Two-year efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: SPIRIT open-label extension study.

STUDY QUESTION: What is the efficacy and safety of long-term treatment (up to 2 years) with relugolix combination therapy (CT) in women with moderate to severe endometriosis-associated pain? SUMMARY ANSWER: For up to 2 years, treatment with relugolix CT improved menstrual and non-menstrual pain, dyspareunia, and function in women with endometriosis; after an initial decline of <1%, the mean bone mineral density (BMD) remained stable with continued treatment. WHAT IS KNOWN ALREADY: Endometriosis is a chronic condition characterized by symptoms of dysmenorrhea, non-menstrual pelvic pain (NMPP), and dyspareunia, which have a substantial impact on the lives of affected women, their partners, and families. SPIRIT 1 and 2 were phase 3, randomized, double-blind, placebo-controlled studies of once-daily relugolix CT (relugolix 40 mg, oestradiol 1 mg, norethisterone acetate 0.5 mg) in premenopausal women (age 18-50 years) with endometriosis and moderate-to-severe dysmenorrhea and NMPP. These trials demonstrated a significant improvement of dysmenorrhea, NMPP, and dyspareunia in women treated with relugolix CT, with minimal decline (<1%) in BMD versus placebo at 24 weeks. STUDY DESIGN, SIZE, DURATION: Patients participating in this open-label, single-arm, long-term extension (LTE) study of the 24-week SPIRIT pivotal studies (SPIRIT 1 and 2) received up to an additional 80 weeks of once-daily oral relugolix CT treatment between May 2018 and January 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: Premenopausal women with confirmed endometriosis and moderate to severe dysmenorrhea and NMPP who completed the 24-week pivotal studies (SPIRIT 1 and 2 trials; Giudice et al., 2022) and who met all entry criteria were eligible to enrol. Two-year results were analysed by treatment group based on original randomization in pivotal studies: relugolix CT, delayed relugolix CT (relugolix 40 mg monotherapy for 12 weeks, followed by relugolix CT), or placebo→relugolix CT (placebo for 24 weeks followed by relugolix CT). The primary endpoints of the LTE study were the proportion of dysmenorrhea and NMPP responders at Week 52 and Week 104/end-of-treatment (EOT). A responder was a participant who achieved a predefined, clinically meaningful reduction from baseline in Numerical Rating Scale (NRS) scores (0 = no pain, 10 = worst pain imaginable) for the specific pain type with no increase in analgesic use. The predefined clinically meaningful threshold for dysmenorrhea was 2.8 points and for NMPP was 2.1 points. Secondary efficacy endpoints included change from baseline in Endometriosis Health Profile-30 (EHP-30) pain domain scores, a measure of the effects of endometriosis-associated pain on daily activities (function), NRS scores for dysmenorrhea, NMPP, dyspareunia, and overall pelvic pain, and analgesic/opioid use. Safety endpoints included adverse events and changes in BMD. MAIN RESULTS AND THE ROLE OF CHANCE: Of 1261 randomized patients, 1044 completed the pivotal studies, 802 enrolled in the LTE, 681 completed 52 weeks of treatment, and 501 completed 104 weeks of treatment. Demographics and baseline characteristics of the extension population were consistent with those of the original randomized population. Among patients randomized to relugolix CT at pivotal study baseline who continued in the LTE (N = 277), sustained improvements in endometriosis-associated pain were demonstrated through 104 weeks. The proportion of responders at Week 104/EOT for dysmenorrhea and NMPP was 84.8% and 75.8%, respectively. Decreases in dyspareunia and improvement in function assessed by EHP-30 pain domain were also sustained over 2 years. At Week 104/EOT, 91% of patients were opioid-free and 75% of patients were analgesic-free. Relugolix CT over 104 weeks was well tolerated with a safety profile consistent with that observed over the first 24 weeks. After initial least squares mean BMD loss <1% at Week 24, BMD plateaued at Week 36 and was sustained for the duration of 104 weeks of treatment. Efficacy and safety results were generally consistent in women in the placebo→relugolix CT and delayed relugolix CT groups. 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. Of the 802 patients who were enrolled in this LTE study, 681 patients (84.9%) and 501 patients (62.5%) of patients completed 52 and 104 weeks of treatment, respectively. In addition, there currently are no comparative data to other hormonal medications. Finally, a third (37.4%) of the study population terminated participation early. WIDER IMPLICATIONS OF THE FINDINGS: In conclusion, relugolix CT offers an additional option to help address an important unmet clinical need for effective, safe, and well-tolerated medical treatments for endometriosis that can be used longer-term, reducing the need for opioids and improving quality of life. The findings from this study may help support the care of women with endometriosis seeking longer-term effective medical management of their symptoms. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Myovant Sciences GmbH (now Sumitomo Pharma Switzerland GmbH). C.M.B. reports fees from Myovant, grants from Bayer Healthcare, fees from ObsEva, and Chair of ESHRE Endometriosis Guideline Group (all funds went to the University of Oxford); N.P.J. reports personal fees from Myovant Sciences, during the conduct of the study, personal fees from Guerbet, personal fees from Organon, personal fees from Roche Diagnostics; S.A.-S. reports personal fees from Myovant Sciences, personal fees from Bayer, personal fees from Abbvie, personal fees from UpToDate; J.S.P., and R.B.W. are employees and shareholders of Myovant Sciences; J.C.A.F. and S.J.I. are shareholders of Myovant Sciences (but at time of publicaion are no longer employess of Myovant Sciences); M.S.A. and K.W. have no conflicts to declare; V.M. is a consultant to Myovant; L.C.G. reports personal fees from Myovant Sciences, Inc and Bayer. The authors did not receive compensation for manuscript writing, review, and revision. TRIAL REGISTRATION NUMBER: NCT03654274.

A Plain Language Summary to learn about relugolix combination therapy for the treatment of pain associated with endometriosis.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of research studies (known as clinical trials) called SPIRIT 1 and SPIRIT 2. The SPIRIT 1 and SPIRIT 2 studies compared how well a medicine called relugolix combination therapy worked in relieving pain in women with moderate to severe endometriosis compared to a placebo, a pill with no active medication. Endometriosis occurs when tissue similar to what normally lines the uterus grows in other places, such as the ovaries, fallopian tubes, and bowels. WHAT WERE THE RESULTS?: Researchers looked at 1261 adult women with moderate to severe endometriosis. Randomly, 420 (33%) of these women were assigned to relugolix combination therapy, 420 (33%) were assigned to delayed relugolix combination therapy (relugolix alone first and then relugolix combination therapy for the remainder of the study), and 421 (33%) were assigned to placebo. The SPIRIT 1 and SPIRIT 2 studies showed that more women taking relugolix combination therapy (75% from SPIRIT 1 and 75% from SPIRIT 2) for 24 weeks had both less pelvic or groin pain during menstrual periods from endometriosis and no need for more pain medicines than women who took placebo (27% from SPIRIT 1 and 30% from SPIRIT 2). The SPIRIT 1 and SPIRIT 2 studies also showed that more women taking relugolix combination therapy (59% from SPIRIT 1 and 66% from SPIRIT 2) for 24 weeks had both less pelvic or groin pain between menstrual periods from endometriosis and no need for more pain medicines than women who took placebo (40% from SPIRIT 1 and 43% from SPIRIT 2). Women taking relugolix combination therapy had less pelvic or groin pain during and between menstrual periods within 4 weeks of starting the medicine. The most common side effects were headaches, the common cold, and hot flushes or feeling hot among women taking relugolix combination therapy, delayed relugolix combination therapy, and placebo. Relugolix combination therapy was considered safe for those with no major medical problems. Women taking relugolix combination therapy had little to no loss of bone mineral density (a way of knowing how strong bones are) after 24 weeks of treatment. WHAT DO THE RESULTS OF THESE STUDIES TELL US?: Women with moderate to severe endometriosis taking relugolix combination therapy had much less pain from endometriosis than women taking placebo. Clinical Trial Registration: NCT03204318 (SPIRIT-1); NCT03204331 (SPIRIT-2) (ClinicalTrials.gov).

Preoperative Ultrasound Scoring of Endometriosis by AAGL 2021 Endometriosis Classification Is Concordant with Laparoscopic Surgical Findings and Distinguishes Early from Advanced Stages.

STUDY OBJECTIVE: To compare the accuracy of preoperative ultrasound (US) in predicting the laparoscopically defined 2021 American Association of Gynecologic Laparoscopists (AAGL) Endometriosis Staging. DESIGN: Retrospective multicenter study of patients treated at 3 specialized endometriosis centers. SETTING: Three specialized endometriosis surgical centers in São Paulo (Brazil), Barcelona (Spain), and Avellino (Italy) participated. PATIENTS: A total of 878 patients aged 15 to 45 years with no history of pelvic malignancy underwent laparoscopic (LPS) treatment for suspected endometriosis. INTERVENTIONS: Retrospective review of preoperative transvaginal and transabdominal US (index test) assessed for endometriosis at all sites used in the 2021 AAGL Endometriosis Classification and classified patients into AAGL-US stages 1 to 4. Results were compared with reference-standard LPS (AAGL-LPS) staging. MEASUREMENTS AND MAIN RESULTS: The AAGL-US and AAGL-LPS stage were concordant in 586 cases (66.7%) (weighted kappa [WK] 0.759; intraclass correlation = 0.906), with the highest agreement observed in patients with no endometriosis (n = 70, 75.3% concordance), AAGL-LPS stage 1 (104, 50.7%) and stage 4 disease (358, 88.2%). Endometriosis was most accurately diagnosed in the rectum/sigmoid colon (WK 0.862), bladder (WK 0.911), and ovaries (WK 0.835/0.795 for right/left, respectively) and least accurately diagnosed at superficial peritoneal (WK 0.442), tubal (WK 0.391/0.363 for right/left, respectively), and retrocervical/uterosacral ligament (WK 0.656) sites. CONCLUSION: Sonographic estimation of the 2021 AAGL Endometriosis Staging is greatest in AAGL-LPS stages 1 and 4 and among patients with no endometriosis. US best identifies endometriosis of the ovaries, bladder, and bowel but is more limited for the tubes and superficial peritoneum.

Deep endometriosis: Can surgical complexity and associated risk factors be evaluated with transvaginal sonography and classification systems?

Deep endometriosis (DE) surgery often requires advanced knowledge in laparoscopic surgery due to the location of affected organs such as the bowel, vagina, rectovaginal space including adjacent nerve structures, ureters and urinary bladder. Patients are at risk of serious complications and sequelae like anastomotic leakage, rectovaginal fistula and voiding dysfunction. Detailed knowledge of disease extent and location by transvaginal sonography (TVS) can aid the clinician to pre-operatively plan complex surgeries and estimate associated risks. Classification systems like #Enzian can be used in combination with TVS to assess surgical risk factors.

Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2).

BACKGROUND: Endometriosis is a common cause of pelvic pain in women, for which current treatment options are suboptimal. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, combined with estradiol and a progestin, was evaluated for treatment of endometriosis-associated pain. METHODS: In these two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled trials at 219 community and hospital research centres in Africa, Australasia, Europe, North America, and South America, we randomly assigned women aged 18-50 years with surgically or directly visualised endometriosis with or without histological confirmation, or with histological diagnosis alone. Participants were eligible if they had moderate to severe endometriosis-associated pain and, during the 35-day run-in period, a dysmenorrhoea Numerical Rating Scale (NRS) score of 4·0 or higher on two or more days and a mean non-menstrual pelvic pain NRS score of 2·5 or higher, or a mean score of 1·25 or higher that included a score of 5 or more on 4 or more days. Women received (1:1:1) once-daily oral placebo, relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0·5 mg), or delayed relugolix combination therapy (relugolix 40 mg monotherapy followed by relugolix combination therapy, each for 12 weeks) for 24 weeks. During the double-blind randomised treatment and follow-up period, all patients, investigators, and sponsor staff or representatives involved in the conduct of the study were masked to treatment assignment. The co-primary endpoints were responder rates at week 24 for dysmenorrhoea and non-menstrual pelvic pain, both based on NRS scores and analgesic use. Efficacy and safety were analysed in the modified intent-to-treat population (randomised patients who received ≥1 study drug dose). The studies are registered at ClinicalTrials.gov (SPIRIT 1 [NCT03204318] and SPIRIT 2 [NCT03204331]) and EudraCT (SPIRIT 1 [2017-001588-19] and SPIRIT 2 [2017-001632-19]). Eligible patients who completed the SPIRIT studies could enrol in a currently ongoing 80-week open-label extension study (SPIRIT EXTENSION [NCT03654274, EudraCT 2017-004066-10]). Database lock for the on-treatment duration has occurred, and post-treatment follow-up for safety, specificially for bone mineral density and menses recovery, is ongoing at the time of publication. FINDINGS: 638 patients were enrolled into SPIRIT 1 and randomly assigned between Dec 7, 2017, and Dec 4, 2019, to receive relugolix combination therapy (212 [33%]), placebo (213 [33%]), or relugolix delayed combination therapy (213 [33%]). 623 patients were enrolled into SPIRIT 2 and were randomly assigned between Nov 1, 2017 and Oct 4, 2019, to receive relugolix combination therapy (208 [33%]), placebo (208 [33%]), or relugolix delayed combination therapy (207 [33%]). 98 (15%) patients terminated study participation early in SPIRIT 1 and 115 (18%) in SPIRIT 2. In SPIRIT 1, 158 (75%) of 212 patients in the relugolix combination therapy group met the dysmenorrhoea responder criteria compared with 57 (27%) of 212 patients in the placebo group (treatment difference 47·6% [95% CI 39·3-56·0]; p<0·0001). In SPIRIT 2, 155 (75%) of 206 patients in the relugolix combination therapy group were dysmenorrhoea responders compared with 62 (30%) of 204 patients in the placebo group (treatment difference 44·9% [95% CI 36·2-53·5]; p<0·0001). In SPIRIT 1, 124 (58%) of 212 patients in the relugolix combination therapy group met the non-menstrual pelvic pain responder criteria versus 84 (40%) patients in the placebo group (treatment difference 18·9% [9·5-28·2]; p<0·0001). In SPIRIT 2, 136 (66%) of 206 patients were non-menstrual pelvic pain responders in the relugolix combination therapy group compared with 87 (43%) of 204 patients in the placebo group (treatment difference 23·4% [95% CI 13·9-32·8]; p<0·0001). The most common adverse events were headache, nasopharyngitis, and hot flushes. There were nine reports of suicidal ideation across both studies (two in the placebo run-in, two in the placebo group, two in the relugolix combination therapy group, and three in the delayed relugolix combination therapy group). No deaths were reported. Least squares mean percentage change in lumbar spine bone mineral density in the relugolix combination therapy versus placebo groups was -0·70% versus 0·21% in SPIRIT 1 and -0·78% versus 0·02% in SPIRIT 2, and in the delayed relugolix combination group was -2·0% in SPIRIT 1 and -1·9% in SPIRIT 2. Decreases in opioid use were seen in treated patients as compared with placebo. INTERPRETATION: Once-daily relugolix combination therapy significantly improved endometriosis-associated pain and was well tolerated. This oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment. FUNDING: Myovant Sciences.

Invariant Natural Killer T-cells and their subtypes may play a role in the pathogenesis of endometriosis.

OBJECTIVE: To evaluate the frequencies of iNKT cells and their subsets in patients with deep endometriosis. METHODS: A case-control study was conducted between 2013 and 2015, with 73 patients distributed into two groups: 47 women with a histological diagnosis of endometriosis and 26 controls. Peripheral blood, endometriosis lesions, and healthy peritoneal samples were collected on the day of surgery to determine the frequencies of iNKT cells and subtypes via flow cytometry analysis. RESULTS: The authors observed a lower number of iNKT (p = 0.01) and Double-Negative (DN) iNKT cells (p = 0.02) in the blood of patients with endometriosis than in the control group. The number of DN iNKT IL-17+ cells in the secretory phase was lower in the endometriosis group (p = 0.049). There was an increase in the secretion of IL-17 by CD4+ iNKT cells in the blood of patients with endometriosis and severe dysmenorrhea (p = 0.038), and severe acyclic pelvic pain (p = 0.048). Patients with severe dysmenorrhea also had a decreased number of CD4+ CCR7+ cells (p = 0.022). CONCLUSION: The decreased number of total iNKT and DN iNKT cells in patients with endometriosis suggests that iNKT cells play a role in the pathogenesis of endometriosis and can be used to develop new diagnostic and therapeutic agents.

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.

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.

The current role of robotic surgery in endometriosis management.

INTRODUCTION: Endometriosis is a chronic inflammatory disease that affects approximately 10%-15% of women of childbearing age. Laparoscopic surgery is the preferred surgical approach. Recently, robotic surgery has been used for benign gynecologic surgery, but its role in the treatment of endometriosis is still unknown. AREAS COVERED: We included studies that evaluated the outcomes of robotic surgery for endometriosis. Using the keywords 'endometriosis' and 'robotics', a comprehensive literature search on PubMed, Embase, and the Cochrane Library was performed in July 2021. EXPERT OPINION: Robotic surgery for endometriosis has similar outcomes as conventional laparoscopy, with no evidence of increased complication rates. Despite the non-inferiority of the surgical route, the associated costs of robotic surgery limit its availability. Rapid development of robot-assisted surgery necessitates long-term prospective randomized controlled trials. However, the limitations of robotic surgery should not be overlooked. If robotic surgery can facilitate the spread of minimally invasive surgery, it will be necessary to evaluate the cost, availability, complexity of the lesions, and most importantly, the results of patient satisfaction and values of value-based medicine.

Invariant Natural Killer T-cells and their subtypes may play a role in the pathogenesis of endometriosis

Abstract Objective To evaluate the frequencies of iNKT cells and their subsets in patients with deep endometriosis. Methods A case-control study was conducted between 2013 and 2015, with 73 patients distributed into two groups: 47 women with a histological diagnosis of endometriosis and 26 controls. Peripheral blood, endometriosis lesions, and healthy peritoneal samples were collected on the day of surgery to determine the frequencies of iNKT cells and subtypes via flow cytometry analysis. Results The authors observed a lower number of iNKT (p= 0.01) and Double-Negative (DN) iNKT cells (p= 0.02) in the blood of patients with endometriosis than in the control group. The number of DN iNKT IL-17+ cells in the secretory phase was lower in the endometriosis group (p= 0.049). There was an increase in the secretion of IL-17 by CD4+ iNKT cells in the blood of patients with endometriosis and severe dysmenorrhea (p= 0.038), and severe acyclic pelvic pain (p= 0.048). Patients with severe dysmenorrhea also had a decreased number of CD4+ CCR7+ cells (p= 0.022). Conclusion The decreased number of total iNKT and DN iNKT cells in patients with endometriosis suggests that iNKT cells play a role in the pathogenesis of endometriosis and can be used to develop new diagnostic and therapeutic agents.

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.

AAGL 2021 Endometriosis Classification: An Anatomy-based Surgical Complexity Score.

STUDY OBJECTIVE: To develop a new endometriosis classification system for scoring intraoperative surgical complexity and to examine its correlation with patient-reported pain and infertility. DESIGN: Multicenter study of patients treated at 3 recognized endometriosis centers. SETTING: Three specialized endometriosis surgical centers in São Paulo, Brazil and Barcelona, Spain. PATIENTS: Patients aged 15 to 45 years with histologically proven endometriosis and no history of pelvic malignancy underwent laparoscopic treatment of endometriosis. INTERVENTIONS: Demographic data and clinical history, including dysmenorrhea, noncyclic pelvic pain, dyspareunia, dysuria and dyschezia, were prospectively recorded. All patients were staged surgically according to the new 2021 American Association of Gynecologic Laparoscopists (AAGL) and revised American Society of Reproductive Medicine (ASRM) classification systems. The staging for each system was compared against a 4-level surgical complexity scale defined by the most complex procedure performed. MEASUREMENTS AND MAIN RESULTS: A total of 1224 patients undergoing surgery met inclusion criteria. The AAGL score discriminated between 4 stages of surgical complexity with high reproducibility (κ = 0.621), whereas the ASRM score discriminated between the complexity stages with poor reproducibility (κ = 0.317). The AAGL staging system correlated with dysmenorrhea, dyspareunia, dyschezia, total pain score, and infertility comparably with the ASRM staging system. CONCLUSION: The AAGL 2021 Endometriosis Classification allows for identifying objective intraoperative findings that reliably discriminate surgical complexity levels better than the ASRM staging system. The AAGL severity stage correlates comparably with pain and infertility symptoms with the ASRM stage.

Immunolocalization of stem/progenitor cell biomarkers Oct-4, C-kit and Musashi-1 in endometriotic lesions.

BACKGROUND: Human endometrium harbors stem/progenitor cells (SPCs) that may contribute to the establishment of endometriosis when seeded outside the uterus. Oct-4, C-kit and Musashi-1 are some of the many proteins used to characterize SPCs, but their association with endometriosis is uncertain. OBJECTIVE AND DESIGN: In this study, specimens of normal endometrium (n = 12), eutopic endometrium from women with endometriosis (n = 9), superficial peritoneal endometriosis (SUP, n = 12) and deep endometriosis (DE, n = 13) lesions were evaluated for localization and intensity of immunostaining for Oct-4, C-kit and Musashi-1. RESULTS: The three markers were abundantly expressed in normal endometrium, eutopic endometrium from endometriosis patients, SUP and DE specimens. Oct-4 and C-kit expression did not vary across groups as regards intensity or frequency. C-kit staining signal was seldom detected in vascular endothelium of normal or eutopic endometrium from endometriosis patients; however, it was positive in 67% of the SUP lesions and in 25% of the DE lesions (p = 0.042). Musashi-1 was expressed in some endometriotic glands as cell clusters, but its signal was similar between the four types of tissue (p = 0.971) CONCLUSION: The wide distribution of Oct-4, C-kit and Musashi-1 in endometria of patients with and without endometriosis and in SUP and DE endometriotic lesions suggests that these markers are not suitable for the in situ characterization of endometrial SPCs and should not be taken as surrogates for the study of SPCs in the pathogenesis of endometriosis.

How to minimize bleeding in laparoscopic myomectomy.

PURPOSE OF REVIEW: Laparoscopic myomectomy is a common surgical procedure for symptomatic myomas. However, bleeding control during surgery may pose a challenge. Therefore, the aim of this study was to review recent evidence regarding interventions to control bleeding during laparoscopic myomectomy. RECENT FINDINGS: The use of vasopressin resulted in less blood loss compared to placebo. Barbed sutures reduced blood loss compared to conventional sutures. Intravenous infusion of tranexamic acid (TXA) in the intraoperative period of large myomectomies showed no significant difference compared to placebo. Uterine artery occlusion (UAO) and emergency uterine artery embolization were reported to be feasible and may reduce and treat bleeding before conversion to laparotomy. SUMMARY: Several methods can control bleeding during laparoscopic myomectomy. Vasopressin and barbed sutures resulted in decreased blood loss, and TXA did not have an impact on bleeding control. The use of UAO and emergency embolization techniques can contribute to the control of bleeding; however, further studies are needed to prove the efficacy of these and other agents.

Reductions in endometriosis-associated pain among women treated with elagolix are consistent across a range of baseline characteristics reflective of real-world patients.

BACKGROUND: Elagolix is an oral, gonadotropin-releasing hormone (GnRH) receptor antagonist, that significantly reduces dysmenorrhea and non-menstrual pelvic pain (NMPP) in women with moderate to severe endometriosis-associated pain. METHODS: Data were pooled from two 6-month, placebo-controlled, phase 3 studies (Elaris Endometriosis [EM]-I and II) in which 2 doses of elagolix were evaluated (150 mg once daily and 200 mg twice daily). Pooled data from > 1600 women, aged 18-49, were used to evaluate the efficacy of elagolix and health-related quality of life (HRQoL) in prespecified subgroups of women with various baseline characteristics. RESULTS: Of the 1686 women treated, 1285 (76.2%) completed the studies. The percentages of women with clinically meaningful reductions in dysmenorrhea and NMPP were generally consistent by subgroup. Significant treatment by subgroup interaction was demonstrated for dysmenorrhea response in baseline analgesic use (p < 0.01) and previous history of pregnancy (p < 0.05) subgroups, and for NMPP response in the baseline NMPP score (p < 0.05) and history of pregnancy (p < 0.05) subgroups. Patient-reported reduction in pain at month 3 was significant across all subgroups taking elagolix 200 mg BID, and significant across most subgroups with elagolix 150 mg QD. Women across subgroups experienced improvement within each domain of the Endometriosis Health Profile-30 (EHP-30), although significant treatment by subgroup interactions were observed in several categories. CONCLUSIONS: Elagolix was effective in reducing dysmenorrhea and NMPP, and improving HRQoL, compared with placebo across numerous subgroups of women with various baseline characteristics, covering a broad segment of the endometriosis disease and patient types. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: https://www.clinicaltrials.gov/ct2/show/NCT01620528 ; https://www.clinicaltrials.gov/ct2/show/NCT01931670 .