FEMaLe: The use of machine learning for early diagnosis of endometriosis based on patient self-reported data-Study protocol of a multicenter trial.

INTRODUCTION: Endometriosis is a chronic disease that affects up to 190 million women and those assigned female at birth and remains unresolved mainly in terms of etiology and optimal therapy. It is defined by the presence of endometrium-like tissue outside the uterine cavity and is commonly associated with chronic pelvic pain, infertility, and decreased quality of life. Despite the availability of various screening methods (e.g., biomarkers, genomic analysis, imaging techniques) intended to replace the need for invasive surgery, the time to diagnosis remains in the range of 4 to 11 years. AIMS: This study aims to create a large prospective data bank using the Lucy mobile health application (Lucy app) and analyze patient profiles and structured clinical data. In addition, we will investigate the association of removed or restricted dietary components with quality of life, pain, and central pain sensitization. METHODS: A baseline and a longitudinal questionnaire in the Lucy app collects real-world, self-reported information on symptoms of endometriosis, socio-demographics, mental and physical health, economic factors, nutritional, and other lifestyle factors. 5,000 women with confirmed endometriosis and 5,000 women without diagnosed endometriosis in a control group will be enrolled and followed up for one year. With this information, any connections between recorded symptoms and endometriosis will be analyzed using machine learning. CONCLUSIONS: We aim to develop a phenotypic description of women with endometriosis by linking the collected data with existing registry-based information on endometriosis diagnosis, healthcare utilization, and big data approach. This may help to achieve earlier detection of endometriosis with pelvic pain and significantly reduce the current diagnostic delay. Additionally, we may identify dietary components that worsen the quality of life and pain in women with endometriosis, upon which we can create real-world data-based nutritional recommendations.

Circulating microRNAs as Non-Invasive Biomarkers in Endometriosis Diagnosis-A Systematic Review.

The aim of this systematic review is to assess the power of circulating miRNAs as biomarkers as a diagnostic tool in endometriosis. In endometriosis-suspected women with uncertain imaging, the only way to confirm or exclude endometriosis with certainty is currently laparoscopy. This creates a need for non-invasive diagnostics. We searched the literature through the PubMed database using the Mesh terms 'endometriosis' and 'miRNAs'. Some, but limited, overlap was found between the 32 articles included, with a total of 20 miRNAs reported as dysregulated in endometriosis in two or more studies. MiR-17-5p was reported as dysregulated in six studies, followed by miR-451a and let-7b-5p in four studies and miR-20a-5p, miR-143-3p, miR-199a-5p and miR-3613-5p in three studies. Furthermore, a possible impact of the menstrual phase on miRNA expression was noted in five studies, while no influence of hormonal intake was observed in any included study. The modest reproducibility between studies may be attributable to biological variability as well as to the lack of universal protocols, resulting in pre- and analytical variability. Despite the identification of several suitable candidate biomarkers among the miRNAs, the need for high-quality studies with larger and well-defined population cohorts and the use of standardized protocols lingers.

Correlation Between Surgical Phenotype and Pain Improvement After Endometriosis Surgery.

STUDY OBJECTIVE: To examine pain improvement after endometriosis surgery and whether it can be predicted by the observed surgical phenotype. DESIGN: Prospective longitudinal survey study. SETTING: A University hospital. PATIENTS: A total of 125 patients completed a preoperative questionnaire (response rate: n = 227 of 277, 81.9%), had surgically confirmed endometriosis (n = 202 of 227), and returned a second postoperative questionnaire (response rate: n = 125 of 202, 61.9%). INTERVENTIONS: All patients underwent complete laparoscopic removal of the endometriotic lesions. Surgical phenotype was classified according to the rASRM and #Enzian classification. MEASUREMENTS AND MAIN RESULTS: The intensity of 5 specific pain symptoms was questioned by postal paper-pencil questionnaires with a numerical rating scale (0-10) both preoperatively (3.01 ± 2.72 months before surgery) and one year after surgery (12.62 ± 1.59 months). A postoperative pain improvement score was computed (postoperative pain-preoperative pain) for each specific pain symptom (0-10) and for the overall/global pain sum score (0-50). The mean intensity of all pain scores was lower postoperatively as compared with preoperatively (p <.0001). A statistically significant weak correlation was observed between the surgical phenotype "rectovaginal endometriosis" and postoperative improvement of dyspareunia (r = .265; p = .003). The other 11 hypothesized correlations between surgical phenotype and postoperative improvement of pain intensity failed to reach statistical significance. CONCLUSION: Clinicians can inform patients that surgery is effective in reducing endometriosis-related pain symptoms and the overall/global pain scores at 12 months postoperatively. From our data, we can conclude that patients with rectovaginal endometriosis might benefit the most from the reduction of their sexual pain. On the basis of these results, we could suggest that deep dyspareunia (even if present as an isolated symptom) might be a valid indication for surgery. Further research could explore the association between a certain surgical phenotype and more detailed assessments of sexual functioning, as well as explore whether feedback from the surgeon on expected pain improvement affects patient-reported outcomes.

An irreversible inhibitor of 17ß-hydroxysteroid dehydrogenase type 1 inhibits estradiol synthesis in human endometriosis lesions and induces regression of the non-human primate endometriosis.

Endometriosis is a gynecological disorder affecting about 10% of women and can lead to invalidating painful symptoms and infertility. Since there is no current definitive cure for this disease, new therapeutic options are necessary. 17ß-Hydroxysteroid dehydrogenase type 1 (17ß-HSD1) is involved in the production of estradiol (E2), the most potent estrogen in women, and of 5-androstene-3ß,17ß-diol (5-diol), a weaker estrogen than E2, but whose importance increases after menopause. 17ß-HSD1 is therefore a pharmacological target of choice for the treatment of estrogen-dependent diseases such as endometriosis. We developed a targeted-covalent (irreversible) and non-estrogenic inhibitor of 17ß-HSD1, a molecule named PBRM, and herein evaluated its efficiency for the treatment of endometriosis. In a cell-free assay containing estrone (E1), the natural substrate of 17ß-HSD1, PBRM was able to block the formation of E2 in a collection of 50 human endometriosis lesions from a different clinical feature type, location, and phase. When given orally by gavage at 15 mg/kg to baboons, the resulting plasmatic concentration of PBRM was found to be sufficiently high (up to 125 ng/mL) for an efficacy study in a non-human primate (baboon) endometriosis model. After 2 months of treatment, the number of lesions/adhesions decreased in 60% of animals (3/5) in the PBRM-treated group, compared to the placebo group which showed an increase in the number of lesion/adhesions in 60% (3/5) of animals. Indeed, the total number of lesions/adhesions decreased in treated group (-6.5 or -19% when excluding one animal) while it increased in the control group receiving a placebo (+11%). Analysis of specific endometriotic lesions revealed that PBRM decreased the number of red lesions (-67%; 8/12) and white lesions (-35%; 11/31), but not of blue-black lesions. Similarly, PBRM decreased the surface area of dense adhesions and filmy adhesions, as compared to placebo. Also, PBRM treatment did not significantly affect the number of menstrual days. Finally, this targeted covalent inhibitor showed no adverse effects and no apparent toxicity for the duration of the treatment. These data indicate that 17ß-HSD1 inhibitor PBRM is a promising candidate for therapy targeting endometriosis and supports the need of additional efforts toward clinical trials.

Similar long-term recurrence rates with cystectomy and CO2 laser vaporization for endometrioma: a retrospective study.

RESEARCH QUESTION: Is there a difference in recurrence rate of endometrioma(s) after cystectomy versus CO2 laser vaporization of the cyst wall? DESIGN: This single-centre retrospective study included 270 patients undergoing laparoscopic surgery for endometriomas between January 2010 and December 2014, stratified according to the surgical technique used. All 270 included patients underwent complete laparoscopic surgery for endometrioma(s): 155 underwent cystectomy, 63 complete CO2 laser vaporization of the cyst wall and 52 a mixed technique. The primary outcome studied was the difference in recurrence rate between the cystectomy group and the CO2 laser vaporization group. RESULTS: The mean duration of follow-up was 58 (±34) months. Imaging-based recurrence (any cyst size) was reported in 9.9% of patients (n = 12/121) treated with cystectomy and in 13.3% of patients (n = 6/45) who underwent a vaporization (P = 0.577). The need for reintervention for endometrioma(s) was also similar in both groups, with a rate of 3.2% (n = 5/155) after cystectomy and 4.8% (n = 3/63) after vaporization (P = 0.476). Of 160 women who wanted to conceive immediately after surgery, 73.8% became pregnant (72.6% [77/106] in the cystectomy group and 75.9% [41/54] in the vaporization group [P = 0.310]). Conception occurred mostly by assisted reproductive technology (57.1% [44/77] in the cystectomy group and 70.7% [29/41] in the vaporization group [P = 0.074]). CONCLUSIONS: Similar rates of recurrence for endometrioma(s) were observed after cystectomy versus CO2 laser vaporization. As other studies have suggested that CO2 laser vaporization may be less harmful to the normal ovarian tissue, it can be considered as a safe alternative for cystectomy in women wishing to preserve their reproductive potential.

ESHRE guideline: endometriosis.

STUDY QUESTION: How should endometriosis be diagnosed and managed based on the best available evidence from published literature? SUMMARY ANSWER: The current guideline provides 109 recommendations on diagnosis, treatments for pain and infertility, management of disease recurrence, asymptomatic or extrapelvic disease, endometriosis in adolescents and postmenopausal women, prevention and the association with cancer. WHAT IS KNOWN ALREADY: Endometriosis is a chronic condition with a plethora of presentations in terms of not only the occurrence of lesions, but also the presence of signs and symptoms. The most important symptoms include pain and infertility. STUDY DESIGN SIZE DURATION: The guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 1 December 2020 and written in English were included in the literature review. PARTICIPANTS/MATERIALS SETTING METHODS: Based on the collected evidence, recommendations were formulated and discussed within specialist subgroups and then presented to the core guideline development group (GDG) until consensus was reached. A stakeholder review was organized after finalization of the draft. The final version was approved by the GDG and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: This guideline aims to help clinicians to apply best care for women with endometriosis. Although studies mostly focus on women of reproductive age, the guideline also addresses endometriosis in adolescents and postmenopausal women. The guideline outlines the diagnostic process for endometriosis, which challenges laparoscopy and histology as gold standard diagnostic tests. The options for treatment of endometriosis-associated pain symptoms include analgesics, medical treatments and surgery. Non-pharmacological treatments are also discussed. For management of endometriosis-associated infertility, surgical treatment and/or medically assisted reproduction are feasible. While most of the more recent studies confirm previous ESHRE recommendations, there are five topics in which significant changes to recommendations were required and changes in clinical practice are to be expected. LIMITATIONS REASONS FOR CAUTION: The guideline describes different management options but, based on existing evidence, no firm recommendations could be formulated on the most appropriate treatments. Also, for specific clinical issues, such as asymptomatic endometriosis or extrapelvic endometriosis, the evidence is too scarce to make evidence-based recommendations. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides clinicians with clear advice on best practice in endometriosis care, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in endometriosis. STUDY FUNDING/COMPETING INTERESTS: The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payments. C.M.B. reports grants from Bayer Healthcare and the European Commission; Participation on a Data Safety Monitoring Board or Advisory Board with ObsEva (Data Safety Monitoring Group) and Myovant (Scientific Advisory Group). A.B. reports grants from FEMaLE executive board member and European Commission Horizon 2020 grant; consulting fees from Ethicon Endo Surgery, Medtronic; honoraria for lectures from Ethicon; and support for meeting attendance from Gedeon Richter; A.H. reports grants from MRC, NIHR, CSO, Roche Diagnostics, Astra Zeneca, Ferring; Consulting fees from Roche Diagnostics, Nordic Pharma, Chugai and Benevolent Al Bio Limited all paid to the institution; a pending patent on Serum endometriosis biomarker; he is also Chair of TSC for STOP-OHSS and CERM trials. O.H. reports consulting fees and speaker's fees from Gedeon Richter and Bayer AG; support for attending meetings from Gedeon-Richter, and leadership roles at the Finnish Society for Obstetrics and Gynecology and the Nordic federation of the societies of obstetrics and gynecology. L.K. reports consulting fees from Gedeon Richter, AstraZeneca, Novartis, Dr KADE/Besins, Palleos Healthcare, Roche, Mithra; honoraria for lectures from Gedeon Richter, AstraZeneca, Novartis, Dr KADE/Besins, Palleos Healthcare, Roche, Mithra; support for attending meetings from Gedeon Richter, AstraZeneca, Novartis, Dr KADE/Besins, Palleos Healthcare, Roche, Mithra; he also has a leadership role in the German Society of Gynecological Endocrinology (DGGEF). M.K. reports grants from French Foundation for Medical Research (FRM), Australian Ministry of Health, Medical Research Future Fund and French National Cancer Institute; support for meeting attendance from European Society for Gynaecological Endoscopy (ESGE), European Congress on Endometriosis (EEC) and ESHRE; She is an advisory Board Member, FEMaLe Project (Finding Endometriosis Using Machine Learning), Scientific Committee Chair for the French Foundation for Research on Endometriosis and Scientific Committee Chair for the ComPaRe-Endometriosis cohort. A.N. reports grants from Merck SA and Ferring; speaker fees from Merck SA and Ferring; support for meeting attendance from Merck SA; Participation on a Data Safety Monitoring Board or Advisory Board with Nordic Pharma and Merck SA; she also is a board member of medical advisory board, Endometriosis Society, the Netherlands (patients advocacy group) and an executive board member of the World Endometriosis Society. E.S. reports grants from National Institute for Health Research UK, Rosetrees Trust, Barts and the London Charity; Royalties from De Gruyter (book editor); consulting fees from Hologic; speakers fees from Hologic, Johnson & Johnson, Medtronic, Intuitive, Olympus and Karl Storz; Participation in the Medicines for Women's Health Expert Advisory Group with Medicines and Healthcare Products Regulatory Agency (MHRA); he is also Ambassador for the World Endometriosis Society. C.T. reports grants from Merck SA; Consulting fees from Gedeon Richter, Nordic Pharma and Merck SA; speaker fees from Merck SA, all paid to the institution; and support for meeting attendance from Ferring, Gedeon Richter and Merck SA. The other authors have no conflicts of interest to declare. DISCLAIMER: This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgement to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose (Full disclaimer available at www.eshre.eu/guidelines.).

Endometriosis Classification Systems: An International Survey to Map Current Knowledge and Uptake.

OBJECTIVE: In the field of endometriosis, several classification, staging and reporting systems have been developed, but do clinicians routinely use these classification systems, which system do they use and what are the clinicians' motivations? DATA SOURCES: A cross-sectional study was performed to gather data on the current use of endometriosis classification systems, problems encountered and interest in a new simple surgical descriptive system for endometriosis. Of particular focus were three systems most commonly used: the Revised American Society for Reproductive Medicine (rASRM) classification, the Endometriosis Fertility Index (EFI), and the ENZIAN classification. Data were analysed by SPSS. A survey was designed using the online SurveyMonkey tool consisting of 11 questions concerning three domains-participants background, existing classification systems and intentions with regards to a new classification system for endometriosis. Replies were collected between 15 May and 1 July 2020. METHODS OF STUDY SELECTION: na TABULATION, INTEGRATION AND RESULTS: The final dataset included the replies of 1178 clinicians, including surgeons, gynecologists, reproductive endocrinologists, fertility specialists and sonographers, all managing women with endometriosis in their clinical practice. Overall, 75.5% of the professionals indicate that they currently use a classification system for endometriosis. The rASRM classification system was the best known and used system, the EFI system and ENZIAN system were known by a majority of the professionals but used by only a minority. The lack of clinical relevance was most often selected as a problem with using any system. The findings of the survey suggest that clinicians worldwide are open to using a new classification system for endometriosis that can achieve standardized reporting, and is clinically relevant and simple. The findings therefore support future initiatives for the development of a new descriptive system for endometriosis and provide information on user expectations and conditions for universal uptake of such a system. CONCLUSION: Even with a high uptake of the existing endometriosis classification systems (rASRM, ENZIAN and EFI), most clinicians managing endometriosis would like a new simple surgical descriptive system for endometriosis.

Endometriosis classification systems: an international survey to map current knowledge and uptake.

STUDY QUESTION: Which classification system for endometriosis do clinicians use most frequently, and why? SUMMARY ANSWER: Even with a high uptake of the three existing endometriosis classification systems, most clinicians managing endometriosis would like a new simple surgical descriptive system for endometriosis. WHAT IS KNOWN ALREADY: In the field of endometriosis, several classifications, staging and reporting systems have been developed and published, but there are no data on the uptake of these systems in clinical practice. STUDY DESIGN SIZE DURATION: A survey was designed using the online SurveyMonkey tool consisting of 11 questions concerning three domains-participants background, existing classification systems and intentions with regards to a new classification system for endometriosis. Replies were collected between 15 May and 1 July 2020. PARTICIPANTS/MATERIALS SETTING METHODS: A cross-sectional study was performed to gather data on the current use of endometriosis classification systems, problems encountered and interest in a new simple surgical descriptive system for endometriosis. The particular focus was on the three systems most commonly used: the Revised American Society for Reproductive Medicine (rASRM) classification, the endometriosis fertility index (EFI), and the ENZIAN classification. Data were analysed to detect statistically significant differences among user groups. MAIN RESULTS AND THE ROLE OF CHANCE: The final dataset included the replies of 1178 clinicians, including surgeons, gynaecologists, reproductive endocrinologists, fertility specialists and sonographers, all managing women with endometriosis in their clinical practice. Overall, 75.5% of the professionals indicate that they currently use a classification system for endometriosis. The rASRM classification system was the best known and used system, while the EFI system and ENZIAN system were known by a majority of the professionals but used by only a minority. The lack of clinical relevance was most often selected as a problem with using any system. The vast majority of respondents replied positively to the question on whether they would use a simple surgical descriptive system available for endometriosis, if available. LIMITATIONS REASONS FOR CAUTION: While the total number of respondents was acceptable, some regions/professions were not sufficiently represented to draw conclusions. WIDER IMPLICATIONS OF THE FINDINGS: The findings of the survey suggest that clinicians worldwide are open to using a new classification system for endometriosis that can achieve standardized reporting and is clinically relevant and simple. The findings therefore support future initiatives for the development of a new descriptive system for endometriosis and provide information on user expectations and conditions for universal uptake of such a system. STUDY FUNDING/COMPETING INTERESTS: The meetings and activities of the working group were funded by the American Association of Gynecologic Laparoscopists, European Society for Gynecological Endoscopy, ESHRE and World Endometriosis Society. A.W.H. reports grant funding from the MRC, NIHR, CSO, Roche Diagnostics, Astra Zeneca, Ferring, Charles Wolfson Charitable Trust, Standard Life, and consultancy fees from Roche Diagnostics, AbbVie, Nordic Pharma and Ferring, outside the submitted work. In addition, A.W.H. has a patent Serum biomarker for endometriosis pending. He is Chair of TSC for STOP-OHSS and CERM trials and Chair of RCOG Academic Board 2018-2021. M.A. reports being member of the executive board and vice president of AAGL. N.P.J. reports personal fees from Abbott, Guerbet, Myovant Sciences, Vifor Pharma, Roche Diagnostics outside the submitted work; he is also President of the World Endometriosis Society and chair of the trust board. S.M. reports grants from AbbVie, DoD, NIH and Marriot Family Foundation, honoraria from University British Columbia and WERF, support for speaking at conferences (ESHRE, CanSAGE, Endometriosis UK, UEARS, IFFS, IASP, National Endometriosis Network UK) participation on Advisory Boards from AbbVie and Roche, outside the submitted work. She also discloses having a leadership or fiduciary role in SWHR, WERF, WES, ASRM and ESHRE. C.T. reports grants, consulting and speakers' fees non-financial support and other from Merck SA, non-financial support and other consulting fees from Gedeon Richter and Nordic Pharma, and support for meeting attendance non-financial support from Ferring Pharmaceuticals, outside the submitted work and without private revenue. K.T.Z. reports grants from Bayer Healthcare, MDNA Life Sciences, Volition Rx, and Evotec (Lab282-Partnership programme with Oxford University), non-financial support from AbbVie Ltd, all outside the submitted work; and is a Board member (Secretary) of the World Endometriosis Society and World Endometriosis Research Foundation. J.P. reports personal fees from Hologic, Inc., outside the submitted work; he is also a member of the executive boards of ASRM and SRS. The other authors had nothing to disclose.

Endometriotic lung cyst causing catamenial hemoptysis; a case report and review of literature.

We report a rare case of an endometriotic lung cyst in a 47-year woman with recurrent catamenial hemoptysis. Chest computed tomography (CT) obtained outside the menstruation in October 2019 revealed a cystic lesion (2.5 cm) located in the right inferior lobe near the distal esophagus and the inferior pulmonary vein. Compared to CT abdomen in May 2019, this lesion had increased with a larger volume and a thicker wall. An endometrial lung cyst was suspected as episodes of hemoptysis no longer occurred after initiating hormonal treatment with nomegestrol acetate. Exploratory video-assisted thoracoscopic surgery with wedge resection of the cyst was performed. Histopathologic examination confirmed the diagnosis of an endometriotic cystic lesion. Postoperative course was uneventful with no further symptoms since then.

An International Terminology for Endometriosis, 2021.

OBJECTIVE: Different classification systems have been developed for endometriosis, using different definitions for the disease, the different subtypes, symptoms and treatments. In addition, an International Glossary on Infertility and Fertility Care has been published in 2017 by the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) in collaboration with other organisations. An international working group convened over the development of a classification or descriptive system for endometriosis. As a basis for such system, a terminology for endometriosis was considered a condition sine qua non. The aim of the current study was to develop a set of terms and definitions be prepared on endometriosis that would be the basis for standardization in disease description, classification and research. DATA SOURCES: The working group listed a number of terms relevant to be included in the terminology, documented currently used and published definitions, and discussed and adapted them until consensus was reached within the working group. Following stakeholder review, further terms were added, and definitions further clarified. Although definitions were collected through published literature, the final set of terms and definitions is to be considered consensus-based. After finalization of the first draft, the members of the international societies and other stakeholders were consulted for feedback and comments, which lead to further adaptations. METHODS OF STUDY SELECTION: na TABULATION, INTEGRATION, AND RESULTS: A list of 49 terms and definitions in the field of endometriosis is presented, including a definition for endometriosis and its subtypes, different locations, interventions, symptoms and outcomes. Endometriosis is defined as a disease characterized by the presence of endometrium-like epithelium and/or stroma outside the endometrium and myometrium, usually with an associated inflammatory process. CONCLUSION: The current paper outlines a list of 49 terms and definitions in the field of endometriosis. The application of the defined terms aims to facilitate harmonization in endometriosis research and clinical practice. Future research may require further refinement of the presented definitions.

Endometriosis Classification, Staging and Reporting Systems: A Review on the Road to a Universally Accepted Endometriosis Classification.

OBJECTIVE: In the field of endometriosis, several classification, staging and reporting systems have been developed. Which endometriosis classification, staging and reporting systems have been published and validated for use in clinical practice? DATA SOURCES: A systematic PUBMED literature search was performed. Data were extracted and summarized. METHODS OF STUDY SELECTION: na TABULATION, INTEGRATION AND RESULTS: Twenty-two endometriosis classification, staging and reporting systems have been published between 1973 and 2021, each developed for specific, and different, purposes. There still is no international agreement on how to describe the disease. Studies evaluating the different systems are summarized showing a discrepancy between the intended and the evaluated purpose, and a general lack of validation data confirming a correlation with pain symptoms or quality of life for any of the current systems. A few studies confirm the value of the ENZIAN system for surgical description of deep endometriosis. With regards to infertility, the endometriosis fertility index has been confirmed valid for its intended purpose. CONCLUSION: Of the 22 endometriosis classification, staging and reporting systems identified in this historical overview, only a few have been evaluated for the purpose for which they were developed. The literature search was limited to PUBMED. Unpublished classification, staging or reporting systems, or those published in books were not considered. It can be concluded that there is no international agreement on how to describe endometriosis or how to classify it, and that most classification/staging systems show no or very little correlation with patient outcomes. This overview of existing systems is a first step in working towards a universally accepted endometriosis classification.

An international terminology for endometriosis, 2021.

STUDY QUESTION: Can a set of terms and definitions be prepared on endometriosis that would be the basis for standardization in disease description, classification and research? SUMMARY ANSWER: The current paper outlines a list of 49 terms and definitions in the field of endometriosis. WHAT IS KNOWN ALREADY: Different classification systems have been developed for endometriosis, using different definitions for the disease, the different subtypes, symptoms and treatments. In addition, an International Glossary on Infertility and Fertility Care was published in 2017 by the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) in collaboration with other organisations. STUDY DESIGN SIZE DURATION: An international working group convened over the development of a classification or descriptive system for endometriosis. As a basis for such a system, a terminology for endometriosis was considered a condition sine qua non. The working group listed a number of terms relevant to be included in the terminology, documented currently used and published definitions, and discussed and adapted them until consensus was reached within the working group. Following stakeholder review, further terms were added, and definitions further clarified. PARTICIPANTS/MATERIALS SETTING METHODS: Although definitions were collected through published literature, the final set of terms and definitions is to be considered consensus-based. After finalization of the first draft, the members of the international societies and other stakeholders were consulted for feedback and comments, which led to further adaptations. MAIN RESULTS AND THE ROLE OF CHANCE: A list of 49 terms and definitions in the field of endometriosis is presented, including a definition for endometriosis and its subtypes, different locations, interventions, symptoms and outcomes. Endometriosis is defined as a disease characterized by the presence of endometrium-like epithelium and/or stroma outside the endometrium and myometrium, usually with an associated inflammatory process. LIMITATIONS REASONS FOR CAUTION: Future research may require further refinement of the presented definitions. WIDER IMPLICATIONS OF THE FINDINGS: The application of the defined terms aims to facilitate harmonization in endometriosis research and clinical practice. STUDY FUNDING/COMPETING INTERESTS: The meetings and activities of the working group were funded by the American Association of Gynecologic Laparoscopists, European Society for Gynecological Endoscopy, European Society of Human Reproduction and Embryology and World Endometriosis Society. A.W.H. reports grant funding from the MRC, NIHR, CSO, Wellbeing of Women, Roche Diagnostics, Astra Zeneca, Ferring, Charles Wolfson Charitable Trust, Standard Life, Consultancy fees from Roche Diagnostics, AbbVie, Nordic Pharma and Ferring, outside the submitted work. In addition, A.W.H. has a patent Serum biomarker for endometriosis pending. N.P.J. reports personal fees from Abbott, Guerbet, Myovant Sciences, Vifor Pharma, Roche Diagnostics outside the submitted work; he is also President of the World Endometriosis Society and chair of the trust board. S.M. reports grants and personal fees from AbbVie, and personal fees from Roche outside the submitted work. C.T. reports grants, non-financial support and other from Merck SA, non-financial support and other from Gedeon Richter, non-financial support from Ferring Pharmaceuticals, outside the submitted work and without private revenue. K.T.Z. reports grants from Bayer Healthcare, MDNA Life Sciences, Roche Diagnostics Inc, Volition Rx, outside the submitted work; she is also a Board member (Secretary) of the World Endometriosis Society and World Endometriosis Research Foundation, Research Advisory Board member of Wellbeing of Women, UK (research charity), and Chair, Research Directions Working Group, World Endometriosis Society. J.P reports personal fees from Hologic, Inc., outside the submitted work; he is also a member of the executive boards of ASRM and SRS. The other authors had nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.

Endometriosis classification, staging and reporting systems: a review on the road to a universally accepted endometriosis classification.

STUDY QUESTION: Which endometriosis classification, staging and reporting systems have been published and validated for use in clinical practice? SUMMARY ANSWER: Of the 22 endometriosis classification, staging and reporting systems identified in this historical overview, only a few have been evaluated, in 46 studies, for the purpose for which they were developed. WHAT IS KNOWN ALREADY: In the field of endometriosis, several classification, staging and reporting systems have been developed. PARTICIPANTS/MATERIALS SETTING METHODS: A systematic PUBMED literature search was performed. Data were extracted and summarized. MAIN RESULTS AND THE ROLE OF CHANCE: Twenty-two endometriosis classification, staging and reporting systems have been published between 1973 and 2021, each developed for specific, and different, purposes. There still is no international agreement on how to describe the disease. Studies evaluating the different systems are summarized showing a discrepancy between the intended and the evaluated purpose, and a general lack of validation data confirming a correlation with pain symptoms or quality of life for any of the current systems. A few studies confirm the value of the ENZIAN system for surgical description of deep endometriosis. With regards to infertility, the endometriosis fertility index has been confirmed valid for its intended purpose. LARGE SCALE DATA: NA. LIMITATIONS REASONS FOR CAUTION: The literature search was limited to PUBMED. Unpublished classification, staging or reporting systems, or those published in books were not considered. WIDER IMPLICATIONS OF THE FINDINGS: It can be concluded that there is no international agreement on how to describe endometriosis or how to classify it, and that most classification/staging systems show no or very little correlation with patient outcomes. This overview of existing systems is a first step in working toward a universally accepted endometriosis classification. STUDY FUNDING/COMPETING INTERESTS: The meetings and activities of the working group were funded by the American Association of Gynecologic Laparoscopists, European Society for Gynecological Endoscopy, European Society of Human Reproduction and Embryology and World Endometriosis Society. A.W.H. reports grant funding from the MRC, NIHR, CSO, Wellbeing of Women, Roche Diagnostics, Astra Zeneca, Ferring, Charles Wolfson Charitable Trust, Standard Life, Consultancy fees from Roche Diagnostics, AbbVie, Nordic Pharma and Ferring, outside the submitted work. In addition, A.W.H. has a patent Serum biomarker for endometriosis pending. N.P.J. reports personal fees from Abbott, Guerbet, Myovant Sciences, Vifor Pharma, Roche Diagnostics, outside the submitted work; he is also President of the World Endometriosis Society and chair of the trust board. S.M. reports grants and personal fees from AbbVie, and personal fees from Roche outside the submitted work. C.T. reports grants, non-financial support and other from Merck SA, non-financial support and other from Gedeon Richter, non-financial support from Ferring Pharmaceuticals, outside the submitted work and without private revenue. K.T.Z. reports grants from Bayer Healthcare, MDNA Life Sciences, Roche Diagnostics Inc, Volition Rx, outside the submitted work; she is also a Board member (Secretary) of the World Endometriosis Society and World Endometriosis Research Foundation, Research Advisory Board member of Wellbeing of Women, UK (research charity), and Chair, Research Directions Working Group, World Endometriosis Society. The other authors had nothing to disclose. TRIAL REGISTRATION NUMBER: NA.

Laparoscopic surgery for endometriosis.

BACKGROUND: Endometriosis is associated with pain and infertility. Surgical interventions aim to remove visible areas of endometriosis and restore the anatomy. OBJECTIVES: To assess the effectiveness and safety of laparoscopic surgery in the treatment of pain and infertility associated with endometriosis. SEARCH METHODS: This review has drawn on the search strategy developed by the Cochrane Gynaecology and Fertility Group including searching the Cochrane Gynaecology and Fertility Group's specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, reference lists for relevant trials, and trial registries from inception to April 2020. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) that compared the effectiveness and safety of laparoscopic surgery with any other laparoscopic or robotic intervention, holistic or medical treatment, or diagnostic laparoscopy only. DATA COLLECTION AND ANALYSIS: Two review authors independently performed selection of studies, assessment of trial quality and extraction of relevant data with disagreements resolved by a third review author. We collected data for the core outcome set for endometriosis. Primary outcomes included overall pain and live birth. We evaluated the quality of evidence using GRADE methods. MAIN RESULTS: We included 14 RCTs. The studies randomised 1563 women with endometriosis. Four RCTs compared laparoscopic ablation or excision with diagnostic laparoscopy only. Two RCTs compared laparoscopic excision with diagnostic laparoscopy only. One RCT compared laparoscopic ablation or excision with laparoscopic ablation or excision and uterine suspension. Two RCTs compared laparoscopic ablation and uterine nerve transection with diagnostic laparoscopy only. One RCT compared laparoscopic ablation with diagnostic laparoscopy and gonadotropin-releasing hormone (GnRH) analogues. Two RCTs compared laparoscopic ablation with laparoscopic excision. One RCT compared laparoscopic ablation or excision with helium thermal coagulator with laparoscopic ablation or excision with electrodiathermy. One RCT compared conservative laparoscopic surgery with laparoscopic colorectal resection of deep endometriosis infiltrating the rectum. Common limitations in the primary studies included lack of clearly described blinding, failure to fully describe methods of randomisation and allocation concealment, and poor reporting of outcome data. Laparoscopic treatment versus diagnostic laparoscopy We are uncertain of the effect of laparoscopic treatment on overall pain scores compared to diagnostic laparoscopy only at six months (mean difference (MD) 0.90, 95% confidence interval (CI) 0.31 to 1.49; 1 RCT, 16 participants; very low quality evidence) and at 12 months (MD 1.65, 95% CI 1.11 to 2.19; 1 RCT, 16 participants; very low quality evidence), where a positive value means pain relief (the higher the score, the more pain relief) and a negative value reflects pain increase (the lower the score, the worse the increase in pain). No studies looked at live birth. We are uncertain of the effect of laparoscopic treatment on quality of life compared to diagnostic laparoscopy only: EuroQol-5D index summary at six months (MD 0.03, 95% CI -0.12 to 0.18; 1 RCT, 39 participants; low quality evidence), 12-item Short Form (SF-12) mental health component (MD 2.30, 95% CI -4.50 to 9.10; 1 RCT, 39 participants; low quality evidence) and SF-12 physical health component (MD 2.70, 95% CI -2.90 to 8.30; 1 RCT, 39 participants; low quality evidence). Laparoscopic treatment probably improves viable intrauterine pregnancy rate compared to diagnostic laparoscopy only (odds ratio (OR) 1.89, 95% CI 1.25 to 2.86; 3 RCTs, 528 participants; I2 = 0%; moderate quality evidence). We are uncertain of the effect of laparoscopic treatment compared to diagnostic laparoscopy only on ectopic pregnancy (MD 1.18, 95% CI 0.10 to 13.48; 1 RCT, 100 participants; low quality evidence) and miscarriage (MD 0.94, 95% CI 0.35 to 2.54; 2 RCTs, 112 participants; low quality evidence). There was limited reporting of adverse events. No conversions to laparotomy were reported in both groups (1 RCT, 341 participants). Laparoscopic ablation and uterine nerve transection versus diagnostic laparoscopy We are uncertain of the effect of laparoscopic ablation and uterine nerve transection on adverse events (more specifically vascular injury) compared to diagnostic laparoscopy only (OR 0.33, 95% CI 0.01 to 8.32; 1 RCT, 141 participants; low quality evidence). No studies looked at overall pain scores (at six and 12 months), live birth, quality of life, viable intrauterine pregnancy confirmed by ultrasound, ectopic pregnancy and miscarriage. Laparoscopic ablation versus laparoscopic excision There was insufficient evidence to determine whether there was a difference in overall pain, measured at 12 months, for laparoscopic ablation compared with laparoscopic excision (MD 0.00, 95% CI -1.22 to 1.22; 1 RCT, 103 participants; very low quality evidence). No studies looked at overall pain scores at six months, live birth, quality of life, viable intrauterine pregnancy confirmed by ultrasound, ectopic pregnancy, miscarriage and adverse events. Helium thermal coagulator versus electrodiathermy We are uncertain whether helium thermal coagulator compared to electrodiathermy improves quality of life using the 30-item Endometriosis Health Profile (EHP-30) at nine months, when considering the components: pain (MD 6.68, 95% CI -3.07 to 16.43; 1 RCT, 119 participants; very low quality evidence), control and powerlessness (MD 4.79, 95% CI -6.92 to 16.50; 1 RCT, 119 participants; very low quality evidence), emotional well-being (MD 6.17, 95% CI -3.95 to 16.29; 1 RCT, 119 participants; very low quality evidence) and social support (MD 5.62, 95% CI -6.21 to 17.45; 1 RCT, 119 participants; very low quality evidence). Adverse events were not estimable. No studies looked at overall pain scores (at six and 12 months), live birth, viable intrauterine pregnancy confirmed by ultrasound, ectopic pregnancy and miscarriage. AUTHORS' CONCLUSIONS: Compared to diagnostic laparoscopy only, it is uncertain whether laparoscopic surgery reduces overall pain associated with minimal to severe endometriosis. No data were reported on live birth. There is moderate quality evidence that laparoscopic surgery increases viable intrauterine pregnancy rates confirmed by ultrasound compared to diagnostic laparoscopy only. No studies were found that looked at live birth for any of the comparisons. Further research is needed considering the management of different subtypes of endometriosis and comparing laparoscopic interventions with lifestyle and medical interventions. There was insufficient evidence on adverse events to allow any conclusions to be drawn regarding safety.

Outcome after surgery for deep endometriosis infiltrating the rectum.

OBJECTIVE: To evaluate the rate of postoperative complications between conservative surgery and segmental resection in patients with rectal endometriosis. DESIGN: Single-center retrospective study. SETTING: University hospital. PATIENT(S): A total of 232 women undergoing surgery for deep endometriosis infiltrating the rectum up to 15 cm from the anus with at least involvement of the muscularis layer, stratified into two arms according to surgical technique. Subgroup analysis was performed in patients without previous therapeutic laparoscopy for endometriosis (n = 108). A propensity-score approach was used to correct for group differences. INTERVENTION(S): All patients underwent CO2-laser laparoscopic surgery: 61 underwent conservative surgery, and 171 had a segmental resection. MAIN OUTCOME MEASURE(S): Postoperative complication rate (Clavien-Dindo classification). RESULT(S): Clavien-Dindo type 1 and 2 complications did not differ between both groups. Clavien-Dindo type 3 complications were more frequent in the segmental resection group (1/61 [1.6%] conservative vs. 18/171 [10.5%] segmental), after propensity analysis only a trend was retained. In the subgroup analysis, no difference or trend was found (1/27 [3.7%] conservative vs. 5/81 [6.2%] segmental). A low rate of temporary diverting stoma was recorded: 24/232 (10.3%). CONCLUSION(S): A higher major complication (Clavien-Dindo ≥3) rate for segmental resections compared with conservative surgical treatment was shown in the overall population, although after correction for group differences this was attenuated to a trend only. However, in patients without previous therapeutic laparoscopy no significant difference or trend was found regardless of the surgical technique used. This not only suggests that redo/repeated surgery has a potentially increased morbidity, but also emphasizes the importance of a well executed primary surgery.

Mimicking Sampson's Retrograde Menstrual Theory in Rats: A New Rat Model for Ongoing Endometriosis-Associated Pain.

Endometriosis is a prevalent gynecologic disease, defined by dysfunctional endometrium-like lesions outside of the uterine cavity. These lesions are presumably established via retrograde menstruation, i.e., endometrial tissue that flows backwards during menses into the abdomen and deposits on the organs. As ongoing pain is one of the main pain symptoms of patients, an animal model that illuminates this problem is highly anticipated. In the present study, we developed and validated a rat model for ongoing endometriosis-associated pain. First, menstrual endometrial tissue was successfully generated in donor rats, as validated by gross examination, histology and qPCR. Next, endometriosis was induced in recipient animals by intraperitoneal injection of menstrual tissue. This resulted in neuro-angiogenesis as well as established endometriosis lesions, which were similar to their human counterparts, since epithelial and stromal cells were observed. Furthermore, significant differences were noted between control and endometriosis animals concerning bodyweight and posture changes, indicating the presence of ongoing pain in animals with endometriosis. In summary, a rat model for endometriosis was established that reliably mimics the human pathophysiology of endometriosis and in which signs of ongoing pain were detected, thus providing a new research tool for therapy development.

Recommendations for the surgical treatment of endometriosis. Part 2: deep endometriosis.

STUDY QUESTION: How should surgery for endometriosis be performed? SUMMARY ANSWER: This document provides recommendations covering technical aspects of different methods of surgery for deep endometriosis in women of reproductive age. WHAT IS KNOWN ALREADY: Endometriosis is highly prevalent and often associated with severe symptoms. Yet compared to equally prevalent conditions, it is poorly understood and a challenge to manage. Previously published guidelines have provided recommendations for (surgical) treatment of deep endometriosis, based on the best available evidence, but without technical information and details on how to best perform such treatment in order to be effective and safe. STUDY DESIGN SIZE DURATION: A working group of the European Society for Gynaecological Endoscopy (ESGE), ESHRE and the World Endometriosis Society (WES) collaborated on writing recommendations on the practical aspects of surgery for treatment of deep endometriosis. PARTICIPANTS/MATERIALS SETTING METHODS: This document focused on surgery for deep endometriosis and is complementary to a previous document in this series focusing on endometrioma surgery. MAIN RESULTS AND THE ROLE OF CHANCE: The document presents general recommendations for surgery for deep endometriosis, starting from preoperative assessments and first steps of surgery. Different approaches for surgical treatment are discussed and are respective of location and extent of disease; uterosacral ligaments and rectovaginal septum with or without involvement of the rectum, urinary tract or extrapelvic endometriosis. In addition, recommendations are provided on the treatment of frozen pelvis and on hysterectomy as a treatment for deep endometriosis. LIMITATIONS REASONS FOR CAUTION: Owing to the limited evidence available, recommendations are mostly based on clinical expertise. Where available, references of relevant studies were added. WIDER IMPLICATIONS OF THE FINDINGS: These recommendations complement previous guidelines on management of endometriosis and the recommendations for surgical treatment of ovarian endometrioma. STUDY FUNDING/COMPETING INTERESTS: The meetings of the working group were funded by ESGE, ESHRE and WES. Dr Roman reports personal fees from ETHICON, PLASMASURGICAL, OLYMPUS and NORDIC PHARMA, outside the submitted work; Dr Becker reports grants from Bayer AG, Volition Rx, MDNA Life Sciences and Roche Diagnostics Inc. and other relationships or activities from AbbVie Inc., and Myriad Inc, during the conduct of the study; Dr Tomassetti reports non-financial support from ESHRE, during the conduct of the study; and non-financial support and other were from Lumenis, Gedeon-Richter, Ferring Pharmaceuticals and Merck SA, outside the submitted work. The other authors had nothing to disclose. TRIAL REGISTRATION NUMBER: na.

Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening.

Endometrial disorders represent a major gynaecological burden. Current research models fail to recapitulate the nature and heterogeneity of these diseases, thereby hampering scientific and clinical progress. Here we developed long-term expandable organoids from a broad spectrum of endometrial pathologies. Organoids from endometriosis show disease-associated traits and cancer-linked mutations. Endometrial cancer-derived organoids accurately capture cancer subtypes, replicate the mutational landscape of the tumours and display patient-specific drug responses. Organoids were also established from precancerous pathologies encompassing endometrial hyperplasia and Lynch syndrome, and inherited gene mutations were maintained. Endometrial disease organoids reproduced the original lesion when transplanted in vivo. In summary, we developed multiple organoid models that capture endometrial disease diversity and will provide powerful research models and drug screening and discovery tools.