A lack of sociodemographic participant diversity in endometriosis evidence risks unrepresentative clinical guidance: a structured review of the evidence contributing to a NICE guideline.

BACKGROUND: Women who are black are less likely to be diagnosed with endometriosis than white women. There is no confirmed biological basis, so this likely represents structural barriers around health care. There is a lack of evidence exploring the interface between ethnicity and symptoms or experience of care and treatment. AIM: To map recording of sociodemographic diversity in the evidence informing an endometriosis guideline. METHOD: Inclusion of study setting, ethnicity, age, and socioeconomic status was documented within the evidence cited in National Institute for Health and Care Excellence (NICE) NG73 (2017) Endometriosis diagnosis and management. Included were 44 studies with 43 sample groups from the chapters: 'Signs and Symptoms', 'Information and Support', and 'Diagnosis'. Data were extracted independently by two researchers. RESULTS: No studies were conducted in primary care. The evidence cited in 'Signs and Symptoms' and 'Diagnosis' was exclusively from tertiary care. 'Information and Support' included 9/16 studies from tertiary care, and 7/16 recruited through community and advocacy networks. For ethnicity, 4/44 studies formally reported participant ethnicity (three from 'Information and Support', one from 'Diagnosis'). In these, 93%, 90%, 60%, and 75% of participants were white/Caucasian (mean 79.5%). For age, 3/44 studies included adolescents. Many studies excluded women who were deemed outside reproductive age. For socioeconomic status, eight studies, all from 'Information and Support', reported socioeconomic status in some form. The majority of participants were tertiary educated. CONCLUSION: These results highlight the missing demographics within evidence cited in a national guideline for endometriosis. These align with documented inequities in diagnosis of endometriosis and warrant urgent attention.

Incidence of menstrual symptoms suggestive of possible endometriosis in adolescents: and variance in these by ethnicity and socio-economic status.

BACKGROUND: Dysmenorrhoea affects up to 94% of adolescents who menstruate; approximately one third miss school and activities. Dysmenorrhoea can occur without identified pelvic pathology (primary dysmenorrhoea) or in association with other conditions (secondary dysmenorrhoea). In adolescence, the commonest cause of secondary dysmenorrhoea is endometriosis. The incidence of symptoms in adolescence suggesting possible endometriosis has not been previously documented in GP records. AIM: To document incidence of adolescent endometriosis and symptoms associated with endometriosis in English GP records. METHOD: Data from the QResearch primary care database were used for adolescent females aged 10- 19 years between 1 January 2011 and 30 June 2021, reported using descriptive statistics. RESULTS: The population cohort included 2 843 347 female adolescents; 98 887 participants had coded dysmenorrhoea (3.48%) and 1994 (0.07%) had documented endometriosis. The cumulative incidence for the cohort who turned 10 years old in 2011 was 7.2% for dysmenorrhoea and 0.12% for endometriosis. The period prevalence of coded symptoms during adolescence potentially associated with dysmenorrhoea and endometriosis includes: heavy menstrual bleeding (3.73%), irregular menstrual bleeding (2.21%), pelvic pain (0.63%), dyspareunia (0.40%), premenstrual syndrome (PMS)/premenstrual dysphoric disorder (PMDD) (0.22%), cystitis (8.45%), and irritable bowel syndrome (IBS) (1.00%). Disparities in coding were observed for these variables by ethnicity and socioeconomic status. Incidence of prescribed hormonal medication, with and without coded dysmenorrhoea, varied by ethnicity. This was less apparent for non-steroidal anti-inflammatory medications. CONCLUSION: Prevalence of coded dysmenorrhoea in GP records is significantly lower than community surveys suggest; however, adolescent menstrual symptoms are commonly encountered in primary care, and deserve specific guidance and resources. There are demographic patterns, likely structural, that warrant further exploration.

Uncovering moderators of pain perception by women with endometriosis from Latin America and Spain: the roles of sociodemographics, racial self-identity, and pain catastrophizing.

ABSTRACT: A cross-sectional multinational collaborative study on women with endometriosis from Latin America and Spain uncovered high levels of painful symptomatology and high pain catastrophizing scores. Associations between pain perception/catastrophizing and race/ethnicity have been documented. This study was conducted to uncover factors moderating pelvic pain severity, including socioeconomic variables, self-identified race, and pain catastrophizing in women with endometriosis from Latin America and Spain, a population encompassing diverse racial and sociocultural contexts. Self-reported data on demographics, clinical history, Ob-Gyn history, pelvic pain intensity, and pain catastrophizing were collected with the Spanish World Endometriosis Research Foundation (WERF) Endometriosis Phenome Project (EPhect) Clinical Questionnaire (ECQ). Multiple logistic regression was conducted to analyze effects of self-identified race, demographic clusters (defined as countries with similar racial population distribution), socioeconomic factors, and pain catastrophizing on reporting severe vs moderate-mild levels of dysmenorrhea, dyspareunia, and pelvic pain. Self-identified race did not affect the likelihood of reporting severe pelvic pain; however, there were significant differences in reporting severe dysmenorrhea at worst among demographic clusters. Older age was associated with severe dyspareunia at worst and recent pelvic pain. Pain catastrophizing score was highly predictive of reporting most types of severe pelvic pain, regardless of race and demographic cluster. These results negate a role of racial categories as moderator of pain in women from Latin America and Spain and support integration of pain catastrophizing assessments and psychological interventions into the pain management plan to enhance therapeutic outcomes and QoL for patients with endometriosis.

Reframing pain: the power of individual and societal factors to enhance pain treatment.

The effectiveness of analgesics can be increased if synergistic behavioural, psychological, and pharmacological interventions are provided within a supportive environment.

World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project: V. Physical examination standards in endometriosis research.

OBJECTIVE: The World Endometriosis Research Foundation established the Endometriosis Phenome and Biobanking Harmonisation Project (EPHect) to create standardized documentation tools (with common data elements) to facilitate the comparison and combination of data across different research sites and studies. In 2014, 4 data research standards were published: clinician-reported surgical data, patient-reported clinical data, and fluid and tissue biospecimen collection. Our current objective is to create an EPHect standard for the clinician-reported physical examination (EPHect-PE) for research studies. DESIGN: An international consortium involving 26 clinical and academic experts and patient partners from 11 countries representing 25 institutions and organizations. Two virtual workshops, followed by the development of the physical examination standards underwent multiple rounds of iterations and revisions. SUBJECTS: N/A MAIN OUTCOME MEASURE(S): N/A RESULT(S): The EPHect-PE tool provides standardized assessment of physical examination characteristics and pain phenotyping. Data elements involve examination of back and pelvic girdle; abdomen including allodynia and trigger points; vulva including provoked vestibulodynia; pelvic floor muscle tone and tenderness; tenderness on unidigital pelvic examination; presence of pelvic nodularity; uterine size and mobility; presence of adnexal masses; presence of incisional masses; speculum examination; tenderness and allodynia at an extra-pelvic site (e.g., forearm); and recording of anthropometrics. CONCLUSION(S): The EPHect-PE standards will facilitate the standardized documentation of the physical examination, including the assessment and documentation of examination phenotyping of endometriosis-associated pelvic pain.

Developing consensus on core outcome sets of domains for acute, the transition from acute to chronic, recurrent/episodic, and chronic pain: results of the INTEGRATE-pain Delphi process.

Background: Pain is the leading cause of disability worldwide among adults and effective treatment options remain elusive. Data harmonization efforts, such as through core outcome sets (COS), could improve care by highlighting cross-cutting pain mechanisms and treatments. Existing pain-related COS often focus on specific conditions, which can hamper data harmonization across various pain states. Methods: Our objective was to develop four overarching COS of domains/subdomains (i.e., what to measure) that transcend pain conditions within different pain categories. We hosted a meeting to assess the need for these four COS in pain research and clinical practice. Potential COS domains/subdomains were identified via a systematic literature review (SLR), meeting attendees, and Delphi participants. We conducted an online, three step Delphi process to reach a consensus on domains to be included in the four final COS. Survey respondents were identified from the SLR and pain-related social networks, including multidisciplinary health care professionals, researchers, and people with lived experience (PWLE) of pain. Advisory boards consisting of COS experts and PWLE provided advice throughout the process. Findings: Domains in final COS were generally related to aspects of pain, quality of life, and physical function/activity limitations, with some differences among pain categories. This effort was the first to generate four separate, overarching COS to encourage international data harmonization within and across different pain categories. Interpretation: The adoption of the COS in research and clinical practice will facilitate comparisons and data integration around the world and across pain studies to optimize resources, expedite therapeutic discovery, and improve pain care. Funding: Innovative Medicines Initiative 2 Join Undertaking; European Union Horizon 2020 research innovation program, European Federation of Pharmaceutical Industries and Associations (EFPIA) provided funding for IMI-PainCare. RDT acknowledges grants from Esteve and TEVA.

What are important areas where better technology would support women's health? Findings from a priority setting partnership.

BACKGROUND: Women's health has historically lacked investment in research and development. Technologies that enhance women's health ('FemTech') could contribute to improving this. However, there has been little work to understand which priority unmet needs should be a focus for women's health technology development. The voices of clinicians and those who experience and utilise these technologies (including those used at home or encountered in clinical settings) are needed to ensure that device development aligns with need, without risking exacerbating or creating health inequities. METHOD: We undertook a priority setting partnership project exploring unmet needs in women's health and well-being where physical technologies or innovations could help. This comprised gathering feedback from: patients and clinicians using both qualitative surveys and discussions; collating and publishing these responses and asking for feedback; evidence checking unmet needs identified, and holding a partnership priority setting event to agree a top 10 and top 20 list of priorities. RESULTS: We generated a 'longlist' of 54 suggestions for areas where better kit, devices or equipment could support women's health. For three, we found evidence of existing technologies which mitigated against that need. We took the remaining 51 suggestions to a partnership priority setting meeting which brought together clinicians and service users. Through discussion as this group, we generated a list of the top 10 areas identified as priorities for technological development and improvement. These included better devices to manage examination, diagnosis and treatment of pelvic pain (including endometriosis), prolapse care, continence (treatment and prevention, related to pregnancy and beyond), menstruation, vaginal pain and vaginismus, point of care tests for common infections, and nipple care when breastfeeding. CONCLUSION: The top priorities suggest far-reaching areas of unmet need across women's life course and across multiple domains of health and well-being, and opportunities where innovation in the devices that people use themselves or encounter in health settings could potentially enhance health and healthcare experiences.

Endometriosis - a painful disease.

PURPOSE OF REVIEW: This review looks to overview advances in endometriosis-associated pain, both in understanding the pain mechanisms involved and increasing treatment options with well designed clinical trials and meta-analyses. RECENT FINDINGS: Our understanding of endometriosis-associated pain has progressed from a purely nociceptive model to an awareness that both neuropathic and nociplastic mechanisms can be present for some people with endometriosis. Clinical trials and meta-analyses have demonstrated efficacy of surgical treatments and hormonal therapies. It is notable that currently, the basic science and clinical trials are not cross-fertilising. SUMMARY: Following growth in other areas of chronic pain, there have been significant advances in our understanding of endometriosis-associated pain. However, there remains lots to explore and we are currently a long way from our goal of timely personalized holistic multidisciplinary treatment for all sufferers of endometriosis-associated pain.

Clinical profiling of specific diagnostic subgroups of women with chronic pelvic pain.

Introduction: Chronic pelvic pain (CPP) is a common condition affecting up to 26.6% of women, with many suffering for several years before diagnosis and/or treatment. Its clinical presentation is varied and there are frequently comorbid conditions both within and outside the pelvis. We aim to explore whether specific subgroups of women with CPP report different clinical symptoms and differing impact of pain on their quality of life (QoL). Methods: The study is part of the Translational Research in Pelvic Pain (TRiPP) project which is a cross-sectional observational cohort study. The study includes 769 female participants of reproductive age who completed an extensive set of questions derived from standardised WERF EPHect questionnaires. Within this population we defined a control group (reporting no pelvic pain, no bladder pain syndrome, and no endometriosis diagnosis, N = 230) and four pain groups: endometriosis-associated pain (EAP, N = 237), interstitial cystitis/bladder pain syndrome (BPS, N = 72), comorbid endometriosis-associated pain and BPS (EABP, N = 120), and pelvic pain only (PP, N = 127). Results: Clinical profiles of women with CPP (13-50 years old) show variability of clinical symptoms. The EAP and EABP groups scored higher than the PP group (p < 0.001) on the pain intensity scales for non-cyclical pelvic pain and higher than both the BPS and PP groups (p < 0.001) on the dysmenorrhoea scale. The EABP group also had significantly higher scores for dyspareunia (p < 0.001), even though more than 50% of sexually active participants in each pain group reported interrupting and/or avoiding sexual intercourse due to pain in the last 12 months. Scores for the QoL questionnaire (SF-36) reveal that CPP patients had significantly lower QoL across all SF-36 subscales (p < 0.001). Significant effects were also observed between the pain groups for pain interference with their work (p < 0.001) and daily lives (p < 0.001), with the EABP suffering more compared to the EAP and PP groups (p < 0.001). Discussion: Our results demonstrate the negative impact that chronic pain has on CPP patients' QoL and reveal an increased negative impact of pain on the comorbid EABP group. Furthermore, it demonstrates the importance of dyspareunia in women with CPP. Overall, our results demonstrate the need for further exploration of interventions targeting QoL more broadly and suggest that novel approaches to classifying women with CPP are needed.

Comprehensive quantitative sensory testing shows altered sensory function in women with chronic pelvic pain: results from the Translational Research in Pelvic Pain (TRiPP) Study.

ABSTRACT: Chronic pelvic pain (CPP), despite its high prevalence, is still relatively poorly understood mechanistically. This study, as part of the Translational Research in Pelvic Pain (TRiPP) project, has used a full quantitative sensory testing (QST) paradigm to profile n = 85 women with and without CPP (endometriosis or bladder pain specifically). We used the foot as a control site and abdomen as the test site. Across 5 diagnostically determined subgroups, we found features which are common across different aetiologies, eg, gain of function in pressure pain threshold (PPT) when assessing responses from the lower abdomen or pelvis (referred pain site). However, disease-specific phenotypes were also identified, eg, greater mechanical allodynia in endometriosis, despite there being large heterogeneities within diagnostic groups. The most common QST sensory phenotype was mechanical hyperalgesia (>50% across all the groups). A "healthy' sensory phenotype was seen in <7% of CPP participants. Specific QST measures correlated with sensory symptoms assessed by the painDETECT questionnaire (pressure-evoked pain [painDETECT] and PPT [QST] [ r = 0.47, P < 0.001]; mechanical hyperalgesia (painDETECT) and mechanical pain sensitivity [MPS from QST] [ r = 0.38, P = 0.009]). The data suggest that participants with CPP are sensitive to both deep tissue and cutaneous inputs, suggesting that central mechanisms may be important in this cohort. We also see phenotypes such as thermal hyperalgesia, which may be the result of peripheral mechanisms, such as irritable nociceptors. This highlights the importance of stratifying patients into clinically meaningful phenotypes, which may have implications for the development of better therapeutic strategies for CPP.

Effectiveness of laparoscopic removal of isolated superficial peritoneal endometriosis for the management of chronic pelvic pain in women (ESPriT2): protocol for a multi-centre randomised controlled trial.

BACKGROUND: Endometriosis affects 190 million women and those assigned female at birth worldwide. For some, it is associated with debilitating chronic pelvic pain. Diagnosis of endometriosis is often achieved through diagnostic laparoscopy. However, when isolated superficial peritoneal endometriosis (SPE), the most common endometriosis subtype, is identified during laparoscopy, limited evidence exists to support the common decision to surgically remove it via excision or ablation. Improved understanding of the impact of surgical removal of isolated SPE for the management of chronic pelvic pain in women is required. Here, we describe our protocol for a multi-centre trial to determine the effectiveness of surgical removal of isolated SPE for the management of endometriosis-associated pain. METHODS: We plan to undertake a multi-centre participant-blind parallel-group randomised controlled clinical and cost-effectiveness trial with internal pilot. We plan to randomise 400 participants from up to 70 National Health Service Hospitals in the UK. Participants with chronic pelvic pain awaiting diagnostic laparoscopy for suspected endometriosis will be consented by the clinical research team. If isolated SPE is identified at laparoscopy, and deep or ovarian endometriosis is not seen, participants will be randomised intraoperatively (1:1) to surgical removal (by excision or ablation or both, according to surgeons' preference) versus diagnostic laparoscopy alone. Randomisation with block-stratification will be used. Participants will be given a diagnosis but will not be informed of the procedure they received until 12 months post-randomisation, unless required. Post-operative medical treatment will be according to participants' preference. Participants will be asked to complete validated pain and quality of life questionnaires at 3, 6 and 12 months after randomisation. Our primary outcome is the pain domain of the Endometriosis Health Profile-30 (EHP-30), via a between randomised group comparison of adjusted means at 12 months. Assuming a standard deviation of 22 points around the pain score, 90% power, 5% significance and 20% missing data, 400 participants are required to be randomised to detect an 8-point pain score difference. DISCUSSION: This trial aims to provide high quality evidence of the clinical and cost-effectiveness of surgical removal of isolated SPE. TRIAL REGISTRATION: ISRCTN registry ISRCTN27244948. Registered 6 April 2021.

Exploring the interface between adolescent dysmenorrhoea and endometriosis: a protocol for a cohort and nested case-control study within the QResearch Database.

INTRODUCTION: Dysmenorrhoea affects up to 70%-91% of adolescents who menstruate, with approximately one-third experiencing severe symptoms with impacts on education, work and leisure. Dysmenorrhoea can occur without identifiable pathology, but can indicate underlying conditions, including congenital genital tract anomalies or endometriosis. There is a need for evidence about the management and incidence of dysmenorrhoea in primary care, the impact of treatments in adolescence on long-term outcomes and when to consider the possibility of endometriosis in adolescence. METHODS AND ANALYSIS: This study aims to improve the evidence base for adolescents presenting to primary care with dysmenorrhoea. It comprises three interlinked studies. Using the QResearch Database, the study population includes all female at birth participants aged 10-19 years any time between 1 January 2000 and 30 June 2021. We will undertake (1) a descriptive study documenting the prevalence of coded dysmenorrhoea in primary care, stratified by demographic variables, reported using descriptive statistics; (2) a prospective open cohort study following an index cohort of all adolescents recorded as attending primary care with dysmenorrhoea and a comparator cohort of five times as many who have not, to determine the HR for a diagnosis of endometriosis, adenomyosis, ongoing menstrual pain or subfertility (considered singly and in combination) anytime during the study period; and (3) a nested case-control study for adolescents diagnosed with endometriosis, using conditional logistic regression, to determine the OR for symptom(s) preceding this diagnosis. ETHICS AND DISSEMINATION: The project has been independently peer reviewed and received ethics approval from the QResearch Scientific Board (reference OX46 under REC 18/EM/0400).In addition to publication in peer-reviewed academic journals, we will use the combined findings to generate a resource and infographic to support shared decision-making about dysmenorrhoea in community health settings. Additionally, the findings will be used to inform a subsequent qualitative study, exploring adolescents' experiences of menstrual pain.

Rodent Animal Models of Endometriosis-Associated Pain: Unmet Needs and Resources Available for Improving Translational Research in Endometriosis.

Chronic pain induced by endometriosis is a maladaptive pain experienced by half of women with this disease. The lack of pharmacological treatments suitable for the long-term relief of endometriosis-associated pain, without an impact on fertility, remains an urgent unmet need. Progress has been slowed by the absence of a reproducible rodent endometriosis model that fully replicates human physiopathological characteristics, including pain symptoms. Although pain assessment in rodents is a complicated task requiring qualified researchers, the choice of the behavioral test is no less important, since selecting inappropriate tests can cause erroneous data. Pain is usually measured with reflex tests in which hypersensitivity is evaluated by applying a noxious stimulus, yet this ignores the associated emotional component that could be evaluated via non-reflex tests. We conducted a systematic review of endometriosis models used in rodents and the number of them that studied pain. The type of behavioral test used was also analyzed and classified according to reflex and non-reflex tests. Finally, we determined the most used reflex tests for the study of endometriosis-induced pain and the main non-reflex behavioral tests utilized in visceral pain that can be extrapolated to the study of endometriosis and complement traditional reflex tests.

The influence of sex hormones on musculoskeletal pain and osteoarthritis.

The association of female sex with certain rheumatic symptoms and diseases is now indisputable. Some of the most striking examples of this association occur in individuals with musculoskeletal pain and osteoarthritis, in whom sex-dependent changes in incidence and prevalence of disease are seen throughout the lifecourse. Joint and muscle pain are some of the most common symptoms of menopause, and there is increasingly compelling evidence that changes in or loss of sex hormones (be it natural, autoimmune, pharmacological, or surgical) influence musculoskeletal pain propensity and perhaps disease. However, the effects of modulation or replacement of sex hormones in this context are far less established, particularly whether these approaches could represent a preventative or therapeutic opportunity once symptoms have developed. In this Review, we present evidence for the association of changes in sex hormones with musculoskeletal pain and painful osteoarthritis, discussing data from diverse natural, therapeutic, and experimental settings in humans and relevant animal models relating to hormone loss or replacement and the consequent effects on health, pain, and disease. We also postulate mechanisms by which sex hormones could mediate these effects. Further research is needed; however, increased scientific understanding of this complex area could lead to real benefits in musculoskeletal and women's health.

Hormone replacement therapy (conjugated oestrogens plus bazedoxifene) for post-menopausal women with symptomatic hand osteoarthritis: primary report from the HOPE-e randomised, placebo-controlled, feasibility study.

Background: Symptomatic hand osteoarthritis is more common in women than in men, and its incidence increases around the age of menopause, implicating oestrogen deficiency. No randomised controlled trials of hormone replacement therapy (HRT) have been done in people with hand osteoarthritis. We aimed to determine the feasibility and acceptability of a form of HRT (conjugated oestrogens plus bazedoxifene) in post-menopausal women with painful hand osteoarthritis. Methods: The HOPE-e feasibility study was a randomised, double-blind, placebo-controlled trial, for which we recruited women aged 40-65 years, for whom 1-10 years had passed after their final menstrual period, with definite hand osteoarthritis and at least two painful hand joints. Participants were recruited across three primary or secondary care sites and from the community and were randomly assigned (1:1) to receive conjugated oestrogens plus bazedoxifene or placebo, orally once every day for 24 weeks, before weaning for 4 weeks until the end of the study. The primary feasibility outcomes were rates of identification, recruitment, randomisation, retention, and compliance of eligible participants, and the likelihood of unmasking. The secondary objective was to generate proof-of-concept quantitative and qualitative data on the acceptability of proposed clinical outcomes for a full trial and adverse events. We used an intention-to-treat analysis, and criteria for progression to a full trial were pre-defined as recruitment of at least 30 participants across all sites in 18 months; a dropout rate of less than or equal to 30% of randomised individuals; and acceptability to the majority of participants, including acceptable rates of adverse events. Due to the COVID-19 pandemic, the recruitment window was reduced to 12-15 months. A proportionately reduced minimum sample size of 22 was judged to be sufficient to test feasibility. This trial was registered at ISRCTN, ISRCTN12196200. Findings: From May 9, 2019 to Dec 31, 2020, 434 enquiries or referrals were received. We did 96 telephone pre-screens; of the 35 eligible participants, seven were excluded as ineligible at the telephone or face-to-face screening and 28 (80% [95% CI 63-92]) were randomly assigned. Of the 406 who were not randomly assigned, 250 (62%) were ineligible (with contraindicated medications accounting for 50 [20%] of these), 101 (25%) did not respond to further enquiries, and 55 (14%) chose not to proceed (with the most common reason being not wanting to take a hormone-based drug). All 28 randomised participants completed all follow-up assessments with high compliance and outcome measure completeness. All three adverse event-related treatment withdrawals were in the placebo group. No serious adverse events were reported. Participants and investigators were successfully masked (participant Bang's blinding index placebo group 0·50 [95% CI 0·25-0·75]). The trial met the prespecified criteria for progression to a full trial. Interpretation: This first-ever feasibility study of a randomised controlled trial of HRT for post-menopausal women with painful hand osteoarthritis met its progression criteria, although it was not powered to detect a clinical effect. This outcome indicates that a full trial of an HRT in this population is feasible and acceptable and identifies potential refinements with regard to the design of such a trial. Funding: Research for Patient Benefit programme, National Institute for Health Research.