Abstract Objective Epidemiological data indicate that endometriosis increases the risk of epithelial ovarian cancer (EOC), but the mechanism of cancer transition is unknown. Results from genome-wide ...association studies (GWAS) and transcriptome sequencing have demonstrated that genes located in the 1p36 region are important in both endometriosis and endometriosis-associated cancer development. Therefore, we tested the hypothesis that SNPs in two tumor-suppressor genes (CHD5 and ARID1A) in the 1p36 region are associated with endometriosis. Methods Allele frequencies of SNPs were investigated in 1685 Caucasian women consisting of 947 women with endometriosis and 738 controls. Peripheral blood samples were retrieved, DNA extracted and allelic frequencies of SNPs in two tumor-suppressor genes (CHD5 and ARID1A) were analyzed using TaqMan Open Array technique. Results Associations were observed for 3 SNPs in the CHD5 gene: rs1883603 (OR 1.31, 95% CI 1.00–1.71), rs9434741 (OR 1.41, 95% CI 1.16–1.71) and rs17436816 (OR 1.24, 95% CI 1.02–1.50). After correction for multiple comparisons, rs9434741 (CHD5) remained significantly associated with endometriosis (p < 0.01). No associations were detected for ARID1A. Conclusions In this Caucasian population, endometriosis seems to be associated with the tumor-suppressor gene CHD5. Our findings support recent data, suggesting that the 1p36 region plays an important role in endometrios. To validate these data, replication in an independent population is warranted.
STUDY QUESTION
To what extent do the management of endometriosis and the symptoms that remain after treatment affect the quality of life in women with the disease?
SUMMARY ANSWER
Many women with ...endometriosis had impaired quality of life and continued to suffer from endometriosis-associated symptoms even though their endometriosis has been managed in tertiary care centres.
WHAT IS KNOWN ALREADY
The existing literature indicates that quality of life and work productivity is reduced in women with endometriosis. However, most studies have small sample sizes, are treatment related or examine newly diagnosed patients only.
STUDY DESIGN, SIZE, DURATION
A cross-sectional questionnaire-based survey among 931 women with endometriosis treated in 12 tertiary care centres in 10 countries.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Women diagnosed with endometriosis who had at least one contact related to endometriosis-associated symptoms during 2008 with a participating centre were enrolled into the study. The study investigated the effect of endometriosis on education, work and social wellbeing, endometriosis-associated symptoms and health-related quality of life, by using questions obtained from the World Endometriosis Research Foundation (WERF) GSWH instrument (designed and validated for the WERF Global Study on Women's Health) and the Short Form 36 version 2 (SF-36v2).
MAIN RESULTS AND THE ROLE OF CHANCE
Of 3216 women invited to participate in the study, 1450 (45%) provided informed consent and out of these, 931 (931/3216 = 29%) returned the questionnaires. Endometriosis had affected work in 51% of the women and affected relationships in 50% of the women at some time during their life. Dysmenorrhoea was reported by 59%, dyspareunia by 56% and chronic pelvic pain by 60% of women. Quality of life was decreased in all eight dimensions of the SF-36v2 compared with norm-based scores from a general US population (all P < 0.01). Multivariate regression analysis showed that number of co-morbidities, chronic pain and dyspareunia had an independent negative effect on both the physical and mental component of the SF-36v2.
LIMITATIONS, REASONS FOR CAUTION
The fact that women were enrolled in tertiary care centres could lead to a possible over-representation of women with moderate-to-severe endometriosis, because the participating centres typically treat more complex and referred cases of endometriosis. The response rate was relatively low. Since there was no Institute Review Board approval to do a non-responder investigation on basic characteristics, some uncertainty remains regarding the representativeness of the investigated population.
WIDER IMPLICATIONS OF THE FINDINGS
This international multicentre survey represents a large group of women with endometriosis, in all phases of the disease, which increases the generalizability of the data. Women still suffer from frequent symptoms, despite tertiary care management, in particular chronic pain and dyspareunia. As a result their quality of life is significantly decreased. A patient-centred approach with extensive collaboration across disciplines, such as pain specialists, psychologists, sexologists and social workers, may be a valuable strategy to improve the long-term care of women with endometriosis.
STUDY FUNDING/COMPETING INTEREST(S)
The WERF EndoCost study is funded by the World Endometriosis Research Foundation (WERF) through grants received from Bayer Schering Pharma AG, Takeda Italia Farmaceutici SpA, Pfizer Ltd and the European Society of Human Reproduction and Embryology. The sponsors did not have a role in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript. L.H. is the chief executive and T.D. was a board member of WERF at the time of funding. T.D. holds the Merck-Serono Chair in Reproductive Medicine and Surgery, and the Ferring Chair in Reproductive Medicine at the Katholieke Universiteit Leuven in Belgium and has served as consultant/research collaborator for Merck-Serono, Schering-Plough, Astellas and Arresto.
Endometriosis, a common disorder affecting women of reproductive age, is characterized by ectopic growth of the endometrial tissues, altered steroid hormone response, and inflammation. Previous ...studies revealed that statins, selective inhibitors of the key step of mevalonate pathway, inhibit growth of endometrial stromal cells in vitro and reduce endometriotic lesions in murine models of endometriosis. This study evaluated the effects of simvastatin on the development of endometriosis in a baboon model of this disease. Sixteen baboons were randomly assigned to the treatment group (simvastatin, 20 mg daily) or to the control group. Endometriotic lesions were evaluated by laparoscopy after 3 months. The volume of red, orange-red, and white endometriotic lesions was significantly reduced by 78% in animals treated with simvastatin. The expression of a marker of proliferation, proliferating cell nuclear antigen (PCNA), was significantly reduced in animals receiving simvastatin in red lesions, white lesions, black lesions, and in adhesions. Simvastatin was also associated with an increase in the expression of estrogen receptor alpha in red lesions, and a decrease in the expression of estrogen receptor beta in black lesions, in adhesions, and in eutopic endometrium. Furthermore, simvastatin significantly reduced the expression of neopterin, amarker of inflammation, oxidative stress, and immune system activation. Collectively, the present findings indicate that the inhibition of the mevalonate pathway by simvastatin reduces the risk of developing endometriosis in the primatemodel of this disease by decreasing the growth of endometrial lesions, by modulating the expression of genes encoding for estrogen receptors, and by reducing inflammation. Summary Sentence In the baboon model of endometriosis, simvastatin reduced the volume of active lesions, altered gene expression. and reduced the serum level of neopterin, amarker of immune system activation in the baboon model of endometriosis.
To harmonize standard operating procedures (SOPs) and standardize the recording of associated data for collection, processing, and storage of human tissues relevant to endometriosis.
An international ...collaboration involving 34 clinical/academic centers and three industry collaborators from 16 countries on five continents.
In 2013, two workshops were conducted followed by global consultation, bringing together 54 leaders in endometriosis research and sample processing from around the world.
None.
Consensus SOPs were based on: 1) systematic comparison of SOPs from 24 global centers collecting tissue samples from women with and without endometriosis on a medium or large scale (publication on >100 cases); 2) literature evidence where available, or consultation with laboratory experts otherwise; and 3) several global consultation rounds.
Standard recommended and minimum required SOPs for tissue collection, processing, and storage in endometriosis research.
We developed “recommended standard” and “minimum required” SOPs for the collection, processing, and storage of ectopic and eutopic endometrium, peritoneum, and myometrium, and a biospecimen data collection form necessary for interpretation of sample-derived results.
The EPHect SOPs allow endometriosis research centers to decrease variability in tissue-based results, facilitating between-center comparisons and collaborations. The procedures are also relevant to research into other gynecologic conditions involving endometrium, myometrium, and peritoneum. The consensus SOPs are based on the best available evidence; areas with limited evidence are identified as requiring further pilot studies. The SOPs will be reviewed based on investigator feedback and through systematic triannual follow-up. Updated versions will be made available at: http://endometriosisfoundation.org/ephect.
Endometriosis is an estrogen-dependent disorder where endometrial tissue
forms lesions outside the uterus. Endometriosis affects an estimated 10% of women
in the reproductive-age group, rising to 30% ...to 50% in patients with infertility
and/or pain, with significant impact on their physical, mental, and social
well-being. There is no known cure, and most current medical treatments are not
suitable long term due to their side-effect profiles. Endometriosis has an
estimated annual cost in the United States of $18.8 to $22 billion (2002 figures).
Although endometriosis was first described more than 100 years ago, current
knowledge of its pathogenesis, spontaneous evolution, and the pathophysiology of
the related infertility and pelvic pain, remain unclear. A consensus workshop was
convened following the 10th World Congress on Endometriosis to establish
recommendations for priorities in endometriosis research. One major issue
identified as impacting on the capacity to undertake endometriosis research is the
need for multidisciplinary expertise. A total of 25 recommendations for research
have been developed, grouped under 5 subheadings: (1) diagnosis, (2)
classification and prognosis, (3) treatment and outcome, (4) epidemiology, and (5)
pathophysiology. Endometriosis research is underfunded relative to other diseases
with high health care burdens. This may be due to the practical difficulties of
developing competitive research proposals on a complex and poorly understood
disease, which affects only women. By producing this consensus international
research priorities statement it is the hope of the workshop participants that
researchers will be encouraged to develop new interdisciplinary research proposals
that will attract increased funding support for work on endometriosis.
To examine messenger (m) RNA expression of aromatase, cytokines, and adhesion factors in women with and without endometriosis.
Patients with endometriosis were compared with control patients.
...University Hospital Gasthuisberg, Leuven, Belgium.
A total of 35 patients who had laparoscopic surgery during the luteal phase (n = 20) or the menstrual phase (n = 15) were selected for this study based on cycle phase and presence/absence of endometriosis.
Tissues of endometrium and macroscopically normal peritoneum were collected during hysteroscopy and laparoscopic surgery, respectively, from 24 women with revised American Society for Reproductive Medicine stage (rASRM) stages I-II (n = 12) and III-IV (n = 12) endometriosis and 11 control patients with normal pelvic. Tissue samples were selected from a tissue bank, based on the phase of the cycle (menstrual or luteal) and the presence/absence of endometriosis.
The mRNA levels of aromatase, vimentin, vascular cell adhesion molecule 1 (VCAM-1), alpha(V) and beta(3) integrins, interleukin (IL)-1 beta, regulated on activation normal T-cell expressed and secreted (RANTES), and monocyte chemotactic protein 1 (MCP-1) were evaluated using real-time reverse transcriptase polymerase chain reaction.
During menstrual phase, increased endometrial mRNA levels of alpha(V) integrin, combined alpha(V)beta(3) integrins, and increased peritoneal IL-1 beta mRNA levels--but decreased peritoneal MCP-1 mRNA levels--were observed in women with endometriosis compared with control subjects. During luteal phase, endometrial mRNA levels of IL-1 beta and RANTES were increased in women with endometriosis compared with control subjects. Endometrial aromatase mRNA expression was higher in women with endometriosis than in control subjects in combined phases. Women with endometriosis had increased peritoneal mRNA expression of RANTES and VCAM-1 during menstrual compared with luteal phase.
Aberrant mRNA expression of aromatase, cytokines, and adhesion factors in endometrium and peritoneum suggests that both tissues are involved in the pathogenesis of endometriosis.
To induce endometrial decidualization in rodents, an intrauterine oil stimulus can be delivered via the nontraumatic vagina or via the traumatic laparotomy. However, there is considerable variation ...in amount of decidualization using these inducing methods. Therefore, we studied which oil delivery route could achieve the highest rate of endometrial decidualization along the full length of both uterine horns.
To induce decidualization, ovariectomized C57Bl/6J mice were injected with estrogen (100 ng/day; 3 days). A progesterone pellet (5 mg) was implanted subcutaneously, followed by estrogen injections (5 ng/day; 3 days). Oil (20 µL/horn) was injected in the uterus via laparotomy, laparoscopy, or vagina. Four days later, the pellet was removed, followed by hysterectomy after 4 to 6 hours. Endometrial decidualization was evaluated macroscopically and microscopically using hematoxylin and eosin and desmin staining. Furthermore, uterine weight and hormone levels were measured.
The proportion of animals with macroscopic bicornuate decidualization was higher after laparoscopic (83%) and laparotomic (89%) injection than after sham injection (11%). Furthermore, macroscopic bicornuate decidualization was significantly higher after laparotomic injection (89%) compared to the vaginal injection (38%). Uterine weight and endometrial surface area were significantly higher in both laparotomy and laparoscopy groups compared to the sham group, while the relative desmin-positive endometrial surface area was only significantly different between the laparotomy and the sham animals.
Methods using laparoscopic and laparotomic intrauterine oil injection resulted in a higher amount of decidualized endometrium compared to sham injection, although further optimization is needed to reach full bicornuate decidualization.
To examine differential messenger RNA (mRNA) expression of relevant cytokines, metalloproteases, growth and adhesion factors in endometrium and peritoneum from women with endometriosis when compared ...with women without the disease during menstrual and luteal phases of the cycle.
Patients with endometriosis were compared with control patients.
University hospital.
A total of 35 patients (20 patients during the luteal phase and 15 patients during the menstrual phase) were selected for this study on the basis of cycle phase and presence or absence of endometriosis.
In this study, endometriosis was laparoscopically and histologically confirmed in 24 women with endometriosis of revised American Society for Reproductive Medicine (ASRM) stage I-II (n = 12) and revised ASRM stage III-IV (n = 12), and the presence of a normal pelvis was documented by laparoscopy in 11 control patients. The macroscopically normal peritoneum tissues were collected from lateral wall left or right, near the colon ascendens or descendens.
The expression levels were determined as ratios between the target molecules and beta-actin as housekeeping gene.
In women with endometriosis, peritoneal mRNA levels of matrix metalloproteinase (MMP)-3, transforming growth factor-beta, interleukin (IL)-6, and intercellular adhesion molecule-1 and endometrial mRNA levels of MMP-3, tumor necrosis factor (TNF)-alpha, and IL-8 were significantly higher during the menstrual phase when compared with luteal phase. During the menstrual phase of the cycle, both endometrial expression of TNF-alpha, IL-8, and MMP-3 mRNA levels and peritoneal expression of transforming growth factor-beta, IL-6, and intercellular adhesion molecule-1 mRNA levels were significantly higher in women with endometriosis when compared with controls. Immunohistochemical staining confirmed the presence of TNF-alpha in peritoneum and endometrium in both women with endometriosis and controls.
Increased endometrial and peritoneal cytokine mRNA expression during menstruation may contribute to a pelvic inflammatory microenvironment favoring the development of endometriosis.
Endometriosis is a complex disease that affects 6-10% of women in their reproductive years and 20-50% of women with infertility. Genome-wide and candidate-gene association studies for endometriosis ...have identified 10 independent risk loci, and of these, nine (rs7521902, rs13394619, rs4141819, rs6542095, rs1519761, rs7739264, rs12700667, rs1537377, and rs10859871) are polymorphic in European populations. Here we investigate the replication of nine SNP loci in 998 laparoscopically and histologically confirmed endometriosis cases and 783 disease-free controls from Belgium. SNPs rs7521902, rs13394619, and rs6542095 show nominally significant (p < .05) associations with endometriosis, while the directions of effect for seven SNPs are consistent with the original reports. Association of rs6542095 at the IL1A locus with 'All' (p = .066) and 'Grade_B' (p = .01) endometriosis is noteworthy because this is the first successful replication in an independent population. Meta-analysis with the published results yields genome-wide significant evidence for rs7521902, rs13394619, rs6542095, rs12700667, rs7739264, and rs1537377. Notably, three coding variants in GREB1 (near rs13394619) and CDKN2B-AS1 (near rs1537377) also showed nominally significant associations with endometriosis. Overall, this study provides important replication in a uniquely characterized independent population, and indicates that the majority of the original genome-wide association findings are not due to chance alone.
BACKGROUND Endometriosis occurs in 10% of women and is currently diagnosed by invasive laparoscopic testing. We tested the hypothesis that endometrial gene expression in late secretory phase ...endometrium differs between patients with and without endometriosis. METHODS Ten patients with laparoscopically proven endometriosis (minimal/mild n = 5 and moderate/severe n = 5) and six controls, underwent endometrial biopsy in the late secretory phase (Day 23 onwards). Microarray interrogation of eutopic endometrial gene expression was performed. RESULTS Microarray data were obtained for all control samples and eight samples from the endometriosis patients (n = 4 minimal/mild, n = 4 moderate/severe disease). Eight genes were identified as up-regulated and one gene was down-regulated in all endometriotic samples (more than 1.75-fold, P < 0.01). Real-time PCR analysis of protocadherin-17 (PCDH17), protein tyrosine phosphatase, receptor type, R (PTPRR) and interleukin-6 signal transducer (IL6ST) expression validated the microarray findings. CONCLUSIONS Expression of very few transcripts differs, in late secretory eutopic endometrium, between controls and patients with endometriosis. The median fold changes of these genes are small. No transcripts were identified that could discriminate between minimal/mild and moderate/severe endometriosis. Therefore, interrogation of the late secretory endometrial transcriptome is not likely to form the basis of a minimally invasive diagnostic test for endometriosis.
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