The Cyprus Women's Health Research (COHERE) initiative: normative data from the SF-36v2 questionnaire for reproductive aged women from the Eastern Mediterranean.

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.

Endometriosis classification, staging and reporting systems: a review on the road to a universally accepted endometriosis classification.

BACKGROUND: In the field of endometriosis, several classification, staging and reporting systems have been developed. However, endometriosis classification, staging and reporting systems that have been published and validated for use in clinical practice have not been systematically reviewed up to now. OBJECTIVES: The aim of the current review is to provide a historical overview of these different systems based on an assessment of published studies. MATERIALS AND METHODS: A systematic Pubmed literature search was performed. Data were extracted and summarised. RESULTS: Twenty-two endometriosis classification, staging and reporting systems have been published between 1973 and 2021, each developed for specific and different purposes. There is still no international agreement on how to describe the disease. Studies evaluating different systems are summarised showing a discrepancy between the intended and the evaluated purpose, and a general lack of validation data confirming a correlation with pain symptoms or quality of life for any of the current systems. A few studies confirm the value of the Enzian system for surgical description of deep endometriosis. With regards to infertility, the endometriosis fertility index has been confirmed valid for its intended purpose. CONCLUSIONS: Of the 22 endometriosis classification, staging and reporting systems identified in this historical overview, only a few have been evaluated, in 46 studies, for the purpose for which they were developed. It can be concluded that there is no international agreement on how to describe endometriosis or how to classify it, and that most classification/staging systems show no or very little correlation with patient outcomes. WHAT IS NEW?: This overview of existing systems is a first step in working towards a universally accepted endometriosis classification.

An International Terminology for Endometriosis, 2021.

BACKGROUND: Different classification systems have been developed for endometriosis, using different definitions for the disease, the different subtypes, symptoms and treatments. In addition, an International Glossary on Infertility and Fertility Care was published in 2017 by the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) in collaboration with other organisations. 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. OBJECTIVES: The aim of the current paper is to develop a set of terms and definitions on endometriosis that would be the basis for standardisation in disease description, classification and research. MATERIALS AND METHODS: 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 finalisation of the first draft, the members of the international societies and other stakeholders were consulted for feedback and comments, which led to further adaptations. RESULTS: A list of 49 terms and definitions in the field of endometriosis is presented, including a definition for endometriosis and its subtypes, different locations, interventions, symptoms and outcomes. Endometriosis is defined as a disease characterised by the presence of endometrium-like epithelium and/or stroma outside the endometrium and myometrium, usually with an associated inflammatory process. CONCLUSIONS: 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 harmonisation in endometriosis research and clinical practice. Future research may require further refinement of the presented definitions. WHAT IS NEW?: A consensus based international terminology for endometriosis for clinical and research use.

Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.

Uterine 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.

The management of menopause in women with a history of endometriosis: a systematic review.

BACKGROUND: Endometriosis is typically regarded as a premenopausal disease, resolving after natural or iatrogenic menopause due to declining oestrogen levels. Nonetheless, case reports over the years have highlighted the incidence of recurrent postmenopausal endometriosis. It is now clear that both recurrence and malignant transformation of endometriotic foci can occur in the postmenopausal period. Postmenopausal women are commonly treated with hormone replacement therapy (HRT) to treat climacteric symptoms and prevent bone loss; however, HRT may reactivate endometriosis and stimulate malignant transformation in women with a history of endometriosis. Given the uncertain risks of initiating HRT, it is difficult to determine the best menopausal management for this group of women. OBJECTIVE AND RATIONAL: The aim of this study was to systematically review the existing literature on management of menopausal symptoms in women with a history of endometriosis. We also aimed to evaluate the published literature on the risks associated with HRT in these women, and details regarding optimal formulations and timing (i.e. initiation and duration) of HRT. SEARCH METHODS: Four electronic databases (MEDLINE via OVID, Embase via OVID, PsycINFO via OVID and CINAHL via EbscoHost) were searched from database inception until June 2016, using a combination of relevant controlled vocabulary terms and free-text terms related to 'menopause' and 'endometriosis'. Inclusion criteria were: menopausal women with a history of endometriosis and menopausal treatment including HRT or other preparations. Case reports/series, observational studies and clinical trials were included. Narrative review articles, organizational guidelines and conference abstracts were excluded, as were studies that did not report on any form of menopausal management. Articles were assessed for risk of bias and quality using GRADE criteria. OUTCOMES: We present a synthesis of the existing case reports of endometriosis recurrence or malignant transformation in women undergoing treatment for menopausal symptoms. We highlight common presenting symptoms, potential risk factors and outcomes amongst the studies. Sparse high-quality evidence was identified, with few observational studies and only two randomized controlled trials. Given this paucity of data, no definitive conclusions can be drawn concerning risk. WIDER IMPLICATIONS: Due to the lack of high-quality studies, it remains unclear how to advise women with a history of endometriosis regarding the management of menopausal symptoms. The absolute risk of disease recurrence and malignant transformation cannot be quantified, and the impact of HRT use on these outcomes is not known. Multicentre randomized trials or large observational studies are urgently needed to inform clinicians and patients alike.

Recent insights on the genetics and epigenetics of endometriosis.

Endometriosis is a gynecologic disease affecting up to 10% of the women and a major cause of pain and infertility. It is characterized by the implantation of functional endometrial tissue at ectopic positions generally within the peritoneum. This complex disease has an important genetic component with a heritability estimated at around 50%. This review aims at providing recent insights into the genetic bases of endometriosis, and presents a detailed overview of evidence of epigenetic alterations specific to this disease. In the future, these alterations may constitute therapeutic targets for pharmacological compounds able to modify the epigenetic code.

The future for genetic studies in reproduction.

Genetic factors contribute to risk of many common diseases affecting reproduction and fertility. In recent years, methods for genome-wide association studies (GWAS) have revolutionized gene discovery for common traits and diseases. Results of GWAS are documented in the Catalog of Published Genome-Wide Association Studies at the National Human Genome Research Institute and report over 70 publications for 32 traits and diseases associated with reproduction. These include endometriosis, uterine fibroids, age at menarche and age at menopause. Results that pass appropriate stringent levels of significance are generally well replicated in independent studies. Examples of genetic variation affecting twinning rate, infertility, endometriosis and age at menarche demonstrate that the spectrum of disease-related variants for reproductive traits is similar to most other common diseases. GWAS 'hits' provide novel insights into biological pathways and the translational value of these studies lies in discovery of novel gene targets for biomarkers, drug development and greater understanding of environmental factors contributing to disease risk. Results also show that genetic data can help define sub-types of disease and co-morbidity with other traits and diseases. To date, many studies on reproductive traits have used relatively small samples. Future genetic marker studies in large samples with detailed phenotypic and clinical information will yield new insights into disease risk, disease classification and co-morbidity for many diseases associated with reproduction and infertility.

The ENDOCARE questionnaire (ECQ): a valid and reliable instrument to measure the patient-centeredness of endometriosis care in Europe.

BACKGROUND: Endometriosis is prevalent and women need high-quality care, which should be patient-centered. This study aimed to develop a valid and reliable patient-centeredness questionnaire, based on a defined concept of patient-centered endometriosis care (PCEC). METHODS: A literature review, focus groups (FGs) with patients and an expert panel defined PCEC with 10 dimensions. The ENDOCARE questionnaire (ECQ) was developed. FGs resulted in 43 specific statements covering the 10 dimensions of PCEC, for which the ECQ measured 'importance' and 'performance'. Medical and demographic questions and an open question were added. The Dutch ECQ questionnaire was piloted and reciprocally translated into English and Italian. Patients with endometriosis from Belgium, The Netherlands, Italy and the UK were invited to complete the ECQ online. Item analysis, inter-item analysis and confirmatory and exploratory factor analyses (EFA) and reliability analysis were performed. The theory-driven dimensions were adapted. RESULTS: The ECQ was completed by 541 patients. Based on item analysis, five statements were deleted. Factor analysis was performed on 322 questionnaires (only from respondents with a partner). Insights from the data-driven EFA suggested adaptations of the theory-driven dimensions. The reliability statistics of 9/10 adapted theory-driven dimensions were satisfactory and the root mean square error of approximation was good. CONCLUSIONS: This study resulted in a valid and reliable instrument to measure PCEC. For data presentation, the adapted theory-driven dimensions of PCEC are preferred over the data-driven factors. The ECQ may serve to benchmark patient-centeredness, conduct cross-cultural European research and set targets for improvement.

Coding regions of INHBA, SFRP4 and HOXA10 are not implicated in familial endometriosis linked to chromosome 7p13-15.

Endometriosis is a common, chronic gynaecological disease affecting up to 10% of women in their reproductive years. Its aetiology still remains unclear, but evidence indicates genetic factors play a role. We previously identified a region of significant linkage on chromosome 7 in 52 families comprising at least three affected women, stretching ∼6.4 Mb. We screened coding regions and parts of the regulatory regions of three candidate genes with a known role in endometrial development and function-INHBA, SFRP4 and HOXA10-located under or very near the linkage peak, for potential causal mutations using Sanger sequencing. Sequencing was conducted in 47 cases from the 15 families contributing most to the linkage signal (Z(mean) ≥ 1). Minor allele frequencies (MAFs) of observed variants were compared with MAFs from two publicly available reference populations of European ancestry: 60 individuals in HapMap and 150 individuals in the 1000 Genomes Project. A total of 11 variants were found, 5 (45%) of which were common (MAF > 0.05) among the 15 case families and the reference populations (P-values for MAF difference: 0.88-1.00). The remaining six were rare and unlikely to be individually or cumulatively responsible for the linkage signal. The results indicate that the coding regions of these three genes do not harbour mutations responsible for linkage to endometriosis in these families.

The endothelial nitric oxide synthase Glu298Asp polymorphism is not a risk factor for endometriosis in south Indian women.

OBJECTIVE: To investigate whether the eNOS gene influences the risk of developing endometriosis in south Indian women. STUDY DESIGN: The single nucleotide polymorphism, Glu298Asp, in exon7 of the eNOS gene was tested for association in a case-control study of 232 affected women and 210 women with no evidence of disease. All the women were infertile, ascertained from the same infertility clinic. The genotype frequencies of the polymorphism were compared, using polymerase chain reaction and sequencing analysis. The localization and expression of eNOS in the eutopic endometrium of five cases and four controls was also analyzed using immunohistochemistry and western blotting. RESULTS: No statistically significant differences were observed in the genotype distributions and allele frequencies (p=0.3) between the cases and controls according to codominant, dominant and recessive genotype models. The localization and expression of this protein were similar in the endometrium of cases and controls. CONCLUSION: In the present study we could neither observe a difference in the eNOS expression nor establish an association between the eNOS Glu298Asp exon 7 polymorphism in south Indian women with endometriosis.

Association between endometriosis and N-acetyl transferase 2 polymorphisms in a UK population.

The relationship between endometriosis and polymorphisms in the N-acetyl transferase 2 (NAT 2) gene was investigated in a UK population, as this gene has been previously implicated in the aetiology of the disease. Point mutations in the gene result in the variant alleles NAT 2 *5, *6 and *7 from the wild-type NAT 2 *4 allele. Homozygotes for the NAT 2 *4 wild type allele are fast NAT acetylators, while heterozygotes with one wild-type allele and a variant NAT 2 *5, *6 or *7 allele have reduced enzyme activity, and individuals with two variant alleles are slow acetylators. The NAT 2 *4/*6 genotype was significantly more common among affected women (35.2%) than population controls (8.1%; P = 0.0001) or unaffected women (4.2%; P = 0.02). Significantly more affected women (57.4%) were fast acetylators than were population controls (32.3%; P < 0.01) or unaffected women (33.3%; P < 0.05). These data suggest that altered NAT 2 enzyme activity may be a predisposition factor in endometriosis, or that NAT 2 alleles may be in linkage disequilibrium with a susceptibility allele in the same chromosomal region.

The community prevalence of chronic pelvic pain in women and associated illness behaviour.

BACKGROUND: Chronic pelvic pain has often been described as a major women's health issue, but no information exists on the extent of the problem in the United Kingdom. AIM: To investigate the community prevalence of chronic pelvic pain and its effect on the lives of consulting and non-consulting women. DESIGN OF STUDY: Postal questionnaire survey. SETTING: Women aged 18 to 49 (n = 3916) randomly selected from the Oxfordshire Health Authority Register. METHOD: The questionnaire response rate (adjusted for non-deliveries) was 74% (2304/3106). Chronic pelvic pain was defined as recurrent or constant pelvic pain of at least six months' duration, unrelated to periods, intercourse, or pregnancy. Case subgroups comprised recent consulters, past consulters, and non-consulters. Women who reported dysmenorrhoea alone formed a comparison group. RESULTS: The three-month prevalence of chronic pelvic pain was 24.0% (95% CI = 22.1% to 25.8%). One-third of women reported pain that started more than five years ago. Recent consulters (32% of cases) were most affected by their symptoms in terms of pain severity, use of health care, physical and mental health scores, sleep quality, and pain-related absence from work. Non-consulters (41% of cases) did not differ from women with dysmenorrhoea in terms of symptom-related impairment. Irrespective of consulting behaviour, a high rate of symptom-related anxiety was found in women with chronic pelvic pain (31%) compared with women with dysmenorrhoea (7%). CONCLUSIONS: This study showed a high community prevalence of chronic pelvic pain in women of reproductive age. Cases varied substantially in the degree to which they were affected by their symptoms. The high symptom-related anxiety in these women emphasises the need for more information about chronic pelvic pain and its possible causes.

The genetic basis of endometriosis.

Family studies have long suggested a role for genetic factors in the aetiology of endometriosis. The influence of genes on disease development has mainly been researched independently of environmental factors, yet their interaction must play an important role. Greater exposure to retrograde menstruation and oestrogen is likely to increase the risk of endometriosis; toxic compounds such as dioxin may increase the risk, although the only direct evidence has come from primate studies. Previous association studies implicated GALT (a gene involved in galactose metabolism), and GSTM1 and NAT2 (genes encoding for the detoxification enzymes) as possible disease susceptibility genes. Recent findings have added to the evidence for the involvement of GSTM1 and NAT2, but have cast doubt on the role of GALT. However, the design of many genetic and epidemiological studies has been inadequate with respect to sample size, consistency in phenotype definition, and the choice of control populations. These features are likely to influence results, and could partly explain the lack of consistency in the findings. Future studies should use a consistent disease definition and be of appropriate epidemiological design.

Chronic pelvic pain in the community--symptoms, investigations, and diagnoses.

OBJECTIVES: This study was undertaken to investigate the overlap between chronic pelvic pain, dysmenorrhea, dyspareunia, irritable bowel syndrome, and genitourinary symptoms in the community and also to examine associated investigations and diagnoses. STUDY DESIGN: A postal questionnaire was used to survey 3916 women aged 18 through 49 randomly selected from the Oxfordshire Health Authority Register. The number of responders was 2304 (74% of 3106 questionnaire recipients). Chronic pelvic pain was described as recurrent or constant pelvic pain of > or =6 months' duration unrelated to periods, intercourse, or pregnancy. Case patients (n = 483) were subgrouped as follows: (1) chronic pelvic pain only, (2) chronic pelvic pain and irritable bowel syndrome, (3) chronic pelvic pain and genitourinary symptoms, and (4) chronic pelvic pain, genitourinary symptoms, and irritable bowel syndrome. RESULTS: Half the women with chronic pelvic pain also had either genitourinary symptoms or irritable bowel syndrome, or both. Prevalences of dysmenorrhea and dyspareunia were higher among women with chronic pelvic pain (81% and 41%, respectively) than among women without chronic pelvic pain (58% and 14%, respectively); rates did not differ among the chronic pelvic pain subgroups. Irritable bowel syndrome and stress were the most common diagnoses received by patients with chronic pelvic pain, but 50% had never received a diagnosis. CONCLUSIONS: There is substantial overlap between chronic pelvic pain and other abdominal symptoms in the community. Despite a high prevalence of chronic pelvic pain, many women have never had the condition diagnosed.

Prevalence and incidence of chronic pelvic pain in primary care: evidence from a national general practice database.

OBJECTIVES: To estimate the prevalence and incidence in primary care of chronic pelvic pain in women in the UK. DESIGN: Cross-sectional analysis of MediPlus UK Primary Care Database. SETTING: One hundred and thirty-six general practices in the UK. POPULATION: From 284,162 women aged 12-70 who were registered on the database and who had a general practice contact in 1991, 24,053 chronic pelvic pain cases were identified between 1991 and 1995. METHODS: Chronic pelvic pain was defined as pelvic pain lasting for at least six months, and cases were identified on the basis of contacts with general practice. Pain due to malignancy, chronic inflammatory bowel diseases or pregnancy, or which occurred only during menstruation or sexual intercourse, was excluded. MAIN OUTCOME MEASURES: Prevalence and incidence rates of chronic pelvic pain in primary care by age and region. RESULTS: Monthly prevalence and incidence rates of chronic pelvic pain were 21.5/1000 and 1.58/1000, respectively, with an annual prevalence of 38.3/1000. Monthly prevalence rates increased significantly with age (P < 0.001) from 18.2/1000 in 15-20 year olds to 27.6/1000 in women older than 60, as symptoms persisted longer in older women. Prevalence and incidence rates varied significantly between regions (P < 0.001), with the lowest monthly prevalence in Scotland (16.0/1000) and the highest in Wales (29.4/1000). CONCLUSIONS: Chronic pelvic pain is a common condition in the UK, with a prevalence in primary care comparable to migraine, back pain, and asthma. Its prevalence in the general population is likely to be considerably higher.

Patterns of diagnosis and referral in women consulting for chronic pelvic pain in UK primary care.

OBJECTIVES: To describe duration of symptoms and patterns of diagnosis and referral in women with chronic pelvic pain. DESIGN: Retrospective cohort analysis of the MediPlus UK Primary Care Database. SETTING: One hundred and thirty-six general practices in the UK. STUDY GROUP: A cohort of 5051 incident cases of chronic pelvic pain. METHODS: The cohort was followed up from the start of their symptoms in 1992 until the end of the chronic pelvic pain episode or the end of 1995. MAIN OUTCOME MEASURES: Duration of symptoms, frequency of diagnoses and referral rates. RESULTS: A third of women had symptoms persisting for more than two years. Duration of symptoms increased significantly with age (P < 0.001) from a median of 13.7 months in 13-20 year olds to 20.2 months in women over the age of 60. Irritable bowel syndrome and cystitis were the most common diagnoses at all ages. Twenty-eight percent of women never received a diagnosis during three to four years of follow up after first consultation, and 60% of women had no evidence of a specialist referral. Women aged 21-50 and women whose final diagnosis was endometriosis received the largest number of diagnoses and had the highest referral rates. CONCLUSIONS: The numbers and types of diagnosis given to a woman with chronic pelvic pain and the likelihood of specialist referral depend on her age, as well as on the duration of symptoms. Women seen in secondary care for chronic pelvic pain are a highly selected group and are likely to represent only the tip of the iceberg.

The prevalence of chronic pelvic pain in women in the United Kingdom: a systematic review.

OBJECTIVE: To obtain a prevalence estimate for chronic pelvic pain in women in the United Kingdom by analysing published data. DESIGN: Systematic review of published papers. SETTING: The general population or hospitals in the United Kingdom. POPULATION: Women participating in relevant community surveys or control women participating in hospital-based studies. METHODS: Papers were retrieved by systematically searching the databases MEDLINE, EMBASE and PsycLit, and by hand searching. Studies were included if they 1. were community-based and reported prevalence rates of chronic pelvic pain, dyspareunia, dysmenorrhoea, or abdominal pain, or 2. referred to a clinical population but reported prevalence rates in a disease-free control group. MAIN OUTCOME MEASURES: Prevalence rates for chronic pelvic pain including any overlap with dyspareunia, dysmenorrhoea and abdominal pain. RESULTS: No community-based study has been performed that provides an estimate of the prevalence of chronic pelvic pain in the general UK population. A rate of 39% was reported in women undergoing laparoscopy for sterilisation or investigation of infertility in the single study from the United Kingdom investigating chronic pelvic pain unrelated to menstruation or intercourse. Prevalence rates for dyspareunia, dysmenorrhoea, and abdominal pain found in UK community-based studies were 8%, 45% to 97%, and 23% to 29%, respectively, but definitions used varied greatly. CONCLUSIONS: Because chronic pelvic pain can reduce the quality of life and general wellbeing, there is a need for a community-based study into the prevalence of chronic pelvic pain and its effect upon the lives of women in the UK.