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.

A prerequisite for the success of early detection of a disease is the clear understanding of its natural history. The cellular origin of ovarian cancer has remained elusive, and this has delayed our understanding of the biology of initiation and progression of the disease, and has hampered the development of effective early detection methods. As a consequence, ovarian cancer remains one of the most fatal malignancies in women worldwide. In this issue of BJOG Sharma et al. present important evidence from a prospective study of more than 48 000 postmenopausal women indicating that small ovarian inclusion cysts, of <10 mm in diameter, are not associated with an increased risk of invasive epithelial ovarian cancer. This finding has an important implication for the management of this common condition, as it confirms the safety of the current practice of conservative management of such lesions. In addition, Sharma et al. discuss the implication of their finding for identifying the cellular origin of epithelial ovarian cancers. As 'ovarian cancers' in all probability arise from several different sites, some additional discussion may help to place their paper in perspective.According to Hamilton, 1 the concept that epithelial ovarian cancers arise from ovarian surface epithelial (OSE) cells was proposed by Sir Spencer Wells in 1872. More than a century later, this hypothesis remains controversial. The OSE cells are mesothelial-like cells that share embryological origin with the Müllerian tract epithelium, which eventually gives rise to tubal, endometrial and endocervical epithelium. It has long been thought that epithelial ovarian tumours arise from the less differentiated OSE cells, and subsequently differentiate into histological subtypes according to specific molecular perturbations. This hypothesis is supported by the finding that mouse ovarian surface epithelial cells (MOSEC) grown in culture can undergo spontaneous malignant transformation.2 Importantly, ectopic expression of HOXA9, HOXA10 and HOXA11 genes in MOSEC followed by intraperitoneal injection into mice resulted in the establishment of cancers of serous, endometrioid and mucinous subtypes, respectively.2 These findings give direct evidence that OSE cells can indeed be transformed into cancer cells and forced to differentiate into the three most common types of epithelial ovarian cancers. Therefore, the formation of inclusion cysts (ICs) lined by OSE cells has been suggested as the lesion of origin of epithelial ovarian cancers. The current findings from Sharma et al. argue against this hypothesis, at least in a subset of epithelial cancers. In their study, out of the 48 230 postmenopausal women with no family history of ovarian cancer who had a pelvic ultrasound in the first year of the study, 1234 women had inclusion cysts (2.6%). For the 22 914 women who had a normal scan in the first year, ICs developed at a rate of 2-3% per year on subsequent annual scans. After a median follow-up period of 6 years, the authors could not find an increase in the risk o...

Study question To assess the long-term efficacy and safety of once-daily Relugolix combination therapy (Relugolix-CT) in the treatment of endometriosis-associated pain over two years. Summary answer Relugolix-CT previously demonstrated sustained improvement of endometriosis-associated pain and was generally well tolerated over 52 weeks. Research is ongoing: two-year results will be reported. What is known already SPIRIT 1&2 were international, Phase 3, replicate, randomized, double-blind, placebo-controlled studies of Relugolix-CT (relugolix 40mg, estradiol 1mg, norethisterone acetate 0.5mg) in premenopausal women with moderate-to-severe endometriosis-associated pain, which were followed by the open-label, 80-week, long-term extension. 52-week results showed sustained improvement in dysmenorrhea and non-menstrual pelvic pain (NMPP) with 84.8% and 73.3% of responders, respectively. Efficacy was evidenced by reductions in dysmenorrhea (82.8%,) NMPP (62.9%,) proportion of women using opioids, and improvements in function. Relugolix-CT was generally well tolerated. Bone mineral density (BMD) assessment showed minimal initial decline (&lt;1%) from baseline followed by stabilization from Week 24 to 52. Study design, size, duration Women who completed the 24-week pivotal studies (SPIRIT 1&2) were eligible to enroll in an 80-week open-label, single-arm, long-term extension study of safety and efficacy, representing up to 104 weeks of treatment in total. All women enrolled in the long-term extension study received once-daily oral Relugolix-CT. Analyses were performed based on the initial randomized treatment groups in pivotal studies: Relugolix-CT, delayed Relugolix-CT (relugolix 40mg alone for 12 weeks, then Relugolix-CT for 12 weeks), or placebo. Participants/materials, setting, methods Primary endpoints are proportion of dysmenorrhea and NMPP responders at Weeks 52 and 104 based on daily Numerical Rating Scale (NRS) scores (0=no pain, 10=worst pain imaginable) and analgesic use. Responders are women who achieved a predefined, clinically meaningful reduction from baseline in NRS score and no increase in analgesic use. Secondary efficacy endpoints include change in Endometriosis Health Profile-30 pain domain scores, use of opioids/analgesics. Safety endpoints include adverse events and BMD (percent change). Main results and the role of chance Of 1251 randomized patients in SPIRIT 1&2, 1044 (83.4%) completed the pivotal studies; 802 (76.8%) enrolled in the long-term extension, and 681 (84.9%) completed 52 weeks of treatment. Baseline demographics and clinical characteristics of the long-term extension population were consistent with those of the pivotal study population. The study remains ongoing at the time of writing. Efficacy and safety data with Relugolix-CT for up to Week 104, will be presented at the scientific session of the 2022 congress. Limitations, reasons for caution The study was conducted as an open-label study without a control group over the 80 weeks of the extension period. Wider implications of the findings Through 52 weeks of treatment, Relugolix-CT demonstrated sustained improvement of dysmenorrhea, NMPP, function, and reduced need for opiates in women with endometriosis-associated pain. No new safety concerns were identified, and treatment was associated with BMD loss &lt;1%. Data from 104 weeks of treatment will be presented at the 2022 congress. Trial registration number NCT03654274

Study question In this previous undescribed population of women, what is the prevalence of endometriosis and associated symptomatology, and how are women affected? Summary answer Prevalence of endometriosis was 5.4% (95%CI; 4.9%-5.9%). Cases suffered from worse physical health, higher use of pain medication and decreased productivity at work. What is known already There is a lack of population level data on prevalence and distribution of women’s health conditions, such as endometriosis, from the Eastern Mediterranean region, despite their known negative effects on quality of life. In addition, there is a complete absence of any health statistics from Northern Cyprus, an emerging region in Europe. Most current endometriosis research comes from Western populations and is not generalisable to non-Western populations due to differences in culture, lifestyle, and care seeking patterns. Therefore, it is important to investigate endometriosis in a variety of settings. Study design, size, duration The COHERE Initiative is a cross-sectional, population-based study that recruited 7,646 women between the ages 18-55 residing in Northern Cyprus between January 31st 2018, and January 31st 2020. Recruitment took place face-to-face (90%) and online (10%). Participants completed an expanded version of the WERF Endometriosis Phenome and Biobanking Harmonisation Project (EPHect) questionnaire, consisting of previously validated measurement instruments, such as the Short-Form-36-version-2 questionnaire (SF-36v2) and the Work Productivity and Impairment Questionnaire: General Health (WPAI:GH). Participants/materials, setting, methods Endometriosis cases were defined using a combination of self-reported and pelvic ultrasound data. Controls were women without endometriosis. Chi-square, Fisher’s exact test, Student’s t-test, linear regression, and multivariable logistic regression were used for data analysis. The significance level was set at p &lt; 0.05. Main results and the role of chance Endometriosis prevalence was 5.4% (95%CI; 4.9%-5.9%;n=410). The mean age women with endometriosis reported to first experience related-symptoms was 25.9-years, despite average age of first menstrual-pain occurring at 16.2-years. Average age of first gynaecologist visit was 21.0-years and endometriosis diagnostic-delay was 1.5-years. Physical health-related-quality-of-life was lower in women with endometriosis compared to those without (48.4 vs 50.2, p = 0.001). Cases had a higher mean percentage of activity impairment (25.8% vs 22.5%, p = 0.03) and reduced effectiveness whilst working (23.4% vs 19.5%, p = 0.006) than controls. Hormone-use was higher in women with endometriosis compared to controls for heavy-bleeding (5.9% vs 1.4%, p &lt; 0.001), irregular periods (14.4% vs 7.2%, p &lt; 0.001) and pelvic-pain (9.3% vs 1.7%, p &lt; 0.001), though overall hormone use was low at 24.1%. Iron and vitamin-D deficiency were the most reported co-morbidities, and these proportions were significantly different from women without endometriosis (38.8% vs 28.3%, 23.9% vs 17.0% respectively, p &lt; 0.001). Migraine headaches were more frequent in women with endometriosis than in those without (19.8% vs 13.2%, p &lt; 0.001). Women with endometriosis were more likely to have ever used drugs for pain relief (77.1% vs 60.5%, p &lt; 0.001). Further analysis will include estimation of economic burden of endometriosis and investigation into Mediterranean-specific factors including sun-exposure and dietary-habits. Limitations, reasons for caution Given the cross-sectional nature of this study, causality cannot be inferred. The majority of endometriosis cases are self-reported which is not as reliable as hospital diagnosis/surgeries and laparoscopy is not available in Northern Cyprus. However, research has shown that women self-report endometriosis diagnoses with reasonable accuracy (&gt;70%). Wider implications of the findings This is the first study that has estimated prevalence of endometriosis in the region and provided insight into the current-status of healthcare. It has highlighted gaps in the public’s general knowledge of common gynaecological conditions. The results form the basis for targeted follow-up-studies and promotes evidence-based reproductive-medicine in the Eastern-Mediterranean-region. Trial registration number Not applicable

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