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.

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.

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.

Identification of Altered Evoked and Non-Evoked Responses in a Heterologous Mouse Model of Endometriosis-Associated Pain.

The aim of this study was to develop and refine a heterologous mouse model of endometriosis-associated pain in which non-evoked responses, more relevant to the patient experience, were evaluated. Immunodeficient female mice (N = 24) were each implanted with four endometriotic human lesions (N = 12) or control tissue fat (N = 12) on the abdominal wall using tissue glue. Evoked pain responses were measured biweekly using von Frey filaments. Non-evoked responses were recorded weekly for 8 weeks using a home cage analysis (HCA). Endpoints were distance traveled, social proximity, time spent in the center vs. outer areas of the cage, drinking, and climbing. Significant differences between groups for von Frey response, climbing, and drinking were detected on days 14, 21, and 35 post implanting surgery, respectively, and sustained for the duration of the experiment. In conclusion, a heterologous mouse model of endometriosis-associated evoked a non-evoked pain was developed to improve the relevance of preclinical models to patient experience as a platform for drug testing.

Preclinical models of endometriosis and interstitial cystitis/bladder pain syndrome: an Innovative Medicines Initiative-PainCare initiative to improve their value for translational research in pelvic pain.

ABSTRACT: Endometriosis (ENDO) and interstitial cystitis/bladder pain syndrome (IC/BPS) are chronic pain conditions for which better treatments are urgently needed. Development of new therapies with proven clinical benefit has been slow. We have conducted a review of existing preclinical in vivo models for ENDO and IC/BPS in rodents, discussed to what extent they replicate the phenotype and pain experience of patients, as well as their relevance for translational research. In 1009 publications detailing ENDO models, 41% used autologous, 26% syngeneic, 18% xenograft, and 11% allogeneic tissue in transplantation models. Intraperitoneal injection of endometrial tissue was the subcategory with the highest construct validity score for translational research. From 1055 IC/BPS publications, most interventions were bladder centric (85%), followed by complex mechanisms (8%) and stress-induced models (7%). Within these categories, the most frequently used models were instillation of irritants (92%), autoimmune (43%), and water avoidance stress (39%), respectively. Notably, although pelvic pain is a hallmark of both conditions and a key endpoint for development of novel therapies, only a small proportion of the studies (models of ENDO: 0.5%-12% and models of IC/BPS: 20%-44%) examined endpoints associated with pain. Moreover, only 2% and 3% of publications using models of ENDO and IC/BPS investigated nonevoked pain endpoints. This analysis highlights the wide variety of models used, limiting reproducibility and translation of results. We recommend refining models so that they better reflect clinical reality, sharing protocols, and using standardized endpoints to improve reproducibility. We are addressing this in our project Innovative Medicines Initiative-PainCare/Translational Research in Pelvic Pain.

Developing consensus on core outcome domains for assessing effectiveness in perioperative pain management: results of the PROMPT/IMI-PainCare Delphi Meeting.

ABSTRACT: Postoperative pain management is still insufficient, leading to major deficits, including patient suffering, impaired surgical recovery, long-term opioid intake, and postsurgical chronic pain. Yet, identifying the best treatment options refers to a heterogeneous outcome assessment in clinical trials, not always reflecting relevant pain-related aspects after surgery and therefore hamper evidence synthesis. Establishing a core outcome set for perioperative pain management of acute pain after surgery may overcome such limitations. An international, stepwise consensus process on outcome domains ("what to measure") for pain management after surgery, eg, after total knee arthroplasty, sternotomy, breast surgery, and surgery related to endometriosis, was performed. The process, guided by a steering committee, involved 9 international stakeholder groups and patient representatives. The face-to-face meeting was prepared by systematic literature searches identifying common outcome domains for each of the 4 surgical procedures and included breakout group sessions, world-café formats, plenary panel discussions, and final voting. The panel finally suggested an overall core outcome set for perioperative pain management with 5 core outcome domains: physical function (for a condition-specific measurement), pain intensity at rest, pain intensity during activity, adverse events, and self-efficacy. Innovative aspects of this work were inclusion of the psychological domain self-efficacy, as well as the specific assessment of pain intensity during activity and physical function recommended to be assessed in a condition-specific manner. The IMI-PROMPT core outcome set seeks to improve assessing efficacy and effectiveness of perioperative pain management in any clinical and observational studies as well as in clinical practice.

Development of a visual, patient-reported tool for assessing the multi-dimensional burden of endometriosis.

OBJECTIVE: Inadequate communication about endometriosis symptom burden between women and healthcare providers is a barrier for optimal treatment. This study describes the development of the EndoWheel, a patient-reported assessment tool that visualizes the multi-dimensional burden of endometriosis to facilitate patient-provider communication. METHODS: Assessment questions for the tool were developed using an iterative Delphi consensus process. A consensus phase included additional practitioners and specialists to broaden perspectives and select revised statements. Semi-structured qualitative interviews were conducted with 13 women with endometriosis to assess the scoring and content of the measures. RESULTS: Symptoms included in the tool were pelvic pain, vaginal bleeding, bowel/bladder symptoms, energy levels, fertility, impact on activities, emotional and sexual well-being, and self-perceived global health. Additional life impact areas included relationships, social and occupational activity, and self-perception. The 13 interviewees completed the tool in approximately 5-6 min (range 4.0-7.5 min). Most participants (92%) perceived that the tool would enable better patient-provider communication, including addressing symptoms and areas of impact not normally discussed during office visits. CONCLUSION: Similar to visual circular tools used in burden assessment of other chronic diseases, the tool may facilitate improved patient dialogue with providers around endometriosis treatment goals and options.

Laparoscopic treatment of isolated superficial peritoneal endometriosis for managing chronic pelvic pain in women: study protocol for a randomised controlled feasibility trial (ESPriT1).

BACKGROUND: Endometriosis (where endometrial-like tissue is found outside the uterus) affects ~ 176 million women worldwide and can lead to debilitating pelvic pain. Three subtypes of endometriosis exist, with ~ 80% of women having superficial peritoneal endometriosis (SPE). Endometriosis is diagnosed by laparoscopy and, if SPE is found, gynaecologists usually remove it surgically. However, many women get limited pain relief from surgical removal of SPE. We plan to undertake a future large trial where women who have only SPE found at initial laparoscopy are randomly allocated to have surgical removal (excision or ablation) of SPE, or not. Ultimately, we want to determine whether surgical removal improves overall symptoms and quality of life, or whether surgery is of no benefit, exacerbates symptoms, or even causes harm. The primary objective of this feasibility study is to determine what proportion of women with suspected SPE undergoing diagnostic laparoscopy will agree to randomisation. The secondary objectives are to determine if there are differences in key prognostic parameters between eligible women that agree to be randomised and those that decline; how many women having laparoscopy for investigation of chronic pelvic pain are eligible for the trial; the range of treatment effects and variability in outcomes and the most acceptable methods of recruitment, randomisation and assessment tools. METHODS: We will recruit up to 90 women with suspected SPE undergoing diagnostic laparoscopy over a 9-month recruitment period in four Scottish hospitals and randomise them 1:1 to either diagnostic laparoscopy alone (with a sham port to achieve blinding of the allocation) or surgical removal of endometriosis. Baseline characteristics, e.g. age, index of social deprivation, ethnicity, and intensity/duration of pain will be collected. Participants will be followed up by online questionnaires assessing pain, physical and emotional function at baseline, 3 months, 6 months and 12 months. DISCUSSION: Recruitment to a randomised controlled trial to assess the effectiveness of surgery for endometriosis may be challenging because of preconceived ideas about treatment success amongst patients and clinicians. We have designed this study to assess feasibility of recruitment and to inform the design of our future definitive trial. TRIAL REGISTRATION: ClincicalTrials.gov, NCT04081532 STATUS: Recruiting.

Is There a Neuropathic-Like Component to Endometriosis-Associated Pain? Results From a Large Cohort Questionnaire Study.

Background: Pain is one of the primary symptoms of endometriosis, a chronic inflammatory condition characterised by the presence of endometrial tissue outside the uterus. Endometriosis-associated pain is commonly considered as nociceptive in nature, but its clinical presentation suggests that it might have neuropathic-like properties in a subgroup of patients. Methods: This is a cross sectional study using an online survey. The survey was distributed by patient support websites. The survey was composed of validated questionnaires assessing pain symptoms, psychological measures and questions about number of surgeries. Main Results: We had 1,417 responses which met the inclusion criteria. Using standard painDETECT cut-off scores, we found that pain was classified as neuropathic in 40% of patients and as mixed neuropathic/nociceptive in a further 35%. In line with observations in other neuropathic conditions, the neuropathic subgroup reported higher pain intensities, greater psychological distress and cognitive impairment. Neuropathic pain was also more likely in those with more surgeries to the abdomen and a longer history of pain. As revealed by a cluster analysis, those with a neuropathic pain component could further be divided into two subgroups based on their sensory profile. Conclusions: The data presented here indicate that endometriosis-associated pain includes a neuropathic-like component in a substantial proportion of women. Although further investigation is required, our finding challenges the current conceptualisation of endometriosis-associated pain as nociceptive and advocates for a new perspective on this type of pain, which is so debilitating to a large number of women.

Research Design Characteristics of Published Pharmacologic Randomized Clinical Trials for Irritable Bowel Syndrome and Chronic Pelvic Pain Conditions: An ACTTION Systematic Review.

Chronic pain conditions occurring in the lower abdomen and pelvis are common, often challenging to manage, and can negatively affect health-related quality of life. Methodological challenges in designing randomized clinical trials (RCTs) for these conditions likely contributes to the limited number of available treatments. The goal of this systematic review of RCTs of pharmacologic treatments for irritable bowel syndrome and 3 common chronic pelvic pain conditions are to: 1) summarize the primary end points and entry criteria, and 2) evaluate the clarity of reporting of important methodological details. In total, 127 RCTs were included in the analysis. The most common inclusion criteria were a minimum pain duration (81%), fulfilling an established diagnostic criteria (61%), and reporting a minimum pain intensity (42%). Primary end points were identified for only 57% of trials. These end points, summarized in this article, were highly variable. The results of this systematic review can be used to inform future research to optimize the entry criteria and outcome measures for pain conditions occurring in the lower abdomen and pelvis, to increase transparency in reporting to allow for proper interpretation of RCT results for clinical and policy applications, and to facilitate the aggregation of data in meta-analyses. PERSPECTIVE: This article summarizes entry criteria and outcome measures and the clarity of reporting of these important design features in RCTs of irritable bowel syndrome and 3 common chronic pelvic pain conditions. These results can be used to improve design of future trials of these largely unaddressed pain conditions.

An Exploratory Study into Objective and Reported Characteristics of Neuropathic Pain in Women with Chronic Pelvic Pain.

Chronic pelvic pain (CPP) affects 5.7-26.6% women worldwide. 55% have no obvious pathology and 40% have associated endometriosis. Neuropathic pain (NeP) is pain arising as a consequence of a lesion/disease affecting the somatosensory system. The prevalence of NeP in women with CPP is not known. The diagnosis of NeP is challenging because there is no gold-standard assessment. Questionnaires have been used in the clinical setting to diagnose NeP in other chronic pain conditions and quantitative sensory testing (QST) has been used in a research setting to identify abnormal sensory function. We aimed to determine if women with chronic pelvic pain (CPP) have a neuropathic pain (NeP) component to their painful symptoms and how this is best assessed. We performed an exploratory prospective cohort study of 72 pre-menopausal women with a diagnosis of CPP. They underwent a clinician completed questionnaire (DN4) and completed the S-LANSS and PainDETECT™ questionnaires. Additionally QST testing was performed by a clinician. They also completed a patient acceptability questionnaire. Clinical features of NeP were identified by both questionnaires and QST. Of the women who were NeP positive, 56%, 35% and 26% were identified by the S-LANSS, DN4 and PainDETECT™ respectively. When NeP was identified by questionnaire, the associated laparoscopy findings were similar irrespective of which questionnaire was used. No subject had entirely unchanged QST parameters. There were distinct loss and gain subgroups, as well as mixed alteration in function, but this was not necessarily clinically significant in all patients. 80% of patients were confident that questionnaires could diagnose NeP, and 90% found them easy to complete. Early identification of NeP in women with CPP with a simple questionnaire could facilitate targeted therapy with neuromodulators, which are cheap, readily available, and have good safety profiles. This approach could prevent unnecessary or fertility-compromising surgery and prolonged treatment with hormones.

Peripheral changes in endometriosis-associated pain.

BACKGROUND: Pain remains the cardinal symptom of endometriosis. However, to date, the underlying mechanisms are still only poorly understood. Increasing evidence points towards a close interaction between peripheral nerves, the peritoneal environment and the central nervous system in pain generation and processing. Recently, studies demonstrating nerve fibres and neurotrophic and angiogenic factors in endometriotic lesions and their vicinity have led to increased interest in peripheral changes in endometriosis-associated pain. This review focuses on the origin and function of these nerves and factors as well as possible peripheral mechanisms that may contribute to the generation and modulation of pain in women with endometriosis. METHODS: We conducted a systematic search using several databases (PubMed, MEDLINE, EMBASE and CINAHL) of publications from January 1977 to October 2013 to evaluate the possible roles of the peripheral nervous system in endometriosis pathophysiology and how it can contribute to endometriosis-associated pain. RESULTS: Endometriotic lesions and peritoneal fluid from women with endometriosis had pronounced neuroangiogenic properties with increased expression of new nerve fibres, a shift in the distribution of sensory and autonomic fibres in some locations, and up-regulation of several neurotrophins. In women suffering from deep infiltrating endometriosis and bowel endometriosis, in which the anatomical distribution of lesions is generally more closely related to pelvic pain symptoms, endometriotic lesions and surrounding tissues present higher nerve fibre densities compared with peritoneal lesions and endometriomas. More data are needed to fully confirm a direct correlation between fibre density in these locations and the amount of perceived pain. A better correlation between the presence of nerve fibres and pain symptoms seems to exist for eutopic endometrium. However, this appears not to be exclusive to endometriosis. No correlation between elevated neurotrophin levels and pain severity appears to exist, suggesting the involvement of other mediators in the modulation of pain. CONCLUSIONS: The increased expression of neurotrophic factors and nerve fibres in endometriotic lesions, eutopic endometrium and the peritoneum imply a role of such peripheral changes in the pathogenesis of endometriosis-associated pain. However, a clear link between these findings and pain in patients with endometriosis has so far not been demonstrated.

Brain imaging reveals that engagement of descending inhibitory pain pathways in healthy women in a low endogenous estradiol state varies with testosterone.

The combined oral contraceptive pill (COCP) has been implicated in the development of a number of chronic pain conditions. Modern COCP formulations produce a low endogenous estradiol, low progesterone environment similar to the early follicular phase of the natural menstrual cycle, with a variable effect on serum androgen levels. We used behavioural measures and functional magnetic resonance imaging to investigate the response to experimental thermal stimuli in healthy women, in both a natural and COCP-induced low endogenous estradiol state, to investigate whether alterations in central pain processing may underlie these observations in COCP users. Although COCP users overall did not require lower temperatures to obtain a fixed pain intensity, alterations in the brain response to these stimuli were observed. In a subgroup of COCP users with significantly reduced serum testosterone, however, lower temperatures were required. Region-of-interest analysis revealed that within key regions of the descending pain inhibitory system, activity in response to noxious stimulation varied with serum testosterone levels in both groups of women. Of particular interest, in COCP users, activity in the rostral ventromedial medulla increased with increasing testosterone and in those women with low testosterone, was significantly reduced compared to controls. These findings suggest that, in a low endogenous estradiol state, testosterone may be a key factor in modulating pain sensitivity via descending pathways. Specifically, failure to engage descending inhibition at the level of the rostral ventromedial medulla may be responsible for the reduction in temperature required by COCP users with low circulating testosterone.