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The Nuffield Department of Obstetrics & Gynaecology (NDOG) is pleased to announce that Professor Peter Hammond, a world leader in the analysis of facial dysmorphism in rare genetic syndromes, has joined the department.
Crimson clues: advancing endometriosis detection and management with novel blood biomarkers.
Endometriosis is an inflammatory condition affecting approximately 10% of the female-born population. Despite its prevalence, the lack of noninvasive biomarkers has contributed to an established global diagnostic delay. The intricate pathophysiology of this enigmatic disease may leave signatures in the blood, which, when detected, can be used as noninvasive biomarkers. This review provides an update on how investigators are utilizing the established disease pathways and innovative methodologies, including genome-wide association studies, next-generation sequencing, and machine learning, to unravel the clues left in the blood to develop blood biomarkers. Many blood biomarkers show promise in the discovery phase, but because of a lack of standardized and robust methodologies, they rarely progress to the development stages. However, we are now seeing biomarkers being validated with high diagnostic accuracy and improvements in standardization protocols, providing promise for the future of endometriosis blood biomarkers.
Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis
AbstractUterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10−8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.
Protocol for the Cultural Translation and Adaptation of the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project Endometriosis Participant Questionnaire (EPHect)
Endometriosis affects 10% of women worldwide and is one of the most common causes of chronic pelvic pain and infertility. However, causal mechanisms of this disease remain unknown due to its heterogeneous presentation. In order to successfully study its phenotypic variation, large sample sizes are needed. Pooling of data across sites is not always feasible given the large variation in the complexity and quality of the data collected. The World Endometriosis Research Foundation (WERF) Endometriosis Phenome and Biobanking Harmonization Project (EPHect) have developed an endometriosis participant questionnaire (EPQ) to harmonize non-surgical clinical participant characteristic data relevant to endometriosis research, allowing for large-scale collaborations in English-speaking populations. Although the WERF EPHect EPQs have been translated into different languages, no study has examined the cross-cultural translation and adaptation for content and face validity. In order to investigate this, we followed the standard guidelines for cross-cultural adaptation and translation of the minimum version of the EPQ (EPQ-M) using 40 patients who underwent laparoscopic surgery in Turkey and 40 women in Northern Cyprus, aged between 18 and 55. We assessed the consistency by using cognitive testing and found the EPHect EPQ-M to be comprehensive, informative, and feasible in these two Turkish-speaking populations. The translated and adapted questionnaire was found to be epidemiologically robust, taking around 30–60 min to complete; furthermore, participants reported a similar understanding of the questions, showing that common perspectives were explored. Results from the cognitive testing process led to minor additions to some items such as further descriptive and/or visuals in order to clarify medical terminology. This paper illustrates the first successful cross-cultural translation and adaptation of the EPHect EPQ-M and should act as a tool to allow for further studies that wish to use this questionnaire in different languages. Standardized tools like this should be adopted by researchers worldwide to facilitate collaboration and aid in the design and conduction of global studies to ultimately help those affected by endometriosis and its associated symptoms.
Impact of Endometriosis in Women of Arab Ancestry on: Health-Related Quality of Life, Work Productivity, and Diagnostic Delay.
Introduction: Endometriosis has a negative effect on health-related quality of life (HRQoL), wellbeing and daily functioning. Endometriosis is an under-researched condition within non-western populations. Cultural representations are needed to understand the relative roles of societal norms, traditional factors, and religious sensitivities on the impact of endometriosis on HRQoL in various populations. In particular, there is a lack of emphasis placed in understanding the association of HRQoL on endometriosis in Arab women. Method: In this prospective case-control study, 2,610 Arab ancestry women in the United Arab Emirates were recruited to investigate the impact of endometriosis on HRQoL, diagnostic delay, psychological co-morbidities, work productivity, and physical activity. Participants completed the following standardized, validated questionnaires: Short Form-36 version 2 questionnaire, the World Endometriosis Research Foundation EPHect minimum clinical questionnaire version, and Work Productivity and Activity Impairment questionnaire. Translations to the Arabic language, validated using the forward-backward translation method, of the questionnaires were utilized. Results: HRQoL scores were significantly impaired in women with endometriosis, as demonstrated in the Physical Composite Scores and Mental Composite Scores in the symptomatic control group (p = 0.001; p = 0.003, respectively) and the asymptomatic control group (p < 0.001; p < 0.001, respectively). Susceptibility and severity of multiple pain syndromes and infertility in women with endometriosis was the main indicator of lower HRQoL. Anxiety (p = 0.007) and depression (p = 0.005) were significantly associated with endometriosis, in comparison to symptomatic controls. The average diagnostic delay was 11.61 years, however single women experience 15.81 years of diagnosis delay, with approximately 18% (n = 15) of the single women experiencing more than a 20-year delay in diagnosis. The intensity of physical activity was not associated with endometriosis, when compared to symptomatic (p = 0.405) or asymptomatic controls (p = 0.144). Conclusion: For the first time, we provide evidence from a combined hospital, clinic, and population-based study that Arab women with endometriosis experience significant impacts on HRQoL, substantial diagnostic delay after the onset of symptoms, significant association to psychological disorders (anxiety and depression), and a negative impact on work productivity. Future research must focus on understanding the personal and culturally centered beliefs of Arab women to ensure a positive HRQoL trajectory by improving diagnosis and management strategies.
Author Correction: Amine oxidase 3 is a novel pro-inflammatory marker of oxidative stress in peritoneal endometriosis lesions
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Genetics and genomics of endometriosis
Endometriosis is an estrogen-dependent, progesterone-resistant, inflammatory disease with symptoms that include pelvic pain, infertility, and compromised quality of life in millions of women worldwide. Approximately 50% of the risk of developing endometriosis is due to genetic factors with the remaining 50% due to environmental (i.e., exposome) causes. Treatments are hormonal, surgical, or both, with limited efficacy in the long term. Diagnosis of pelvic endometriosis is through visual identification and confirmatory histopathology of lesions. Recent innovations in genomics, genetics and epigenetics, molecular and cell biology, imaging, and a worldwide effort to standardize patient phenotyping and biospecimen collection have contributed to understanding mechanisms underlying the pathogenesis and pathophysiology of endometriosis. Furthermore, integration of “big data” obtained through these technologies holds great promise for novel targeted therapies, noninvasive diagnostics, and prognostic indicators. This chapter reviews current advances in genomics, genetics, and epigenetics of endometriosis that are providing translational approaches for preventing, diagnosing, and effectively treating this enigmatic disease.
Prevalence of Common Gynecological Conditions in the Middle East: Systematic Review and Meta-Analysis.
Introduction: High prevalence of gynecological conditions in women of Middle Eastern origin is reported, likely due to regional risk factors and mediators. The objective of this systematic review and meta-analysis is to investigate the prevalence of polycystic ovary syndrome (PCOS), endometriosis, uterine fibroids, and adenomyosis in women of Middle Eastern origin. Methods: MEDLINE, EMBASE, PsycINFO, Global Health, and Google Scholar databases were searched from database inception until 14 February 2021 to identify relevant studies. Peer-reviewed research articles that reported the prevalence of PCOS, endometriosis, uterine fibroids, and adenomyosis in the Middle Eastern population were written in English or Arabic. The primary outcome was the estimated pooled prevalence of PCOS, endometriosis, uterine fibroids, and adenomyosis in the Middle Eastern populations. The secondary outcome was to assess the evidence in the data for the presence of heterogeneity, by conducting subtype-pooled analysis of prevalence estimates of the conditions. Total weighted prevalence was calculated via Freeman-Tukey arcsine transformation and heterogeneity through the I 2 statistic. Quality control was performed using GRADE criteria. Results: A total of 47 studies, 26 on PCOS, 12 on endometriosis, eight on uterine fibroids, and seven on adenomyosis, were included. The pooled prevalence of PCOS diagnosed according to the NIH criteria was 8.9% (95% CI: 6.5-11.7; prevalence range: 4.0-27.6%), with a higher prevalence from the Gulf Arab states (18.8%, 95% CI: 9.5-30.3; range: 12.1-27.6%). According to the Rotterdam criteria, the pooled prevalence of PCOS was 11.9% (95% CI: 7.1-17.7; range: 3.4-19.9%) with studies limited to the Persian and Levant regions. Endometriosis was diagnosed in 12.9% (95% CI: 4.2-25.4; range: 4.2-21.0%) of women undergoing laparoscopy, for any indication. Uterine fibroid and adenomyosis prevalence of women was 30.6% (95% CI: 24.9-36.7; range: 18.5-42.6%) and 30.8% (95% CI: 27.1-34.6, range: 25.6-37.7%), respectively. Heterogeneity was present between studies due to statistical and methodological inconsistencies between studies, and quality of evidence was low due to sample size and unrepresentative participant selection. Conclusion: This is the first review that has reported the prevalence of gynecological diseases in the Middle Eastern population, suggesting that gynecological morbidity is a public health concern. Due to the health disparities in women, further research is required to understand the relative roles of environmental and genetic factors in the region to serve as a benchmark for evaluation and comparative purposes with other populations.
The Cyprus Women’s Health Research (COHERE) initiative: normative data from the SF-36v2 questionnaire for reproductive aged women from the Eastern Mediterranean
Abstract Purpose Describe the health-related quality of life for a representative cohort of women aged 18–55 in Northern Cyprus. Methods We utilised the SF-36-Health-Survey-version-2 (SF-36v2) questionnaire as part of the COHERE Initiative study to calculate the eight physical and mental subscale scores, as well as the two overall summary measures for physical and mental health, where we present results using Cyprus-specific scoring as well as scores based on the test developers’ algorithms. We examined associations between sociodemographic characteristics for both scores. Results A total of 7089 women fully completed the SF-36v2 questionnaire (mean age = 36.9), which was reliable and valid in this population. We observed better physical health in ages 18–25 compared to 46–55 (53.32 vs. 46.72 (p < 0.001)) and better mental health in women aged 46–55 compared to 18–25 (52.07 vs. 47.95 (p < 0.001)). Women in employment had better physical and mental health compared to those who were unemployed (physical: 50.25 vs 49.95, p < 0.001 and mental: 50.25 vs 49.24, p = 0.083) and scores increased as educational attainment increased (physical: 47.55 for primary to 51.58 for postgraduate, mental: 48.88 to 50.59, p < 0.001). Turkish Cypriot women had higher scores than Turkish women (physical: 50.42 vs 49.30, mental: 50.43 vs 49.10, p < 0.001). Conclusion These are the first population normative values published from a large representative sample of women between 18 and 55 years from the Eastern Mediterranean region. We found better physical health in younger women and better mental health in older women. Turkish Cypriot women and non-migrant women had better mental health, and HRQOL was highest in those in paid employment and those with a higher educational achievement.
Global endometrial DNA methylation analysis reveals insights into mQTL regulation and associated endometriosis disease risk and endometrial function
AbstractEndometriosis is a leading cause of pain and infertility affecting millions of women globally. Herein, we characterize variation in DNA methylation (DNAm) and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genotype data and methylation in endometrial samples from 984 deeply-phenotyped participants. We estimate that 15.4% of the variation in endometriosis is captured by DNAm and identify significant differences in DNAm profiles associated with stage III/IV endometriosis, endometriosis sub-phenotypes and menstrual cycle phase, including opening of the window for embryo implantation. Menstrual cycle phase was a major source of DNAm variation suggesting cellular and hormonally-driven changes across the cycle can regulate genes and pathways responsible for endometrial physiology and function. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis-mQTLs including 51 associated with risk of endometriosis, highlighting candidate genes contributing to disease risk. Our work provides functional evidence for epigenetic targets contributing to endometriosis risk and pathogenesis. Data generated serve as a valuable resource for understanding tissue-specific effects of methylation on endometrial biology in health and disease.
Prevalence, diagnostic delay and economic burden of endometriosis and its impact on quality of life: results from an Eastern Mediterranean population
Abstract Background There are limited data on endometriosis from the Eastern Mediterranean region. This study for the first time estimates the prevalence and impact of endometriosis on women in Northern Cyprus, an under-represented region in Europe. Methods Cyprus Women’s Health Research Initiative, a cross-sectional study recruited 7646 women aged 18–55 in Northern Cyprus between January 2018 and February 2020. Cases were identified using self-reported and ultrasound data and two control groups were defined, with (n = 2922) and without (n = 4314) pain. Standardized tools, including the 11-point Numerical Rating Scale and the Short Form 36 Health Survey version 2, were used to assess pain and quality of life, respectively. Results Prevalence and median diagnostic delay of endometriosis were 5.4% [95% confidence interval (CI): 4.9–5.9%, n = 410] and 7 (interquartile range 15.5) years. Endometriosis cases experienced a higher prevalence of bladder pain compared with asymptomatic pain controls (6.3% vs. 1.0%, P < 0.001) and irritable bowel syndrome relating to pelvic pain compared with symptomatic (4.6% vs. 2.6%, P = 0.027) and asymptomatic (0.3%, P < 0.001) controls. The odds of endometriosis cases reporting an anxiety diagnosis was 1.56 (95% CI: 1.03–2.38) higher than the symptomatic and 1.95 (95% CI: 1.30–2.92) times higher than the asymptomatic controls. The physical component score of the health-related quality-of-life instrument suggested a significant difference between the endometriosis cases and the symptomatic controls (46.8 vs. 48.5, P = 0.034). Average annual economic cost of endometriosis cases was Int$9864 (95% CI: $8811–$10 917) including healthcare, costs relating to absence and loss of productivity at work. Conclusion Prevalence was lower than the global 10% estimate, and substantial proportion of women without endometriosis reported moderate/severe pelvic pain hinting at many undiagnosed cases within this population. Coupled with lower quality of life, significant economic burden and underutilized pain management options, the study highlights multiple opportunities to improve care for endometriosis patients and women with pelvic pain.
Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata.
Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1 A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.