ESHRE guideline: endometriosis

Endometriosis is a disease characterized by the presence of endometrium-like epithelium and/or stroma outside the endometrium and myometrium, usually with an associated inflammatory process ( International Working Group of AAGL, ESGE, ESHRE and WES et al. , 2021 ). The exact prevalence of endometriosis is unknown, but estimates range from 2% to 10% within the general female population and up to 50% in infertile women ( Eskenazi and Warner, 1997 ; Meuleman et al. , 2009 ; Zondervan et al. , 2020 ). The ESHRE Guideline for the Diagnosis and Treatment of Endometriosis (2005) and the ESHRE Guideline: Management of women with endometriosis (2013) have been a reference point for best clinical care in endometriosis for years ( Kennedy et al. , 2005 ; Dunselman et al. , 2014 ). Based on continuous new research and developments, it was considered that the last recommendations formulated in 2013/2014 required a revision.

The scope of the ESHRE guideline on endometriosis is to provide guidance on the management of endometriosis; either diagnosed or strongly suspected. In line with endometriosis research, terminology and discussion, the guideline is focused on females and menstruation. The GDG recognizes that there are individuals living with endometriosis who are transgender, who do not menstruate, who do not have a uterus or who do not identify with the terms used in the literature. Throughout, the term ‘women with endometriosis’ is used, but this is not intended to isolate, exclude or diminish any individual’s experience nor to discriminate against any group. The recommended diagnostic process for endometriosis is summarized in Fig. 2 . The recommended diagnostic process for endometriosis. DE, deep endometriosis; US, ultrasound. As no recommendation could be made, the following conclusion was formulated. Although currently no evidence exists that a symptom diary/questionnaire/app reduces the time to diagnosis or leads to earlier diagnosis, the GDG considers their potential benefit in complementing the traditional history taking process as it aids in objectifying pain and empowering women to demonstrate their symptoms (conclusion, not recommendation) . Strong recommendation ⊕○○○ Strong recommendation ⊕⊕○○ Strong recommendation ⊕⊕⊕○ Strong recommendation ⊕⊕○○ As 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 both diagnostic laparoscopy and imaging combined with empirical treatment (hormonal contraceptives or progestogens) can be considered in women suspected of endometriosis. Pros and cons should be discussed with the patient (conclusion, not recommendation) . Weak recommendation ⊕○○○ Although no adequate studies exist to support the benefits of early versus late diagnosis, the GDG recommends that in symptomatic women, attempts should be made to relieve symptoms, either by empirical treatment or after a diagnosis of endometriosis (conclusion, not recommendation) . The recommendations for treatment of pain symptoms linked to endometriosis are summarized in Fig. 3 . Summary of the recommendations for treatment of pain symptoms linked to endometriosis. NSAID, non-steroidal anti-inflammatory. Weak recommendation ⊕○○○ Strong recommendation ⊕⊕⊕○ Strong recommendation ⊕⊕○○ Weak recommendation ⊕⊕○○ Strong recommendation ⊕⊕○○ Strong recommendation ⊕⊕⊕○ Strong recommendation ⊕⊕○○ Strong recommendation ⊕⊕⊕○ Weak recommendation ⊕⊕⊕○ Strong recommendation ⊕⊕○○ Strong recommendation ⊕⊕○○ It can be concluded that laparoscopic uterosacral nerve ablation (LUNA) is not beneficial as an additional procedure to conventional laparoscopic surgery for endometriosis, as it offers no additional benefit over surgery alone ( Proctor et al. , 2005 ). Presacral neurectomy (PSN) is beneficial for treatment of endometriosis-associated midline pain as an adjunct to conventional laparoscopic surgery, but it should be stressed that PSN requires a high degree of skill and is associated with an increased risk of adverse effects such as intraoperative bleeding, and postoperative constipation, urinary urgency and painless first stage of labour ( Miller et al. , 2020 ) (conclusion, not recommendation) . Weak recommendation ⊕○○○ Strong recommendation ⊕○○○ Weak recommendation ⊕⊕○○ Owing to the heterogeneity of patient populations, surgical approaches, preferences and techniques, the GDG decided not to make any conclusions or recommendations on the techniques to be applied for treatment of pain associated with deep endometriosis (conclusion, not recommendation) . Weak recommendation ⊕⊕○○ There are currently no prognostic markers that can be used to select patients that would benefit from surgery. Such markers would need to be assessed prior to surgery and predict a clinically meaningful improvement of pain symptoms. In the absence of prognostic markers, no recommendation could be formulated (conclusion, not recommendation). Strong recommendation ⊕⊕○○ Weak recommendation ⊕⊕○○ The recommendations for treatment of endometriosis-associated infertility are summarized in Fig. 4 . Summary of the recommendations on treatment of endometriosis-associated infertility. EFI, endometriosis fertility index; MAR, medically assisted reproduction. Strong recommendation ⊕⊕○○ Strong recommendation ⊕⊕○○ Weak recommendation ⊕⊕○○ Strong recommendation ⊕○○○ Weak recommendation ⊕⊕○○ Weak recommendation ⊕○○○ Weak recommendation ⊕○○○ While no recommendation could be formulated, the GDG concluded that women should be counselled of their chances of becoming pregnant after surgery. To identify patients that may benefit from ART after surgery, the EFI should be used as it is validated, reproducible and cost-effective. The results of other fertility investigations, such as their partner’s sperm analysis, should be taken into account (conclusion, not recommendation) . Weak recommendation ⊕○○○ Weak recommendation ⊕○○○ Weak recommendation ⊕⊕○○ Weak recommendation ⊕○○○ Weak recommendation ⊕⊕⊕○ Strong recommendation ⊕○○○ Weak recommendation ⊕○○○ Strong recommendation ⊕⊕○○ Strong recommendation ⊕⊕○○ Strong recommendation ⊕○○○ Regarding non-medical strategies on infertility, there is no clear evidence that any non-medical interventions for women with endometriosis will be of benefit to increase the chance of pregnancy. No recommendation can be made to support any non-medical interventions (nutrition, Chinese medicine, electrotherapy, acupuncture, physiotherapy, exercise and psychological interventions) to increase fertility in women with endometriosis. The potential benefits and harms are unclear (conclusion, not recommendation) . Strong recommendation ⊕○○○ Strong recommendation ⊕○○○ Strong recommendation ⊕○○○ Complications related directly to pre-existing endometriosis lesions are rare, but probably under-reported. Such complications may be related to their decidualization, adhesion formation/stretching and endometriosis-related chronic inflammation. Although rare, they may represent life-threatening situations that may require surgical management ( Leone Roberti Maggiore et al. , 2016 ; Leone Roberti Maggiore et al. , 2017 ; Lier et al. , 2017 ; Glavind et al. , 2018 ). Strong recommendation ⊕⊕○○ Strong recommendation ⊕⊕○○ The recommendations and information on endometriosis and pregnancy are summarized in Fig. 5 . Summary of the recommendations and information on endometriosis and pregnancy. Strong recommendation ⊕⊕○○ Strong recommendation ⊕⊕○○ Strong recommendation ⊕○○○ Weak recommendation ⊕○○○ Weak recommendation ⊕⊕⊕○ Weak recommendation ⊕○○○ Strong recommendation ⊕○○○ Weak recommendation ⊕○○○ chronic or acyclical pelvic pain, particularly combined with nausea, dysmenorrhoea, dyschezia, dysuria, dyspareunia; cyclical pelvic pain ( Greene et al. , 2009 ; Treloar et al. , 2010 ; Vicino et al. , 2010 ; Yang et al. , 2012 ; DiVasta et al. , 2018 ). Strong recommendation ⊕○○○ In the absence of evidence for adolescents specifically, the recommendations for clinical examination in adults can be applied. Strong recommendation ⊕⊕○○ Strong recommendation ⊕⊕○○ Weak recommendation ⊕⊕○○ Strong recommendation ⊕⊕○○ Strong recommendation ⊕○○○ Weak recommendation ⊕⊕○○ Weak recommendation ⊕○○○ Strong recommendation ⊕○○○ The GDG concluded that clinicians should be aware that endometriosis can still be active/symptomatic after menopause (conclusion, not recommendation) . Weak recommendation ⊕○○○ Weak recommendation ⊕○○○ Weak recommendation ⊕⊕○○ Strong recommendation ⊕⊕○○ Clinicians should be aware that women with endometriosis who have undergone an early bilateral salpingo-oophorectomy as part of their treatment have an increased risk of diminished bone density, dementia and cardiovascular disease. It is also important to note that women with endometriosis have an increased risk of cardiovascular disease, irrespective of whether they have had an early surgical menopause (conclusion, not recommendation) . Weak recommendation ⊕○○○ Weak recommendation ⊕○○○ Strong recommendation ⊕○○○ Strong recommendation ⊕○○○ Weak recommendation ⊕○○○ Weak recommendation ⊕⊕○○ Weak recommendation ⊕⊕○○ Strong recommendation ⊕⊕○○ Infographic on the absolute risk of developing cancer in a woman’s lifetime. Based on the limited literature and controversial findings, there is little evidence that somatic mutations in patients with deep endometriosis may be predictive of development and/or progression of ovarian cancer (conclusion, not recommendation) . Strong recommendation ⊕○○○ Strong recommendation ⊕⊕○○ Strong recommendation ⊕⊕○○

The guideline was developed according to a well-documented methodology that is universal to ESHRE guidelines ( Vermeulen et al ., 2019 ). The core guideline development group (GDG) was composed of past members of the guideline group from 2013 and additional experts selected from applicants to a call for experts. All other European experts applying to the call were included as subgroup members, assisting a core group member preparing the guideline on a certain topic. The GDG included two patient representatives, and five patient organizations were represented in the subgroups. Forty-two key questions were formulated by the GDG, of which seven were answered as narrative questions, and 35 as PICO (Patient, Intervention, Comparison, Outcome) questions. For each PICO question, databases (PubMed/MEDLINE and the Cochrane library) were searched from inception to 1 December 2020, limited to studies written in English. From the literature searches, studies were selected based on the PICO questions, assessed for quality and summarized in evidence tables. GDG subgroup meetings were organized, face-to-face and online, for presentation and discussion of the evidence and draft recommendations by the assigned core group member. Proposed recommendations by the subgroups were then discussed in core group meetings until a consensus was reached. Each recommendation was labelled as strong or weak and a grade was assigned based on the strength of the supporting evidence (High ⊕⊕⊕⊕, Moderate ⊕⊕⊕◯, Low ⊕⊕◯◯ and Very low ⊕◯◯◯). Good practice points (GPPs) based on clinical expertise were added where relevant to clarify the recommendations or to provide further practical advice. ‘Research only’ recommendations were also made, and those interventions should be applied only within the context of research, with appropriate precautions and ethical approval. Strong recommendations should be used as a recommendation to be applied for most patients, while weak recommendations require discussion and shared decision-making ( Fig. 1 ). Suggested interpretation of strong and weak recommendations by patients, clinicians and health care policy makers. For the narrative questions, a similar literature search was conducted. Collected data were summarized in a narrative summary and conclusions were formulated. In case of insufficient data to provide recommendations in reply to a PICO question, a conclusion was also added. For clarity, these conclusions are labelled ‘conclusion, not recommendation’ in the current paper. The guideline draft and an invitation to participate in the stakeholder review were published on the ESHRE website between 24 June and 15 August 2021. All comments were processed by the core group, either by adapting the content of the guideline and/or by replying to the reviewer. The review process was summarized in the review report, which is published on the ESHRE website ( www.eshre.eu/Guidelines ). Overall, 56.5% of the 253 comments resulted in an adaptation or correction in the guideline text. This guideline will be considered for update 4 years after publication, with an intermediate assessment of the need for updating 2 years after publication.

This paper provides an overview of recommendations for diagnosis of endometriosis and treatment of associated symptoms during different stages of life. In addition, guidance is provided on the possible connection with development of cancer, and with regards to prevention. Overall, 109 recommendations have been formulated, 79 supported by research data and 30 GPPs based primarily on clinical expertise. The guidelines are based on the best available evidence or, where data of sufficient quality were absent, on recommendations by the GDG (GPPs). The current guideline and recommendations are an update of the ESHRE endometriosis guidelines published in 2013 and 2005 ( Kennedy et al. , 2005 ; Dunselman et al. , 2014 ). The key questions and topics covered in the guideline of 2013 were updated based on data published between 2013 and 2021, where available, and in accordance with changes in clinical practice. The latter applied, for example, to the oral use of danazol and anti-progestogens as a medical treatment and to LUNA, PSN and anti-adhesion agents as surgical interventions. These interventions are still discussed in the guideline, but no longer discussed in recommendations for clinical practice. While most of the more recent studies confirm previous ESHRE recommendations, there are five topics in which significant changes in clinical practice are to be expected. The first change, primarily based on clinical practice rather than published data, is the evolution in the diagnostic process. While previously a laparoscopy was regarded as the diagnostic gold standard, it is now only recommended in patients with negative imaging results and/or where empirical treatment was unsuccessful or inappropriate. Secondly, studies on GnRH antagonist treatments support their use as an additional (second-line) treatment option. Thirdly, recent data indicate that postoperative medical treatment may be beneficial towards pain management and support a recommendation to offer it to women not desiring immediate pregnancy. Fourthly, the extended administration of GnRH agonist prior to ART treatment to improve live birth rate in infertile women with endometriosis (ultralong protocol) is no longer recommended because of unclear benefits. Finally, the EFI was added as a step in the treatment as it can support decision-making for the most appropriate option to achieve pregnancy after surgery. In addition to the topics discussed in the previous guideline, the current guideline addresses highly important previous gaps in clinical management, with an additional chapter on adolescent endometriosis, information on pregnancy and fertility preservation, and extended information on endometriosis in menopause, as well as data on the link between endometriosis and cancer. Despite our best efforts to provide clear guidance on the management of endometriosis using all available evidence, there is still an urgent need for more research both to achieve more clarity on the most appropriate diagnostic and treatment options, and to answer very basic questions as to the natural course of the disease. This guideline provides 30 recommendations for research written to inspire researchers and hopefully also facilitate funding for endometriosis studies ( Supplementary Data ). In summary, the 2022 ESHRE Guideline: Endometriosis is a comprehensive update of the existing evidence and should assist healthcare professionals in their decision making and patients in their understanding of the management suggestions. Active involvement and input by patient representatives at all stages was central to the success of this endeavour. As such, the guideline was created by medical professionals, patient representatives and specialists in epidemiology and guideline methodology. The detailed guideline document and a patient-friendly version can be accessed via the ESHRE website ( https://www.eshre.eu/Guideline/Endometriosis ).

Supplementary data are available at Human Reproduction Open online.

The full guideline and supporting data (literature report, evidence tables) are available on www.eshre.eu/guidelines .

Click here for additional data file.