In two randomized trials, two different doses of the oral gonadotropin-releasing hormone antagonist elagolix significantly reduced endometriosis-related dysmenorrhea and nonmenstrual pelvic pain but ...had hypoestrogenic adverse effects.
Abstract
STUDY QUESTION
What is the global consensus on the classification of endometriosis that considers the views of women with endometriosis?
SUMMARY ANSWER
We have produced an international ...consensus statement on the classification of endometriosis through systematic appraisal of evidence and a consensus process that included representatives of national and international, medical and non-medical societies, patient organizations, and companies with an interest in endometriosis.
WHAT IS KNOWN ALREADY
Classification systems of endometriosis, developed by several professional organizations, traditionally have been based on lesion appearance, pelvic adhesions, and anatomic location of disease. One system predicts fertility outcome and none predicts pelvic pain, response to medications, disease recurrence, risks for associated disorders, quality of life measures, and other endpoints important to women and health care providers for guiding appropriate therapeutic options and prognosis.
STUDY DESIGN, SIZE, DURATION
A consensus meeting, in conjunction with pre- and post-meeting processes, was undertaken.
PARTICIPANTS/MATERIALS, SETTING, METHODS
A consensus meeting was held on 30 April 2014 in conjunction with the World Endometriosis Society's 12th World Congress on Endometriosis. Rigorous pre- and post-meeting processes, involving 55 representatives of 29 national and international, medical and non-medical organizations from a range of disciplines, led to this consensus statement.
MAIN RESULTS AND THE ROLE OF CHANCE
A total of 28 consensus statements were made. Of all, 10 statements had unanimous consensus, however none of the statements was made without expression of a caveat about the strength of the statement or the statement itself. Two statements did not achieve majority consensus. The statements covered women's priorities, aspects of classification, impact of low resources, as well as all the major classification systems for endometriosis. Until better classification systems are developed, we propose a classification toolbox (that includes the revised American Society for Reproductive Medicine and, where appropriate, the Enzian and Endometriosis Fertility Index staging systems), that may be used by all surgeons in each case of surgery undertaken for women with endometriosis. We also propose wider use of the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project surgical and clinical data collection tools for research to improve classification of endometriosis in the future, of particular relevance when surgery is not undertaken.
LIMITATIONS, REASONS FOR CAUTION
This consensus process differed from that of formal guideline development, although based on the same available evidence. A different group of international experts from those participating in this process may have yielded subtly different consensus statements.
WIDER IMPLICATIONS OF THE FINDINGS
This is the first time that a large, global, consortium–representing 29 major stake-holding organizations, from 19 countries – has convened to systematically evaluate the best available evidence on the classification of endometriosis and reach consensus. In addition to 21 international medical organizations and companies, representatives from eight national endometriosis organizations were involved, including lay support groups, thus generating and including input from women who suffer from endometriosis in an endeavour to keep uppermost the goal of optimizing quality of life for women with endometriosis.
STUDY FUNDING/COMPETING INTEREST(S)
The World Endometriosis Society convened and hosted the consensus meeting. Financial support for participants to attend the meeting was provided by the organizations that they represented. There was no other specific funding for this consensus process. Mauricio Abrao is an advisor to Bayer Pharma, and a consultant to AbbVie and AstraZeneca; G David Adamson is the Owner of Advanced Reproductive Care Inc and Ziva and a consultant to Bayer Pharma, Ferring, and AbbVie; Deborah Bush has received travel grants from Fisher & Paykel Healthcare and Bayer Pharmaceuticals; Linda Giudice is a consultant to AbbVie, Juniper Pharmaceutical, and NextGen Jane, holds research grant from the NIH, is site PI on a clinical trial sponsored by Bayer, and is a shareholder in Merck and Pfizer; Lone Hummelshoj is an unpaid consultant to AbbVie; Neil Johnson has received conference expenses from Bayer Pharma, Merck-Serono, and MSD, research funding from AbbVie, and is a consultant to Vifor Pharma and Guerbet; Jörg Keckstein has received a travel grant from AbbVie; Ludwig Kiesel is a consultant to Bayer Pharma, AbbVie, AstraZeneca, Gedeon Richter, and Shionogi, and holds a research grant from Bayer Pharma; Luk Rombauts is an advisor to MSD, Merck Serono, and Ferring, and a shareholder in Monash IVF. The following have declared that they have nothing to disclose: Kathy Sharpe Timms; Rulla Tamimi; Hugh Taylor.
TRIAL REGISTRATION NUMBER
N/A
Polycystic ovary syndrome (PCOS) is an endocrinopathy characterised by increased resistance to insulin. Metformin is one of the longest established oral insulin sensitising agents. For decades its ...use was restricted to management of type 2 diabetes. However, in the past two decades, its properties as an insulin sensitising agent have been explored in relation to its applicability for women with PCOS. Metformin is an effective ovulation induction agent for non-obese women with PCOS and offers some advantages over other first line treatments for anovulatory infertility such as clomiphene. For clomiphene-resistant women, metformin alone or in combination with clomiphene is an effective next step. Women with PCOS undergoing in vitro fertilisation should be offered metformin to reduce their risk of ovarian hyperstimulation syndrome. Limited evidence suggests that metformin may be a suitable alternative to the oral contraceptive pill (OCP) for treating hyperandrogenic symptoms of PCOS including hirsutism and acne. More research is required to define whether metformin has a role in improving long term health outcomes for women with PCOS, including the prevention of diabetes, cardiovascular disease and endometrial cancer.
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.
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.
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.
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.
Myovant Sciences.
Understanding vaccine-elicited protection against SARS-CoV-2 variants and other sarbecoviruses is key for guiding public health policies. We show that a clinical stage multivalent SARS-CoV-2 spike ...receptor-binding domain nanoparticle (RBD-NP) vaccine protects mice from SARS-CoV-2 challenge after a single immunization, indicating a potential dose-sparing strategy. We benchmarked serum neutralizing activity elicited by RBD-NPs in non-human primates against a lead prefusion-stabilized SARS-CoV-2 spike (HexaPro) using a panel of circulating mutants. Polyclonal antibodies elicited by both vaccines are similarly resilient to many RBD residue substitutions tested, although mutations at and surrounding position 484 have negative consequences for neutralization. Mosaic and cocktail nanoparticle immunogens displaying multiple sarbecovirus RBDs elicit broad neutralizing activity in mice and protect mice against SARS-CoV challenge even in the absence of SARS-CoV RBD in the vaccine. This study provides proof of principle that multivalent sarbecovirus RBD-NPs induce heterotypic protection and motivates advancing such broadly protective sarbecovirus vaccines to the clinic.
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•RBD-NP enables dose-sparing and protects mice after only one dose•RBD-NP elicits diverse polyclonal antibody responses in non-human primates•RBD-NP and HexaPro confer similar resilience to antigenic drift•Mosaic and cocktail RBD-NPs protect against heterotypic SARS-CoV challenge
A clinical stage multivalent SARS-CoV-2 spike receptor-binding domain nanoparticle (RBD-NP) vaccine is protective in mice after a single immunization and elicits strong antibody responses across circulating mutants and some sarbecoviruses. Multivalent sarbecovirus RBD-NP vaccines elicit heterotypic protection against sarbecoviruses.
STUDY QUESTION
Is there a global consensus on the management of endometriosis that considers the views of women with endometriosis?
SUMMARY ANSWER
It was possible to produce an international ...consensus statement on the current management of endometriosis through engagement of representatives of national and international, medical and non-medical societies with an interest in endometriosis.
WHAT IS KNOWN ALREADY
Management of endometriosis anywhere in the world has been based partially on evidence-based practices and partially on unsubstantiated therapies and approaches. Several guidelines have been developed by a number of national and international bodies, yet areas of controversy and uncertainty remain, not least due to a paucity of firm evidence.
STUDY DESIGN, SIZE, DURATION
A consensus meeting, in conjunction with a pre- and post-meeting process, was undertaken.
PARTICIPANTS/MATERIALS, SETTING, METHODS
A consensus meeting was held on 8 September 2011, in conjunction with the 11th World Congress on Endometriosis in Montpellier, France. A rigorous pre- and post-meeting process, involving 56 representatives of 34 national and international, medical and non-medical organizations from a range of disciplines, led to this consensus statement.
MAIN RESULTS AND THE ROLE OF CHANCE
A total of 69 consensus statements were developed. Seven statements had unanimous consensus; however, none of the statements were made without expression of a caveat about the strength of the statement or the statement itself. Only two statements failed to achieve majority consensus. The statements covered global considerations, the role of endometriosis organizations, support groups, centres or networks of expertise, the impact of endometriosis throughout a woman's life course, and a full range of treatment options for pain, infertility and other symptoms related to endometriosis.
LIMITATIONS, REASONS FOR CAUTION
This consensus process differed from that of formal guideline development. A different group of international experts from those participating in this process would likely have yielded subtly different consensus statements.
WIDER IMPLICATIONS OF THE FINDINGS
This is the first time that a large, global, consortium, representing 34 major stake-holding organizations from five continents, has convened to systematically evaluate the best available current evidence on the management of endometriosis, and to reach consensus. In addition to 18 international medical organizations, representatives from 16 national endometriosis organizations were involved, including lay support groups, thus generating input from women who suffer from endometriosis.
STUDY FUNDING/COMPETING INTEREST(S)
The World Endometriosis Society commissioned and hosted the consensus meeting. Financial support for participants to attend the meeting was provided by the organizations that they represented. There was no other specific funding for this consensus process. Full disclosures of all participants are presented herein.
IMPORTANCE: Acupuncture is widely used by women undergoing in vitro fertilization (IVF), although the evidence for efficacy is conflicting. OBJECTIVE: To determine the efficacy of acupuncture ...compared with a sham acupuncture control performed during IVF on live births. DESIGN, SETTING, AND PARTICIPANTS: A single-blind, parallel-group randomized clinical trial including 848 women undergoing a fresh IVF cycle was conducted at 16 IVF centers in Australia and New Zealand between June 29, 2011, and October 23, 2015, with 10 months of pregnancy follow-up until August 2016. INTERVENTIONS: Women received either acupuncture (n = 424) or a sham acupuncture control (n = 424). The first treatment was administered between days 6 to 8 of follicle stimulation, and 2 treatments were administered prior to and following embryo transfer. The sham control used a noninvasive needle placed away from the true acupuncture points. MAIN OUTCOMES AND MEASURES: The primary outcome was live birth, defined as the delivery of 1 or more living infants at greater than 20 weeks’ gestation or birth weight of at least 400 g. RESULTS: Among 848 randomized women, 24 withdrew consent, 824 were included in the study (mean SD age, 35.4 4.3 years); 371 45.0% had undergone more than 2 previous IVF cycles), 607 proceeded to an embryo transfer, and 809 (98.2%) had data available on live birth outcomes. Live births occurred among 74 of 405 women (18.3%) receiving acupuncture compared with 72 of 404 women (17.8%) receiving sham control (risk difference, 0.5% 95% CI, −4.9% to 5.8%; relative risk, 1.02 95% CI, 0.76 to 1.38). CONCLUSIONS AND RELEVANCE: Among women undergoing IVF, administration of acupuncture vs sham acupuncture at the time of ovarian stimulation and embryo transfer resulted in no significant difference in live birth rates. These findings do not support the use of acupuncture to improve the rate of live births among women undergoing IVF. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12611000226909
A lipiodol hysterosalpingogram was the routine test for tubal patency as recently as the 1970s. Observational studies, then randomised controlled trials, provided evidence of a fertility enhancing ...effect of lipiodol. It has been found to improve fertility for women with normal tubal patency, particularly where the woman has a history of endometriosis. Previous successful treatment for infertility with lipiodol is a marker of further successful treatment for infertility in a repeat procedure. Whilst lipiodol is probably effective at flushing debris that could hinder fertility from fallopian tubes, it also exerts immunobiological effects in pelvic peritoneum and on the endometrium that could be responsible for fertility enhancement. Effects of lipiodol on the endometrium that might be important at the time of the implantation window are a reduced expression of osteopontin and an increased number of uterine natural killer cells postlipiodol. The effect of lipiodol uterine bathing for women with endometriosis, repeat in vitro fertilisation (IVF) implantation failure and other reproductive disorders merits further investigation. Lipiodol presents a new, simple, low invasive, inexpensive treatment option for endometriosis‐related infertility and might have wider applications.
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.
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.
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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.
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.
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