growing outside the uterus, affecting up to 50% of infertile women. Ovarian endometrioma, or ovarian chocolate cysts, are a frequent manifestation, found in approximately 17-44% of women with endometriosis. The impact of OMAs on ovarian function and fertility, and the optimal management strategy—especially concerning surgery before assisted reproductive technology (ART) like IVF—has been a subject of extensive debate.

Early reports in the 21st century highlighted significant ovarian damage following laparoscopic stripping of endometriomas, leading to concerns about diminished ovarian reserve. Serum Anti-Müllerian Hormone (AMH), a reliable biomarker of ovarian reserve, has been shown to be significantly reduced after such surgery. In ART settings, the responsiveness of operated ovaries to stimulation was found to be halved, with a concerning rate of complete non-response. Damage was inevitably worse after surgery for bilateral endometriomas and, rarely, led to post-surgical ovarian failure.

In response to these findings, awareness among surgeons has increased, leading to a push for more refined techniques and restricted surgical indications. Current guidelines suggest that surgery for endometriomas should primarily be considered for larger cysts (over 4 cm), for pain refractory to hormonal treatments, or when ultrasound findings raise suspicion of malignancy. Routine surgical removal of endometriomas before IVF is generally not indicated, as publications show surgery does not increase IVF success rates and may even harm ART by reducing ovarian response.

However, the real-life impact of these efforts to limit ovarian damage through improved techniques and restricted indications has been questioned. Recent studies, like the one by Invernici et al. (2025), found that the rate of severe ovarian damage following surgery for endometriomas has not improved over the years, with absence of follicular growth recorded in 18% of operated ovaries, a rate not lower than previously observed more than a decade ago. This suggests that ovarian reserve continues to be significantly compromised after endometrioma surgery.

Deng et al. Study Design and Methodology The study by Deng et al. was a retrospective case-control study focusing specifically on women with diminished ovarian reserve (DOR), defined by a serum AMH level of ≤ 1.1 ng/mL. The researchers aimed to investigate whether the presence of OMA, rather than its surgical removal, affects IVF outcomes and the time to achieve live birth in DOR patients. This differentiates it from many studies that focus on the impact of surgery.

The study included two main groups:

  • Group A (Endometrioma group): 90 DOR patients with current unilateral or bilateral OMAs, diagnosed by transvaginal ultrasound (cysts > 3 cm). Importantly, these patients had not been previously operated for their endometriomas.
  • Group B (Non-Endometrioma group): 403 DOR patients without current OMA and no history of ovarian surgery for OMA.

Patients were excluded if they had conditions like polycystic ovary syndrome (PCOS), untreated hydrosalpinx, or chromosomal abnormalities. The IVF cycles included both fresh and frozen embryo transfers. The main outcome measure was cumulative live birth rate per patient, defined as live birth following all ART treatments. Another key outcome was time to achieve live birth, measured from the first day of controlled ovarian stimulation (COH) to the date of live birth. Statistical analysis involved comparing clinical and demographic characteristics, laboratory parameters (e.g., number of oocytes retrieved, fertilization rates), and IVF outcomes.

Key Findings of Deng et al. The study found no statistically significant differences in key reproductive outcomes between DOR patients with current endometrioma and those without.

  • Ovarian Reserve and Response: While the presence of OMA is often associated with reduced ovarian reserve (e.g., lower AMH and AFC) in other studies, Deng et al. found no significant differences in baseline AMH, AFC, or FSH levels between their DOR groups with and without OMA. This is notable because both groups were already characterized by diminished ovarian reserve, suggesting that within this specific population, the presence of OMA did not further differentiate ovarian reserve markers. Similarly, the mean number of oocytes retrieved per patient and per cycle, 2PN zygotes, embryos, and good-quality embryos were all similar between the two groups. This contrasts with some previous meta-analyses that reported lower oocyte numbers in un-operated OMA patients. Deng et al. suggest that ovarian reserve status itself might be a more significant confounding factor for oocyte numbers than the mere presence of endometrioma.
  • Oocyte and Embryo Quality: Despite ongoing debate about OMA’s impact on oocyte quality, Deng et al. observed that the current presence of OMA was not detrimental for oocyte quality, fertility rate, or embryo quality in DOR patients. Both groups had similar numbers of good-quality embryos and comparable good-quality embryo rates per oocyte. This aligns with other findings that, while endometriosis might affect oocyte microenvironment, it doesn’t necessarily impair fertilization or blastocyst rates.
  • Pregnancy and Live Birth Rates: The most impactful finding was the lack of significant differences in implantation rate, live birth rate per OPU and per ET cycle, and the cumulative live birth rate per patient (including per patient with good-quality embryos) between the endometrioma group and the non-endometrioma control group. This result indicates that, for DOR women, having an OMA does not hinder their overall chances of achieving a live birth through multiple IVF cycles.
  • Time to Live Birth: Crucially, the study also found no statistically significant difference in the total time required to achieve a live birth between the two groups of DOR patients. This suggests that the presence of OMA does not prolong the IVF treatment journey for these women.
  • Complications: The study reported infrequent accidental aspiration of endometrioma fluid during oocyte retrieval (11 cases) and no ovarian abscess complications, reinforcing the safety of conservative management in this context.

Discussion and Implications The findings of Deng et al. are significant because they suggest that for women already diagnosed with diminished ovarian reserve, the presence of an endometrioma does not negatively impact IVF outcomes or the efficiency of treatment. This supports the argument that surgical intervention for endometriomas may not be necessary in patients with poor ovarian reserve.

This conclusion is consistent with several other sources:

  • The SAFE trial (Ban Frangež et al.) found that despite women with previous laparoscopic cystectomy for endometrioma needing higher gonadotropin doses and having lower oocyte numbers, their pregnancy and delivery rates remained comparable to those with other infertility types.
  • Wu et al. concluded that ovarian endometrioma negatively impacts oocyte quality and quantity, but not overall pregnancy outcomes in women undergoing IVF/ICSI. They also noted that surgery prior to IVF improved oocyte maturation and fertilization but did not impact pregnancy outcomes.
  • Zeng et al. similarly found that while OMAs lead to considerable decreases in ovarian reserve and response to stimulation, they have no apparent adverse effects on oocyte quality or clinical outcomes, and CLBRs were comparable regardless of prior surgery.
  • Younis & Nelson’s systematic review highlights that meta-analyses consistently report comparable clinical pregnancy and live birth rates whether women had intact endometriomas or underwent cystectomy prior to IVF, even if oocyte numbers were reduced.

These consistent findings reinforce the general recommendation for conservative management of endometriomas when fertility is the primary concern, especially in DOR patients. Routine surgical removal is not supported by evidence for improving IVF results and carries clear risks to ovarian reserve due to inadvertent removal of healthy tissue and thermal damage.

However, some nuances remain. While Deng et al. found no difference in AMH/AFC within their DOR cohort, other studies show a general reduction of ovarian reserve in the presence of OMA. The choice of surgical technique, such as the use of bipolar coagulation for hemostasis, has also been shown to be more detrimental to ovarian reserve compared to non-thermal methods. Despite increased awareness and efforts to refine surgical techniques, the rate of severe ovarian damage following stripping has not demonstrably improved over the past two decades, with a significant proportion of operated ovaries still showing no follicular growth.

Limitations and Future Directions The study by Deng et al. acknowledges its retrospective nature and a relatively smaller sample size as limitations, which may affect statistical power and generalizability. It also notes the heterogeneity of DOR causes and OMA characteristics (e.g., painful symptoms, size, laterality) that could influence outcomes. While propensity score matching was used to control for confounders, it cannot eliminate all biases present in observational studies.

Future research should focus on:

  • Prospective randomized controlled trials with larger sample sizes to definitively confirm these findings.
  • Detailed subgroup analyses to explore the impact of specific OMA characteristics (size, laterality, pain) on IVF outcomes in DOR patients.
  • Clarifying pathogenetic mechanisms of ovarian damage, as a deeper understanding is crucial for developing truly tissue-sparing surgical techniques or non-surgical interventions that effectively mitigate damage without compromising other important outcomes like pain relief or recurrence rates.
  • Exploring advanced non-conservative modalities such as ultrasound-guided sclerotherapy or laser vaporization, and comparing them with cystectomy regarding their impact on ovarian reserve and fertility.
  • Considering fertility preservation strategies for women, especially those with pre-existing impaired ovarian reserve or when surgery is unavoidable.

In conclusion, Deng et al.’s study provides compelling evidence that for women already facing diminished ovarian reserve, the mere presence of an endometrioma does not negatively influence the success rates or efficiency of IVF, including the time it takes to achieve a live birth. This reinforces the broader consensus in the literature against routine surgical removal of endometriomas before IVF, especially given the established risks of ovarian damage associated with surgery and the comparable clinical outcomes observed with conservative management.

Background on Endometriosis and OMA Impact Endometriosis is estimated to affect 10-15% of women of reproductive age and 20-50% of infertile women. Ovarian endometriomas are found in approximately 17-44% of women with endometriosis. While some women with endometriosis may be asymptomatic, others experience symptoms such as dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility. The mechanisms by which OMAs impact ovarian function and fertility are complex and debated. It is suggested that OMAs can negatively affect oocyte quality and quantity through various means, including mechanical stress, which may destroy normal anatomy and impair blood supply and innervation. Additionally, local inflammation and toxic contents such as free iron from the cyst can diffuse into nearby ovarian tissue, potentially leading to oocyte loss, poor embryo quality, and premature follicular recruitment and atresia (a “burnout” effect).

Historically, surgical removal of endometriomas was often considered before IVF treatment. However, concerns have been raised about the potential for iatrogenic reduction of ovarian reserve following surgery due to inadvertent removal of healthy parenchyma and thermal damage from coagulation. Serum Anti-Müllerian Hormone (AMH) levels, a reliable biomarker of ovarian reserve, have been shown to significantly decrease after such surgeries. Despite these risks, some still argue that surgery might facilitate oocyte retrieval or reduce infection risk. Current guidelines often suggest that routine surgical removal of endometriomas before IVF is generally not indicated, as evidence suggests it does not consistently increase IVF success rates and may even harm ART by reducing ovarian response.

Zeng et al. Study Design and Methodology The study by Zeng et al. was a retrospective cohort study that included 2067 patients undergoing their first IVF/ICSI cycles between January 2018 and December 2020. The researchers aimed to assess the impact of OMAs on various IVF cycle parameters and outcomes.

The study population was divided into two main groups:

  • Study Group: 154 infertile women with OMAs visually confirmed at the start of stimulated cycles.
  • Control Group: 1913 women without visual endometriosis and no prior history of surgery for OMAs.

To account for potential confounding factors and selection biases, the study employed propensity score matching (PSM). The 154 women with OMAs were matched at a 1:2 ratio to 305 control women based on maternal age, body mass index (BMI), and duration of infertility, ensuring comparability between the matched groups. Patients with conditions like hydrosalpinx, polycystic ovarian syndrome (PCOS), or those using hormonal medications, were excluded.

The IVF/ICSI procedures involved standard controlled ovarian stimulation protocols (flexible long GnRH agonist or antagonist protocols). Oocyte retrieval was performed 36 hours after hCG administration, followed by fertilization (standard or ICSI) and embryo culture for up to six days. One or two embryos were transferred based on patient age, cycle rank, and embryo quality.

The primary outcome measure was cumulative live birth rate (CLBR), defined as the rate of live birth after transferring all fresh or frozen-thawed embryos from a stimulated cycle. Secondary outcomes included ovarian reserve markers (AMH, AFC), ovarian sensitivity index (OSI), number of oocytes retrieved, oocyte maturity, fertilization rate, embryo quality, implantation rate, clinical pregnancy rate (CPR), and live birth rate (LBR). The study also performed subgroup analyses to evaluate the effects of prior ovarian surgery, cyst size (<40mm, 40-60mm, ≥60mm), and laterality (unilateral vs. bilateral) on IVF/ICSI outcomes.

Key Findings of Zeng et al.

  1. Ovarian Reserve and Response to Stimulation:
    • After PSM, women with OMAs had significantly lower ovarian reserve markers, including mean serum AMH levels and Antral Follicle Count (AFC), compared to the control group (p=0.001 and p=0.000, respectively).
    • The OMA group also required significantly greater doses of gonadotropins and showed a lower number of follicles on the day of hCG administration.
    • This led to a lower number of oocytes retrieved and a lower Ovarian Sensitivity Index (OSI) in women with OMAs, indicating a decreased ovarian response to stimulation.
    • When comparing ovaries with OMAs to the contralateral ovaries in women with unoperated unilateral OMAs, the OMA-affected ovaries had a significantly lower AFC, though the number of follicles and oocytes retrieved were similar.
  1. Oocyte and Embryo Quality:
    • The study found a significantly lower number of metaphase II (MII) oocytes, fertilized oocytes, total embryos, transplantable embryos, and top-quality embryos in the OMA group compared to controls.
    • However, despite these numerical reductions, the fertilization rate and blastocyst rate were not significantly different between the two groups. This suggests that while OMAs may reduce the quantity of oocytes and embryos, they do not necessarily impair the quality of the remaining oocytes or their developmental potential to the blastocyst stage.
  1. Pregnancy and Live Birth Outcomes:
    • The most impactful finding was that the cumulative live birth rates (CLBRs) were comparable between the OMA group and the control group (55.64% vs. 54.34%, p=0.806). This indicates that, despite compromised ovarian reserve and response, women with OMAs have similar overall chances of achieving a live birth through multiple IVF cycles.
    • Similarly, implantation rates, clinical pregnancy rates (CPRs), and live birth rates (LBRs) per fresh and frozen embryo transfer (FET) cycles were comparable, with only a slight difference in CPRs for FET cycles.
    • Multivariate analysis identified age and the number of top-quality embryos as independent factors associated with CLBRs, but the presence of OMA diagnosis itself was not correlated with live birth after adjustment.
  1. Impact of Prior Ovarian Surgery:
    • Patients with a history of prior ovarian cyst surgery for OMAs had significantly lower ovarian reserve parameters (AMH and AFC) and poorer ovarian response (OSI and number of follicles) compared to those with unoperated OMAs. This resulted in lower numbers of matured and fertilized oocytes and embryos.
    • However, importantly, oocyte maturity rate, fertilization rate, and implantation rate remained comparable between the surgically treated and unoperated OMA groups.
    • The CLBRs for the surgically treated group showed only a slight trend towards being lower (50.00% vs. 57.14%) but did not reach statistical significance, reinforcing that prior surgery did not significantly improve or worsen overall live birth outcomes.
  1. Impact of OMA Size and Laterality:
    • A negative correlation was detected between OMA size and AFC levels in patients with unoperated OMAs.
    • Women with OMAs ≥ 60 mm had a significantly lower AFC, fewer follicles, fewer oocytes retrieved, fewer fertilized oocytes, embryos, transplantable embryos, and top-quality embryos compared to those with OMAs < 40 mm.
    • Despite these reductions, the CLBRs showed a trend towards being lower in the ≥ 60 mm group but did not achieve statistical significance, partly due to the small sample size in this subgroup.
    • Patients with bilateral OMAs had lower AMH, AFC, oocytes, and embryos compared to those with unilateral OMAs, but there was no significant difference in IVF/ICSI outcomes (CPRs, LBRs, CLBRs).

Discussion and Implications The findings by Zeng et al. provide compelling evidence that while ovarian endometriomas significantly diminish ovarian reserve and response to stimulation, they do not negatively affect overall pregnancy outcomes, specifically cumulative live birth rates, in women undergoing IVF/ICSI. This aligns with other meta-analyses which consistently reported comparable clinical pregnancy and live birth rates in women with intact endometriomas compared to controls, or after surgical cystectomy. This suggests that the impact of OMAs is primarily on the quantity of retrieved oocytes and embryos, rather than the intrinsic quality of the surviving gametes or the overall success of the ART treatment.

The study further reinforces the notion that surgical excision of endometriomas prior to IVF/ICSI may not be beneficial. While surgery can partly improve oocyte maturation and fertilization rates and some embryo quality parameters, it often leads to a reduction in ovarian reserve and fewer oocytes retrieved, ultimately not improving overall pregnancy outcomes. This supports a more conservative management approach for OMAs when fertility is the primary concern, especially considering the well-documented risks of iatrogenic ovarian damage during surgery, such as inadvertent removal of healthy tissue and thermal injury. The study’s observation that the impact of OMAs (and prior surgery) on CLBRs was not statistically significant, even in subgroups with larger or bilateral cysts, further strengthens the argument against routine surgical intervention.

Zeng et al.’s work contributes significantly by focusing on CLBRs and incorporating PSM to balance baseline characteristics, providing a more robust analysis than many previous retrospective studies. The direct comparison between ovaries with and without endometrioma in the same patient offers valuable intra-patient insights into ovarian function.

Limitations and Future Directions The study acknowledges its retrospective and observational design as a limitation, which inherently carries the risk of biases, even with PSM. The inability to completely exclude peritoneal endometriosis in the control group is also noted as a potential confounder. Furthermore, the sample size, particularly in some subgroups like those with very large endometriomas, might limit the statistical power for definitive conclusions on specific OMA characteristics.

Future research should include large, prospective randomized controlled trials to definitively confirm these findings. More detailed subgroup analyses are needed to explore the influence of specific OMA characteristics (e.g., painful symptoms, exact size categories, recurrence) on IVF outcomes. Deeper investigations into the pathogenetic mechanisms of ovarian damage and the impact of different treatment modalities (e.g., medical therapies like Dienogest, or non-conservative alternatives like sclerotherapy) on ovarian reserve and fertility outcomes are also crucial to refine clinical guidelines and patient counseling.

In conclusion, Zeng et al. provide strong evidence that while ovarian endometriomas significantly impair ovarian reserve and response to stimulation, they do not substantially compromise the overall cumulative live birth rates in women undergoing IVF/ICSI. This reinforces the current trend towards conservative management of endometriomas in infertile women, advocating against routine surgical intervention unless there are compelling indications beyond improving IVF success rates.

Endometrioma Surgery: Benefits Versus Risks

  • Facilitates Oocyte Retrieval
    • Surgical enucleation of endometriomas may simplify subsequent oocyte retrieval after ovarian stimulation. This can be particularly helpful when the endometrioma interferes with ovarian accessibility, making ovum pick-up problematic.
  • Reduces ART Complications
    • Surgery can decrease the likelihood of follicular fluid contamination or infection during oocyte retrieval procedures. It may also lower the risk of chemical peritonitis.
  • Allows for Histological Diagnosis and Rules out Malignancy
    • Surgery provides tissue for histological diagnosis, which is crucial to exclude occult malignancy. While rare (approximately 0.9% of cases), unexpected malignancies can be found during surgery for ovarian endometriomas. Avoiding surgery increases the risk of missing these occult malignancies. The lifetime ovarian cancer risk is estimated to be slightly higher in women with endometriosis (1.80%) compared to the general population (1.31%).
  • Ameliorates Pain Symptoms
    • A primary objective of endometriosis surgical treatment is to alleviate a woman’s symptoms, such as chronic pelvic pain, dysmenorrhea, and dyspareunia, especially when medical therapies have failed to control these symptoms.
  • Restores Tubo-Ovarian Anatomy
    • Surgical treatment can help restore distorted tubo-ovarian anatomy, which may facilitate natural conception and ease the process of oocyte retrieval.
  • Potential for Spontaneous Pregnancy
    • In some clinical settings, about 60% of women treated surgically for endometriosis-associated infertility are able to conceive spontaneously within 6 to 12 months after the procedure.
  • Addresses Larger Cysts
    • Surgery is often recommended for larger endometriomas (e.g., those over 4 cm in diameter) particularly when pain is resistant to hormonal treatments or when ultrasound findings raise suspicion of malignancy. Some studies have suggested that endometriomas larger than 3 cm can negatively influence the ovarian response to stimulation.
  • Improved Oocyte and Embryo Quality (Limited Evidence)
    • One study indicated that surgical intervention prior to IVF/ICSI could partially improve oocyte maturation and fertilization rates, though it did not impact overall pregnancy outcomes.
  • Better Post-Surgical Fecundability
    • The stripping technique, which is the recommended surgical treatment for ovarian endometriomas, has been associated with better post-surgical fecundability.
  • Detrimental Impact on Ovarian Reserve and Damage to Healthy Tissue
    • Inadvertent Tissue Removal: Laparoscopic stripping of endometriomas is frequently complicated by the unintentional removal of healthy ovarian tissue and primordial follicles located adjacent to the pseudo-capsule, which appears unavoidable even for experienced surgeons. This iatrogenic damage can result from the manipulation of the cortex, tearing of tissue planes, and coagulation damage.
    • Reduced AMH Levels: Surgery leads to a significant reduction in ovarian reserve biomarkers, particularly Anti-Müllerian Hormone (AMH) levels. Some meta-analyses show AMH levels significantly declining by 1.65 ng/mL (equivalent to a 39% decrease) after unilateral cystectomy and by 2.03 ng/mL (57% decrease) after bilateral cystectomy at 9-12 months post-operation. This impact is often considered permanent, with AMH concentrations remaining reduced by an estimated 40-53% at 9-18 months postoperatively.
  • No Improvement in IVF Success Rates
    • Most evidence suggests that surgery does not enhance the success rate of IVF cycles and may even negatively affect Assisted Reproductive Technologies (ART) by reducing the ovarian response to controlled ovarian stimulation. Multiple systematic reviews and meta-analyses have consistently found that clinical pregnancy rates and live birth rates are comparable between women who undergo endometriotic cystectomy and those with intact endometriomas. Some studies report similar pregnancy and live birth rates despite fewer oocytes retrieved in surgically treated patients.
  • Higher Gonadotropin Doses Required
    • Women who have undergone previous laparoscopic cystectomy for endometrioma often require higher doses of gonadotrophins for ovarian stimulation during IVF.
  • Lower Number of Oocytes Retrieved
    • Surgical removal is associated with a lower number of retrieved oocytes compared to women with other types of infertility or those with intact endometriomas.
  • Risk of Post-Surgical Complications
    • Any surgical intervention, even minimally invasive ones, exposes patients to the inherent risks of complications.
  • Endometrioma Itself Can Affect Ovarian Reserve
    • The mere presence of an endometrioma can negatively impact ovarian reserve. Proposed mechanisms include mechanical compression of surrounding ovarian tissue, impaired circulation, inflammatory reactions, toxic elements like free iron radicals, and enhanced follicular recruitment and atresia (a “burnout” effect). One prospective study found that AMH levels in women with intact endometriomas decreased significantly faster (26% over 6 months) compared to healthy women (7%).
  • Risk of Premature Ovarian Insufficiency (POI)
    • Although uncommon (affecting up to 2.4% of women), POI can occur after endometriotic cystectomy, particularly following bilateral surgery or repeat procedures, and is more prevalent in older women undergoing surgery.
  • Less Aggressive Techniques May Lead to Higher Recurrence
    • While non-excisional techniques (such as ablation or sclerotherapy) might be more ovarian-sparing, they can be associated with higher rates of disease recurrence compared to the stripping technique.
  • Low Risk of Complications with Conservative Management
    • The risk of complications, such as infection, during ART procedures in women with intact endometriomas is considered low (e.g., 0.6%). Some studies suggest that accidental or voluntary endometrioma punctures during oocyte retrieval do not increase the risk of pelvic infection, especially when the cysts are completely aspirated and washed.
  • Age Attenuates Differences
    • The differences in ovarian stimulation parameters and reproductive outcomes after IVF between women with endometriosis and those with other types of infertility tend to diminish with increasing maternal age (specifically, over 35-40 years).
  • Unclear Benefit for Smaller Cysts
    • Endometriomas that are 3 cm or smaller in diameter may not have a detrimental effect on ovarian reserve in ICSI cycles. The necessity of surgical resection for endometriomas smaller than 60 mm should be carefully evaluated.
  • Limitations of Retrospective Studies
    • Many meta-analyses that evaluate ART outcomes in women with endometrioma, including those showing no benefit from surgery, are predominantly based on retrospective study designs. This can potentially affect the reliability and strength of the conclusions drawn from such studies.

Podcast

Slides for a 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.