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 organised after finalisation 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 INTEREST(S) 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. CMB 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). AB 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; AH 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. OH 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. LK 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). MK 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. AN 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 World Endometriosis Society. ES 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. CT 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, Merck SA. The other authors have no conflicts of interest to declare.

In 2005, under the auspices of ESHRE, a group of international experts evaluated the existing best evidence and published the first European guideline on the management of endometriosis. This highly successful project was the first guideline by ESHRE and was adopted by many counties as their national standard. A second, fully-updated edition was presented in 2013. For the new ESHRE Endometriosis Guideline, published in February 2022, all available evidence for twelve chosen topics was gathered by a senior research specialist. Subgroups comprised of patient representatives and experts in healthcare, reproductive science and epidemiology evaluated the data according to GRADE criteria. Each subgroup wrote a chapter and formulated their recommendations which were then presented by a representative to the core group. There, a provisional document was generated and made available for stakeholder review. The resulting comments were taken into account and where relevant incorporated into the final guideline document for which approval was sought and gained from the ESHRE Executive Committee. 35 PICO (Patients, Interventions, Comparison, Outcome) and seven narrative questions were addressed resulting in 78 Research Recommendations were formulated. Where sufficient scientific evidence was lacking and the Guideline Development Group (GDG) was of the opinion that an important topic needed to be highlighted Good Clinical Practice Points where created based on experts’ experience. During the process of reviewing the literature it became apparent that large knowledge gaps of the best clinical approach to endometriosis exist. As a result, 30 research recommendations were also produced. One of the main differences to the 2013 version of the ESHRE guidelines is that laparoscopy is no longer the gold standard for endometriosis per se as there exist sufficient data to support the use of transvaginal ultrasound performed by an experienced operator or MRI can equally identify or rule out ovarian and most of deep endometriosis. However, it is recognised by the GDG that the required imaging standards are not ubiquitously available and for peritoneal disease both sensitivity and specificity using either imaging modalities are still poor. As opposed to the 2013 recommendation, the GDG does not anymore recommend an ultralong protocol for the women with rASRM stage III/IV endometriosis to improve IVF success rates. Furthermore, gonadotropin releasing hormone antagonists seem to be effective in the treatment of endometriosis-associate pain and, where available, could be considered as second-line treatment. Other changes were specific chapters on endometriosis in adolescents and in menopausal women as the GDG strongly felt that these groups are concerningly underrepresented in clinical care and research. Finally, a chapter focussing on the association of endometriosis with certain forms of cancer namely subgroups of ovarian cancer, breast and thyroid cancer was added to give both patients and clinicians a better insight into the current evidence of this complex topic. The GDG hope that the new ESHRE Endometriosis Guideline will improve the clinical management of a highly prevalent and heterogenous disease and that the freely-available patient-friendly version of the guideline empowers symptomatic and asymptomatic women to seek the best available advice, support and treatment.

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