{"paper_id":"b2c4f8f1-7d29-4932-8492-c2e609fa6d30","body_text":"Endometriosis is a disease characterized by the presence of endometrium-like epithelium\nand/or stroma outside the endometrium and myometrium, usually with an associated\ninflammatory process ( International Working Group of\nAAGL, ESGE, ESHRE and WES  et al. , 2021 ). The exact prevalence of\nendometriosis is unknown, but estimates range from 2% to 10% within the general female\npopulation and up to 50% in infertile women ( Eskenazi and Warner, 1997 ;  Meuleman\n et al. , 2009 ;  Zondervan\n et al. , 2020 ).\nThe ESHRE Guideline for the Diagnosis and Treatment of Endometriosis (2005) and the ESHRE\nGuideline: Management of women with endometriosis (2013) have been a reference point for\nbest clinical care in endometriosis for years ( Kennedy  et al. , 2005 ;  Dunselman  et al. , 2014 ). Based on continuous new research and\ndevelopments, it was considered that the last recommendations formulated in 2013/2014\nrequired a revision.\n\nThe guideline was developed according to a well-documented methodology that is universal to\nESHRE guidelines ( Vermeulen  et\nal ., 2019 ). The core guideline development group (GDG) was composed of\npast members of the guideline group from 2013 and additional experts selected from\napplicants to a call for experts. All other European experts applying to the call were\nincluded as subgroup members, assisting a core group member preparing the guideline on a\ncertain topic. The GDG included two patient representatives, and five patient organizations\nwere represented in the subgroups.\nForty-two key questions were formulated by the GDG, of which seven were answered as\nnarrative questions, and 35 as PICO (Patient, Intervention, Comparison, Outcome) questions.\nFor each PICO question, databases (PubMed/MEDLINE and the Cochrane library) were searched\nfrom inception to 1 December 2020, limited to studies written in English. From the\nliterature searches, studies were selected based on the PICO questions, assessed for quality\nand summarized in evidence tables. GDG subgroup meetings were organized, face-to-face and\nonline, for presentation and discussion of the evidence and draft recommendations by the\nassigned core group member. Proposed recommendations by the subgroups were then discussed in\ncore group meetings until a consensus was reached. Each recommendation was labelled as\nstrong or weak and a grade was assigned based on the strength of the supporting evidence\n(High ⊕⊕⊕⊕, Moderate ⊕⊕⊕◯, Low ⊕⊕◯◯ and Very low ⊕◯◯◯). Good practice points (GPPs) based on\nclinical expertise were added where relevant to clarify the recommendations or to provide\nfurther practical advice. ‘Research only’ recommendations were also made, and those\ninterventions should be applied only within the context of research, with appropriate\nprecautions and ethical approval.\nStrong recommendations should be used as a recommendation to be applied for most patients,\nwhile weak recommendations require discussion and shared decision-making ( Fig. 1 ).\nSuggested interpretation of strong and weak recommendations by patients, clinicians and\nhealth care policy makers.\nFor the narrative questions, a similar literature search was conducted. Collected data were\nsummarized in a narrative summary and conclusions were formulated. In case of insufficient\ndata to provide recommendations in reply to a PICO question, a conclusion was also added.\nFor clarity, these conclusions are labelled ‘conclusion, not recommendation’ in the current\npaper.\nThe guideline draft and an invitation to participate in the stakeholder review were\npublished on the ESHRE website between 24 June and 15 August 2021. All comments were\nprocessed by the core group, either by adapting the content of the guideline and/or by\nreplying to the reviewer. The review process was summarized in the review report, which is\npublished on the ESHRE website ( www.eshre.eu/Guidelines ). Overall, 56.5% of the 253 comments resulted in an\nadaptation or correction in the guideline text.\nThis guideline will be considered for update 4 years after publication, with an\nintermediate assessment of the need for updating 2 years after publication.\n\nThe scope of the ESHRE guideline on endometriosis is to provide guidance on the\nmanagement of endometriosis; either diagnosed or strongly suspected. In line with\nendometriosis research, terminology and discussion, the guideline is focused on females\nand menstruation. The GDG recognizes that there are individuals living with endometriosis\nwho are transgender, who do not menstruate, who do not have a uterus or who do not\nidentify with the terms used in the literature. Throughout, the term ‘women with\nendometriosis’ is used, but this is not intended to isolate, exclude or diminish any\nindividual’s experience nor to discriminate against any group.\nThe recommended diagnostic process for endometriosis is summarized in  Fig. 2 .\nThe recommended diagnostic process for endometriosis.  DE, deep\nendometriosis; US, ultrasound.\nAs no recommendation could be made, the following conclusion was formulated. Although\ncurrently no evidence exists that a symptom diary/questionnaire/app reduces the time to\ndiagnosis or leads to earlier diagnosis, the GDG considers their potential benefit in\ncomplementing the traditional history taking process as it aids in objectifying pain and\nempowering women to demonstrate their symptoms  (conclusion, not\nrecommendation) .\nStrong recommendation\n⊕○○○\nStrong recommendation\n⊕⊕○○\nStrong recommendation\n⊕⊕⊕○\nStrong recommendation\n⊕⊕○○\nAs there is no evidence of superiority of either approach ( Chapron  et al. , 1998 ;  Byrne  et al. , 2018 ;  Bafort  et al. , 2020 ), the GDG concluded that\nboth diagnostic laparoscopy and imaging combined with empirical treatment (hormonal\ncontraceptives or progestogens) can be considered in women suspected of endometriosis.\nPros and cons should be discussed with the patient  (conclusion, not\nrecommendation) .\nWeak recommendation\n⊕○○○\nAlthough no adequate studies exist to support the benefits of early versus late\ndiagnosis, the GDG recommends that in symptomatic women, attempts should be made to\nrelieve symptoms, either by empirical treatment or after a diagnosis of endometriosis\n (conclusion, not recommendation) .\nThe recommendations for treatment of pain symptoms linked to endometriosis are summarized\nin  Fig. 3 .\nSummary of the recommendations for treatment of pain symptoms linked to\nendometriosis.  NSAID, non-steroidal anti-inflammatory.\nWeak recommendation\n⊕○○○\nStrong recommendation\n⊕⊕⊕○\nStrong recommendation\n⊕⊕○○\nWeak recommendation\n⊕⊕○○\nStrong recommendation\n⊕⊕○○\nStrong recommendation\n⊕⊕⊕○\nStrong recommendation\n⊕⊕○○\nStrong recommendation\n⊕⊕⊕○\nWeak recommendation\n⊕⊕⊕○\nStrong recommendation\n⊕⊕○○\nStrong recommendation\n⊕⊕○○\nIt can be concluded that laparoscopic uterosacral nerve ablation (LUNA) is not\nbeneficial as an additional procedure to conventional laparoscopic surgery for\nendometriosis, as it offers no additional benefit over surgery alone ( Proctor  et al. , 2005 ).\nPresacral neurectomy (PSN) is beneficial for treatment of endometriosis-associated\nmidline pain as an adjunct to conventional laparoscopic surgery, but it should be\nstressed that PSN requires a high degree of skill and is associated with an increased\nrisk of adverse effects such as intraoperative bleeding, and postoperative constipation,\nurinary urgency and painless first stage of labour ( Miller  et al. , 2020 )  (conclusion,\nnot recommendation) .\nWeak recommendation\n⊕○○○\nStrong recommendation\n⊕○○○\nWeak recommendation\n⊕⊕○○\nOwing to the heterogeneity of patient populations, surgical approaches, preferences and\ntechniques, the GDG decided not to make any conclusions or recommendations on the\ntechniques to be applied for treatment of pain associated with deep endometriosis\n (conclusion, not recommendation) .\nWeak recommendation\n⊕⊕○○\nThere are currently no prognostic markers that can be used to select patients that\nwould benefit from surgery. Such markers would need to be assessed prior to surgery and\npredict a clinically meaningful improvement of pain symptoms. In the absence of\nprognostic markers, no recommendation could be formulated  (conclusion, not\nrecommendation).\nStrong recommendation\n⊕⊕○○\nWeak recommendation\n⊕⊕○○\nThe recommendations for treatment of endometriosis-associated infertility are summarized\nin  Fig. 4 .\nSummary of the recommendations on treatment of endometriosis-associated\ninfertility.  EFI, endometriosis fertility index; MAR, medically assisted\nreproduction.\nStrong recommendation\n⊕⊕○○\nStrong recommendation\n⊕⊕○○\nWeak recommendation\n⊕⊕○○\nStrong recommendation\n⊕○○○\nWeak recommendation\n⊕⊕○○\nWeak recommendation\n⊕○○○\nWeak recommendation\n⊕○○○\nWhile no recommendation could be formulated, the GDG concluded that women should be\ncounselled of their chances of becoming pregnant after surgery. To identify patients\nthat may benefit from ART after surgery, the EFI should be used as it is validated,\nreproducible and cost-effective. The results of other fertility investigations, such as\ntheir partner’s sperm analysis, should be taken into account  (conclusion, not\nrecommendation) .\nWeak recommendation\n⊕○○○\nWeak recommendation\n⊕○○○\nWeak recommendation\n⊕⊕○○\nWeak recommendation\n⊕○○○\nWeak recommendation\n⊕⊕⊕○\nStrong recommendation\n⊕○○○\nWeak recommendation\n⊕○○○\nStrong recommendation\n⊕⊕○○\nStrong recommendation\n⊕⊕○○\nStrong recommendation\n⊕○○○\nRegarding non-medical strategies on infertility, there is no clear evidence that any\nnon-medical interventions for women with endometriosis will be of benefit to increase\nthe chance of pregnancy. No recommendation can be made to support any non-medical\ninterventions (nutrition, Chinese medicine, electrotherapy, acupuncture, physiotherapy,\nexercise and psychological interventions) to increase fertility in women with\nendometriosis. The potential benefits and harms are unclear  (conclusion, not\nrecommendation) .\nStrong recommendation\n⊕○○○\nStrong recommendation\n⊕○○○\nStrong recommendation\n⊕○○○\nComplications related directly to pre-existing endometriosis lesions are rare, but\nprobably under-reported. Such complications may be related to their decidualization,\nadhesion formation/stretching and endometriosis-related chronic inflammation. Although\nrare, they may represent life-threatening situations that may require surgical\nmanagement ( Leone Roberti Maggiore  et\nal. , 2016 ;  Leone Roberti\nMaggiore  et al. , 2017 ;  Lier  et al. , 2017 ;  Glavind  et al. , 2018 ).\nStrong recommendation\n⊕⊕○○\nStrong recommendation\n⊕⊕○○\nThe recommendations and information on endometriosis and pregnancy are summarized in\n Fig. 5 .\nSummary of the recommendations and information on endometriosis and pregnancy.\nStrong recommendation\n⊕⊕○○\nStrong recommendation\n⊕⊕○○\nStrong recommendation\n⊕○○○\nWeak recommendation\n⊕○○○\nWeak recommendation\n⊕⊕⊕○\nWeak recommendation\n⊕○○○\nStrong recommendation\n⊕○○○\nWeak recommendation\n⊕○○○\nchronic or acyclical pelvic pain, particularly combined with nausea,\ndysmenorrhoea, dyschezia, dysuria, dyspareunia;\ncyclical pelvic pain ( Greene\n et al. , 2009 ;  Treloar  et al. , 2010 ;  Vicino  et al. ,\n2010 ;  Yang  et\nal. , 2012 ;  DiVasta  et al. , 2018 ).\nStrong recommendation\n⊕○○○\nIn the absence of evidence for adolescents specifically, the recommendations for\nclinical examination in adults can be applied.\nStrong recommendation\n⊕⊕○○\nStrong recommendation\n⊕⊕○○\nWeak recommendation\n⊕⊕○○\nStrong recommendation\n⊕⊕○○\nStrong recommendation\n⊕○○○\nWeak recommendation\n⊕⊕○○\nWeak recommendation\n⊕○○○\nStrong recommendation\n⊕○○○\nThe GDG concluded that clinicians should be aware that endometriosis can still be\nactive/symptomatic after menopause  (conclusion, not\nrecommendation) .\nWeak recommendation\n⊕○○○\nWeak recommendation\n⊕○○○\nWeak recommendation\n⊕⊕○○\nStrong recommendation\n⊕⊕○○\nClinicians should be aware that women with endometriosis who have undergone an early\nbilateral salpingo-oophorectomy as part of their treatment have an increased risk of\ndiminished bone density, dementia and cardiovascular disease. It is also important to\nnote that women with endometriosis have an increased risk of cardiovascular disease,\nirrespective of whether they have had an early surgical menopause  (conclusion,\nnot recommendation) .\nWeak recommendation\n⊕○○○\nWeak recommendation\n⊕○○○\nStrong recommendation\n⊕○○○\nStrong recommendation\n⊕○○○\nWeak recommendation\n⊕○○○\nWeak recommendation\n⊕⊕○○\nWeak recommendation\n⊕⊕○○\nStrong recommendation\n⊕⊕○○\nInfographic on the absolute risk of developing cancer in a woman’s lifetime.\nBased on the limited literature and controversial findings, there is little evidence\nthat somatic mutations in patients with deep endometriosis may be predictive of\ndevelopment and/or progression of ovarian cancer  (conclusion, not\nrecommendation) .\nStrong recommendation\n⊕○○○\nStrong recommendation\n⊕⊕○○\nStrong recommendation\n⊕⊕○○\n\nThis paper provides an overview of recommendations for diagnosis of endometriosis and\ntreatment of associated symptoms during different stages of life. In addition, guidance is\nprovided on the possible connection with development of cancer, and with regards to\nprevention. Overall, 109 recommendations have been formulated, 79 supported by research data\nand 30 GPPs based primarily on clinical expertise. The guidelines are based on the best\navailable evidence or, where data of sufficient quality were absent, on recommendations by\nthe GDG (GPPs).\nThe current guideline and recommendations are an update of the ESHRE endometriosis\nguidelines published in 2013 and 2005 ( Kennedy\n et al. , 2005 ;  Dunselman\n et al. , 2014 ). The key questions and topics covered in the\nguideline of 2013 were updated based on data published between 2013 and 2021, where\navailable, and in accordance with changes in clinical practice. The latter applied, for\nexample, to the oral use of danazol and anti-progestogens as a medical treatment and to\nLUNA, PSN and anti-adhesion agents as surgical interventions. These interventions are still\ndiscussed in the guideline, but no longer discussed in recommendations for clinical\npractice.\nWhile most of the more recent studies confirm previous ESHRE recommendations, there are\nfive topics in which significant changes in clinical practice are to be expected. The first\nchange, primarily based on clinical practice rather than published data, is the evolution in\nthe diagnostic process. While previously a laparoscopy was regarded as the diagnostic gold\nstandard, it is now only recommended in patients with negative imaging results and/or where\nempirical treatment was unsuccessful or inappropriate. Secondly, studies on GnRH antagonist\ntreatments support their use as an additional (second-line) treatment option. Thirdly,\nrecent data indicate that postoperative medical treatment may be beneficial towards pain\nmanagement and support a recommendation to offer it to women not desiring immediate\npregnancy. Fourthly, the extended administration of GnRH agonist prior to ART treatment to\nimprove live birth rate in infertile women with endometriosis (ultralong protocol) is no\nlonger recommended because of unclear benefits. Finally, the EFI was added as a step in the\ntreatment as it can support decision-making for the most appropriate option to achieve\npregnancy after surgery.\nIn addition to the topics discussed in the previous guideline, the current guideline\naddresses highly important previous gaps in clinical management, with an additional chapter\non adolescent endometriosis, information on pregnancy and fertility preservation, and\nextended information on endometriosis in menopause, as well as data on the link between\nendometriosis and cancer.\nDespite our best efforts to provide clear guidance on the management of endometriosis using\nall available evidence, there is still an urgent need for more research both to achieve more\nclarity on the most appropriate diagnostic and treatment options, and to answer very basic\nquestions as to the natural course of the disease. This guideline provides 30\nrecommendations for research written to inspire researchers and hopefully also facilitate\nfunding for endometriosis studies ( Supplementary Data ).\nIn summary, the 2022 ESHRE Guideline: Endometriosis is a comprehensive update of the\nexisting evidence and should assist healthcare professionals in their decision making and\npatients in their understanding of the management suggestions. Active involvement and input\nby patient representatives at all stages was central to the success of this endeavour. As\nsuch, the guideline was created by medical professionals, patient representatives and\nspecialists in epidemiology and guideline methodology. The detailed guideline document and a\npatient-friendly version can be accessed via the ESHRE website ( https://www.eshre.eu/Guideline/Endometriosis ).\n\nSupplementary data  are available\nat  Human Reproduction Open  online.\n\nThe full guideline and supporting data (literature report, evidence tables) are available\non  www.eshre.eu/guidelines .\n\nClick here for additional data file.","source_license":"public-domain-us","license_restricted":false}