The ultra-long study: a randomized controlled trial evaluating long-term GnRH downregulation prior to ART in women with endometriosis.

STUDY QUESTION: Does ultra-long downregulation with a GnRH agonist (triptorelin depot) in previously operated patients with endometriosis improve the rate of clinical pregnancy with positive fetal heart beat (CPHB) in the subsequent initiated fresh ART cycle? SUMMARY ANSWER: Ultra-long downregulation with a GnRH agonist prior to ART did not improve the rate of CPHB in the subsequent fresh ART cycle in previously completely operated patients but the trial was underpowered due to early termination. WHAT IS KNOWN ALREADY: Administration of GnRH agonists for a period of 3-6 months prior to ART in women with endometriosis may increase the odds of clinical pregnancy. However, the quality of the studies on which this statement is based is questionable, so these findings need confirmation. STUDY DESIGN, SIZE, DURATION: A controlled, randomized, open label trial was performed between 1 June 2013 and 31 December 2016 (start and end of recruitment, respectively). Patients with prior complete laparoscopic treatment of any type or stage of endometriosis and an indication for ART were randomized (by a computer-generated allocation sequence) into two groups: the control group underwent ART stimulation in a classical long agonist protocol using preparation with oral contraceptives, the ultra-long group first underwent at least 3 months downregulation followed by a long agonist protocol for ART stimulation. The sample size was calculated to detect a superiority of the ultra-long downregulation protocol, based on the hypothesis that baseline CPHB rate in the control group of 20% would increase to 40% in the ultra-long group. For a power of 20% at a significance level of 5%, based on two-sided testing, including 5% of patients lost to follow-up, the necessary sample size was 172 patients (86 per group). PARTICIPANTS/MATERIALS, SETTING, METHODS: This trial was conducted at the Leuven University Fertility Center, a tertiary care center for endometriosis and infertility, and a total of 42 patients were randomized (21 in the control group and 21 in the ultra-long group). MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics were similar in both groups. The primary outcome studied-CPHB after the initiated ART treatment-did not differ and was 25% (5/20) in the control group, and 20% (4/20) in the ultra-long group (P > 0.999; relative risk (RR) 1.25, 95% CI 0.41-3.88). Cumulative (fresh + associated frozen) CPHB rates were also similar in the control versus ultra-long group (8/20, 40% vs 6/20, 30%, P = 0.7411; RR = 1.33, 95% CI 0.57-3.19). When other secondary outcomes were compared with the ultra-long group, patients from the control group had a shorter duration of stimulation (mean 11.8 days (SD ± 2.4) versus 13.2 days (SD ± 1.5), P = 0.0373), a lower total dose of gonadotrophins used (mean 1793 IU/d (SD ± 787) vs 2329 (SD ± 680), P = 0.0154), and a higher serum estradiol concentration (ng/ml) at the end of ovarian stimulation on the day of ovulation triggering or cycle cancellation (mean1971 (SD ± 1495) vs 929 (± 548); P = 0.0326), suggesting a better ovarian response in the control group. LIMITATIONS, REASONS FOR CAUTION: Due to a strong patient preference, nearly exclusively against ultra-long downregulation (even though patients were thoroughly informed of the potential benefits), the targeted sample size could not be achieved and the trial was stopped prematurely. WIDER IMPLICATIONS OF THE FINDINGS: Conditional power analysis revealed that the probability of confirming the study hypothesis if the study were completed would be low. We hypothesize that in patients with prior complete surgical treatment of endometriosis, the ultra-long protocol does not enhance ART-CPHB rates. Patient's concerns and preferences regarding possible side-effects, and delay of ART treatment start with the ultra-long protocol should be taken into account when considering this type of treatment in women with endometriosis. STUDY FUNDING/COMPETING INTEREST(S): C.T. was during 2 years funded by a grant from the Clinical research Foundation of UZ Leuven (KOF) and during 2 years by the Research Foundation-Flanders (FWO grant number: 1700816N). C.T. reports grants from Clinical Research Foundation of the University Hospitals of Leuven (KOF), grants from Fund for Scientific Research Flanders (FWO), during the conduct of the study; grants, non-financial support and other from Merck SA, non-financial support and other from Gedeon Richter, non-financial support from Ferring Pharmaceuticals, outside the submitted work. T.D. is vice president and head of Global Medical Affairs Fertility, Research and Development, Merck KGaA, Darmstadt, Germany. He is also a professor in Reproductive Medicine and Biology at the Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven (University of Leuven), Belgium and an adjunct professor at the Department of Obstetrics and Gynecology in the University of Yale, New Haven, USA. Neither his corporate role nor his academic roles represent a conflict of interest with respect to the work done by him for this study. A.C. reports personal fees from Merck S.p.A., outside the submitted work. The other co-authors have no conflict of interest. TRIAL REGISTRATION NUMBER: UZ Leuven trial registry SS55300, EudraCT number 2013-000993-32, clinicaltrials.gov NCT02400801. TRIAL REGISTRATION DATE: Registration for EudraCT on 1 March 2013. DATE OF FIRST PATIENT'S ENROLMENT: 4 September 2013.

Estimation of the Endometriosis Fertility Index prior to operative laparoscopy.

STUDY QUESTION: Can the Endometriosis Fertility Index (EFI) be estimated accurately before surgery? SUMMARY ANSWER: The EFI can be estimated accurately based on mere clinical/ultrasound information, with some improvement after adding data from diagnostic laparoscopy. WHAT IS KNOWN ALREADY: The EFI is a validated clinical instrument predicting the probability of pregnancy after endometriosis surgery without the use of ART. Being an end-of-surgery-score, it implies the decision for operative laparoscopy to be made in advance-hence, its role in the pre-surgical decision-making process remains to be established. STUDY DESIGN, SIZE, DURATION: Single-cohort prospective observational study in 82 patients undergoing complete endometriosis excision (between June and December 2016). Two methods were used to estimate the final EFI: type A based on non-surgical clinical/ultrasound findings only, and type B based on the combination of non-surgical clinical/ultrasound findings and diagnostic laparoscopy data. To calculate EFI type A, an algorithm was created to translate non-surgical clinical/imaging information into rASRM (revised American Society of Reproductive Medicine)-and EFI points. EFI type A and type B estimates were assessed for their clinical and numerical agreement with the final EFI score. Agreement was defined as clinical if EFI scores were within the same range (0-4, 5-6, 7-10), and numerical if their difference was ≤1. PARTICIPANTS/MATERIALS, SETTING, METHODS: All 82 patients underwent complete laparoscopic CO2-laser excision of any rASRM stage of endometriosis in the Leuven University Fertility Centre (LUFC) of University Hospitals Leuven, a tertiary referral centre for both endometriosis and infertility. An anonymized clinical research file was created. For each patient, three different data sets were created, in order to allow the estimation of the (surgical part) EFI and of the rASRM scores, defined as follows: 'Estimated type A' contained only non-surgical clinical/imaging data, 'Estimated type B' included type A information plus the information of the diagnostic laparoscopy and 'Final EFI' included information of type A, type B and all intra-operative information required to calculate the final EFI. To calculate EFI type A without surgical information, a set of rules was used to translate pre-surgical clinical/imaging information into (rASRM and EFI points). Scoring was done by one person (C.T.), with a time interval of 4 weeks between sessions for each EFI type. Next to the EFI, also rASRM score and stage were calculated. MAIN RESULTS AND THE ROLE OF CHANCE: Agreement rate between estimated EFI type A and final EFI was high for both the clinical (0.915; 95% CI 0.832-0.965) and numerical definition (0.878; 95% CI 0.787-0.940). Agreement rates between estimated EFI type B and final EFI were even higher (clinical (0.988; 95% CI 0.934-1.000), numerical (0.963; 95% CI 0.897-0.992)). LIMITATIONS, REASONS FOR CAUTION: Type A estimation is dependent on high-level gynaecological ultrasound expertise, which may not be available in all clinics. A small number of patients had no prior clinical, ultrasound (hard markers) or surgical confirmation of the diagnosis of endometriosis. When applying the estimated EFI type A in clinical practice, a priori assumptions of the presence or absence of endometriosis will need to be made in adjunct to the estimation of the estimated type A EFI when counselling patients on the potential benefit of an (at least diagnostic) laparoscopy. The level of agreement for type A or B should also be taken into account when counselling patients on the type of efforts undertaken to attempt to diagnose or rule out endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: As this study reports, the EFI can be estimated accurately based on clinical/ultrasound data only without the need for any surgical data. This means that the EFI could be used as an instrument to guide joint physician-patient decision-making between surgery, ART or other fertility management options for the individualized treatment of women with endometriosis-related infertility. STUDY FUNDING/COMPETING INTEREST(S): During this study period, C.T. was supported by FWO (Research Fund Flanders, Grant number 1700816N) and UZ Leuven KOF (University Hospitals Leuven, Klinisch Onderzoeksfonds).The LUFC received unrestricted research grants from Ferring Pharmaceuticals and Merck SA. Gedeon Richter and MSD sponsored travel to and attendance at scientific meetings. C.M. received consultancy fees from Lumenis (paid to KU Leuven, no private revenue). T.D. has been vice-president and head of global medical affairs infertility for the multinational pharmaceutical company Merck (Darmstadt, Germany) since 1 October 2015. He continues his academic appointment on a part-time basis as Professor of Reproductive Medicine at the University of Leuven (KU Leuven). T.D. has been vice-president and head of global medical affairs infertility for the multinational pharmaceutical company Merck (Darmstadt, Germany) since October 2015. He is also a Guest Professor in Reproductive Medicine and Biology at the Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven (University of Leuven), Belgium, and an Adjunct Professor at the Department of Obstetrics and Gynecology in the University of Yale, New Haven, USA. This work was initiated before he joined Merck KGaA in October 2015, and completed during the subsequent years. TRIAL REGISTRATION NUMBER: study registration number at UZ Leuven Clinical Trial Centre: S59221.

Reproducibility of the Endometriosis Fertility Index: a prospective inter-/intra-rater agreement study.

OBJECTIVE: To evaluate the reproducibility of the Endometriosis Fertility Index (EFI). DESIGN: Single-cohort prospective observational study. SETTING: University hospital. POPULATION: Women undergoing laparoscopic resection of any rASRM-stage endometriosis. METHODS: Details of pre- and peroperative findings were collected into a coded research file. EFI scoring was performed en-bloc by three different raters (expert-1 [C.T.], expert-2 [C.M.], junior [C.B.]). Required sample size: 71. Definitions used for agreement: clinical (scores within same range: 0-4, 5-6, 7-10) and numerical (difference ≤1 EFI point). MAIN OUTCOME MEASURES: Primary outcome: rate of clinical agreement between two experts. SECONDARY OUTCOMES: expert numerical agreement, clinical and numerical agreement between expert-1 and junior, and within expert-1 (intra-observer), agreement of rASRM score and -stage. RESULTS: A near 'inter-expert' clinical agreement rate (1.000, 95% CI 0.956-1.000; P = 0.0149) was observed. The numerical agreement between two experts was also high (0.988, 95% CI 0.934-1.000); similarly, high agreement rates were observed for both 'junior-expert' comparisons (clinical 0 .963, 95% CI 0.897-0.992; numerical 0.988, 95% CI 0.934-1.000) and 'intra-expert' comparisons (clinical 0.988, 95% CI 0.934-1.000; numerical 1.000, 95% CI 0.956-1.000). Reasons for disagreements were different scoring of the least-function score and disagreements in rASRM scores. The reproducibility of the rASRM score was clearly inferior to that of the EFI for all comparisons. CONCLUSION: The EFI can be reproduced reliably by different raters, further supporting its use in daily clinical practice as the principal clinical tool for postoperative fertility counselling/management of women with endometriosis. TWEETABLE ABSTRACT: A study confirming the high reproducibility of the EFI substantiates its use in daily clinical practice.

IDEAL study: magnetic resonance imaging for suspected deep endometriosis assessment prior to laparoscopy is as reliable as radiological imaging as a complement to transvaginal ultrasonography.

OBJECTIVE: To compare the value of using one-stop magnetic resonance imaging (MRI) vs standard radiological imaging as a supplement to transvaginal ultrasonography (TVS) for the preoperative assessment of patients with endometriosis referred for surgery in a tertiary care academic center. METHODS: This prospective observational study compared the diagnostic value of the standard preoperative imaging practice of our center, which involves expert TVS complemented by intravenous urography (IVU) for the evaluation of the ureters and double-contrast barium enema (DCBE) for the evaluation of the rectum, sigmoid and cecum, with that of expert TVS complemented by a 'one-stop' MRI examination evaluating the upper abdomen, pelvis, kidneys and ureters as well as rectum and sigmoid on the same day, for the preoperative triaging of 74 women with clinically suspected deep endometriosis. The findings at laparoscopy were considered the reference standard. Patients were stratified according to their need for monodisciplinary surgical approach, carried out by gynecologists only, or multidisciplinary surgical approach, involving abdominal surgeons and/or urologists, based on the extent to which endometriosis affected the reproductive organs, bowel, ureters, bladder or other abdominal organs. RESULTS: Our standard preoperative imaging approach and the combined findings of TVS and MRI had similar diagnostic performance, resulting in correct stratification for a monodisciplinary or a multidisciplinary surgical approach of 67/74 (90.5%) patients. However, there were differences between the estimation of the severity of disease by DCBE and MRI. The severity of rectal involvement was underestimated in 2.7% of the patients by both TVS and DCBE, whereas it was overestimated in 6.8% of the patients by TVS and/or DCBE. CONCLUSIONS: Complementary to expert TVS, 'one-stop' MRI can predict intraoperative findings equally well as standard radiological imaging (IVU and DCBE) in patients referred for endometriosis surgery in a tertiary care academic center. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Plasma miRNAs as biomarkers for endometriosis.

STUDY QUESTION: Can plasma miRNAs be used for the non-invasive diagnosis of endometriosis in infertile women? SUMMARY ANSWER: miRNA-based diagnostic models for endometriosis failed the test of independent validation. WHAT IS KNOWN ALREADY: Circulating miRNAs have been described to be differentially expressed in patients with endometriosis compared with women without endometriosis, suggesting that they could be used for the non-invasive diagnosis of endometriosis. However, these studies have shown limited consistency or conflicting results, and no miRNA-based diagnostic test has been validated in an independent patient cohort. STUDY DESIGN, SIZE, DURATION: We performed genome-wide miRNA expression profiling by small RNA sequencing to identify a set of plasma miRNAs with discriminative potential between patients with and without endometriosis. Expression of this set of miRNAs was confirmed by RT-qPCR. Diagnostic models were built using multivariate logistic regression with stepwise feature selection. In a final step, the models were tested for validation in an independent patient cohort. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Plasma of all patients was available in the biobank of the Leuven Endometriosis Centre of Excellence. Biomarker discovery and model development were performed in a discovery cohort of 120 patients (controls = 38, endometriosis = 82), and models were tested for validation in an independent cohort of 90 patients (controls = 30, endometriosis = 60). RNA was extracted with the miRNeasy Plasma Kit. Genome-wide miRNA expression analysis was done by small RNA sequencing using the NEBNext small RNA library prep kit and the NextSeq 500 System. cDNA synthesis and qPCR were performed using the Qiagen miScript technology. MAIN RESULTS AND THE ROLE OF CHANCE: We identified a set of 42 miRNAs with discriminative power between patients with and without endometriosis based on genome-wide miRNA expression profiling. Expression of 41 miRNAs was confirmed by RT-qPCR, and 3 diagnostic models were built. Only the model for minimal-mild endometriosis (Model 2: hsa-miR-125b-5p, hsa-miR-28-5p and hsa-miR-29a-3p) had diagnostic power above chance performance in the independent validation (AUC = 60%) with an acceptable sensitivity (78%) but poor specificity (37%). LIMITATIONS, REASONS FOR CAUTION: The diagnostic models were built and tested for validation in two patient cohorts from a single tertiary endometriosis centre. Further validation tests in large cohorts with patients from multiple endometriosis centres are needed. WIDER IMPLICATION OF THE FINDINGS: Our study supports a possible biological link between certain miRNAs and endometriosis, but the potential of these miRNAs as clinically useful biomarkers is questionable in women with infertility. Large studies in well-described patient cohorts, with rigorous methodology for miRNA expression analysis, sufficient statistical power and an independent validation step, are necessary to answer the question of whether miRNAs can be used as diagnostics markers for endometriosis. STUDY FUNDING/COMPETING INTEREST(S): The project was funded by a grant from the Research Foundation - Flanders (FWO). A.V., D.F.O. and D.P. are PhD fellows from the FWO. T.D. is vice president and Head of Global Medical Affairs Fertility, Research and Development, Merck KGaA, Darmstadt, Germany. He is also a professor in Reproductive Medicine and Biology at the Department of Development and Regeneration, Group Biomedical Sciences, KU Leuven (University of Leuven), Belgium and an adjunct professor at the Department of Obstetrics and Gynecology in the University of Yale, New Haven, USA. Neither his corporate role nor his academic roles represent a conflict of interest with respect to the work done by him for this study. The other co-authors have no conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable.

Consensus on Recording Deep Endometriosis Surgery: the CORDES statement.

STUDY QUESTION: Which essential items should be recorded before, during and after endometriosis surgery and in clinical outcome based surgical trials in patients with deep endometriosis (DE)? SUMMARY ANSWER: A DE surgical sheet (DESS) was developed for standardized reporting of the surgical treatment of DE and an international expert consensus proposal on relevant items that should be recorded in surgical outcome trials in women with DE. WHAT IS KNOWN ALREADY: Surgery is an important treatment for symptomatic DE. So far, data have been reported in such a way that comparison of different surgical techniques is impossible. Therefore, we present an international expert proposal for standardized reporting of surgical treatment and surgical outcome trials in women with DE. STUDY DESIGN, SIZE, DURATION: International expert consensus based on a systematic review of literature. PARTICIPANTS/MATERIALS, SETTING, METHODS: Taking into account recommendations from Consolidated Standards of Reporting Trials (CONSORT), the Innovation Development Exploration Assessment and Long-term Study (IDEAL), the Initiative on Methods, Measurement and Pain Assessment in Clinical trials (IMMPACT) and the World Endometriosis Research Foundation Phenome and Biobanking Harmonisation Project (WERF EPHect), a systematic literature review on surgical treatment of DE was performed and resulted in a proposal for standardized reporting, adapted by contributions from eight members of the multidisciplinary Leuven University Hospitals Endometriosis Care Program, from 18 international experts and from audience feedback during three international meetings. MAIN RESULTS AND THE ROLE OF CHANCE: We have developed the DESS to record in detail the surgical procedures for DE, and an international consensus on pre-, intra- and post-operative data that should be recorded in surgical outcome trials on DE. LIMITATIONS, REASONS FOR CAUTION: The recommendations in this paper represent a consensus among international experts based on a systematic review of the literature. For several items and recommendations, high-quality RCTs were not available. Further research is needed to validate and evaluate the recommendations presented here. WIDER IMPLICATIONS OF THE FINDINGS: This international expert consensus for standardized reporting of surgical treatment in women with DE, based on a systematic literature review and international consensus, can be used as a guideline to record and report surgical management of patients with DE and as a guideline to design, execute, interpret and compare clinical trials in this patient population. STUDY FUNDING/COMPETING INTERESTS: None of the authors received funding for the development of this paper. M.A. reports personal fees and non-financial support from Bayer Pharma outside the submitted work; H.T. reports a grant from Pfizer and personal fees for being on the advisory board of Perrigo, Abbvie, Allergan and SPD. TRIAL REGISTRATION NUMBER: N/A.

How do patients score cosmesis after laparoscopic natural orifice specimen extraction colectomy?

AIM: Laparoscopic colorectal resection results in improved cosmetic outcome and better presumed body image. Laparoscopic NOSE colectomy omits an incision for specimen extraction and is supposed to further improve postoperative cosmesis. This study aimed to assess the cosmetic benefit. METHOD: Forty-nine patients who underwent a NOSE colectomy for bowel endometriosis from September 2009 to September 2013 were matched for age, American Society of Anesthesiologists (ASA) grade and body mass index (BMI) with patients who underwent a conventional laparoscopic colectomy for the same indication. Patients were asked to complete a questionnaire consisting of a body scale and a cosmetic scale and the Patient Scar Assessment Questionnaire (PSAQ) including five subscales (appearance, symptoms, scar consciousness, satisfaction with appearance and satisfaction with symptoms). RESULTS: Patient demographics were similar between both groups. Patients were assessed at a median postoperative follow-up of 41 months in the NOSE colectomy group and 35 months in the conventional resection group. The median body image questionnaire score was 15 for NOSE colectomy and 18 for conventional resection (P = 0.027). The respective median PSAQ scores were 56 and 71 (P = 0.002). There was a good relationship between the PSAQ score and the body image questionnaire (Spearman correlation coefficient 0.82). CONCLUSION: Depending on the scoring system used, the cosmetic outcome may be better after NOSE colectomy than conventional laparoscopy in patients having surgery for endometriosis. The comprehensive body image questionnaire, being shorter and easier to use, could be a valid tool for assessing cosmesis after NOSE procedures.

External validation of the endometriosis fertility index (EFI) staging system for predicting non-ART pregnancy after endometriosis surgery.

STUDY QUESTION: Can the ability of the endometriosis fertility index (EFI) to predict non-assisted reproductive technology (ART) pregnancy after endometriosis surgery be confirmed by an external validation study? SUMMARY ANSWER: The significant relationship between the EFI score and the time to non-ART pregnancy observed in our study represents an external validation of this scoring system. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: The EFI was previously developed and tested prospectively in a single center, but up to now no external validation has been published. Our data provide validation of the EFI in an external fertility unit on a robust scientific basis, to identify couples with a good prognosis for spontaneous conception who can therefore defer ART treatment, regardless of their revised American Fertility Society (rAFS) endometriosis staging. DESIGN: Retrospective cohort study where the EFI was calculated based on history and detailed surgical findings, and related to pregnancy outcome in 233 women attempting non-ART conception immediately after surgery; all data used for EFI calculation and analysis of reproductive outcome had been collected prospectively as part of another study. PARTICIPANTS AND SETTING: The EFI score was calculated (score 0-10) for 233 women with all rAFS endometriosis stages (minimal-mild, n = 75; moderate-severe, n = 158) after endometriosis surgery (1 September 2006-30 September 2010) in a university hospital-based reproductive medicine unit with combined expertise in reproductive surgery and medically assisted reproduction. All participants attempted non-ART conception immediately after surgery by natural intercourse, ovulation induction with timed intercourse or intrauterine insemination (with or without ovulation induction or controlled ovarian stimulation). DATA ANALYSIS METHOD: All analyses were performed for three different definitions of pregnancy [overall (any HCG >25 IU/l), clinical and ongoing >20 weeks]. Six groups were distinguished (EFI scores 1-3, 4, 5, 6, 7+8, 9+10), and Kaplan-Meier (K-M) estimates for cumulative pregnancy rate were calculated. Subjects were censored when they were lost to follow-up, had subsequent surgery for endometriosis, started ovarian suppression or underwent ART. As K-M estimates might overestimate the actual event rate, cumulative incidence estimates treating ART as competing event were also calculated. Cox regression analysis was used to assess the performance of EFI and constituting variables. Performance of the score (prediction, discrimination) was quantified with the following methods: mean squared error of prediction (Brier score), areas under the receiver-operating curve and global concordance index C(τ). MAIN RESULTS AND THE ROLE OF CHANCE: There was a highly significant relationship between the EFI and the time to non-ART pregnancy (cumulative overall pregnancy rate, P = 0.0004), with the K-M estimate of cumulative overall pregnancy rate at 12 months after surgery equal to 45.5% [95% confidence interval (CI) 39.47-49.87]-ranging from 16.67% (95% CI 5.01-47.65) for EFI scores 0-3, to 62.55% (95% CI 55.18-69.94) for EFI scores 9-10. For each increase of 1 point in the EFI score, the relative risk of becoming pregnant increased by 31% (95% CI 16-47%; i.e. hazard ratio 1.31). The 'least function score'-which assesses the tubal/ovarian function at conclusion of surgery-was found to be the most important contributor to the total EFI score among all the other variables (age, duration of infertility, prior pregnancy, AFS endometriosis lesion and total score). BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: The EFI score had a moderate performance in the prediction of the pregnancy rate. Indeed, the decrease in prediction error was rather small, as shown by the decrease in Brier score from 0.213 to 0.198, and low estimates for R² (13%) and C(τ) (0.629). GENERALIZABILITY TO OTHER POPULATIONS: As the EFI was validated externally in our own European population after initial testing by Adamson and Pasta (Endometriosis fertility index: the new, validated endometriosis staging system. Fertil Steril 2010;94:1609-1615) in an American population, it appears that the EFI can be used clinically to counsel infertile endometriosis patients receiving reproductive surgery in specialized centers about their post-operative conception options. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by funds obtained via the Clinical Research Fund of the University Hospitals Leuven, Belgium, via the Ferring Chair in Reproductive Medicine and Surgery, and the Serono Chair in Reproductive Medicine granted to the Leuven University Fertility Center. The authors have no conflicts of interest to declare.

Effect of laparoscopic surgery for moderate and severe endometriosis on depression, relationship satisfaction and sexual functioning: comparison of patients with and without bowel resection.

STUDY QUESTION: Is there a difference between women with endometriosis who underwent laparoscopic surgery with bowel resection or without bowel resection regarding depressive symptoms, relational adjustment and sexual functioning? SUMMARY ANSWER: Radical surgery for endometriosis in both groups improved the levels of depression and sexual functioning, but only the bowel resection patients showed improvements in relationship satisfaction. WHAT IS KNOWN ALREADY?: The frequent pain symptoms in endometriosis patients can have an impact on psychological issues, relationships and sexual functioning. There are no data available on depression and relationship adjustment after endometriosis surgery. Sexual dysfunction problems have been described after bowel resection for rectal cancer, but no data are available for endometriosis surgery. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 203 consecutive women operated at the Leuven University Fertility Center (LUFC) between 1 September 2006 and 30 September 2008 for moderate (n = 67) or severe (n = 136) endometriosis. The preoperative response rate was respectively 84% in the bowel resection group and 79% in the no bowel resection group. PARTICIPANTS, SETTING, METHODS: The beck depression inventory (BDI) measured depression, the dyadic adjustment scale (DAS) measured relationship satisfaction and the short sexual functioning scale (SSFS) measured sexual functioning before and 6, 12 and 18 months after women had laparoscopic surgery at the LUFC, a tertiary referral centre for fertility exploration, treatment and surgery. MAIN RESULTS AND THE ROLE OF CHANCE: Both groups had better post-operative outcomes when compared with the preoperative assessments. Mean BDI and DAS levels were comparable with the normal population. Overall assessment points, the bowel resection patients had better outcomes for DAS (P < 0.05) and SSFS 'arousal' (P < 0.05) than the no bowel resection patients. At 6 months after the operation, when compared with the no bowel resection group, the bowel resection group reported lower mean levels of BDI (P < 0.05), a lower incidence of SSFS 'pain during intercourse' and 'orgasm problems' (P < 0.05), and a lower proportion of patients with severe orgasm problems (P < 0.05). The data show that radical but fertility sparing surgery, with or without bowel resection, for the treatment of endometriosis results in comparable and good psychological outcomes concerning depression levels, relationship satisfaction and sexual functioning. LIMITATIONS, REASONS FOR CAUTION: Although the initial response rate was good, response dropped over time and was significantly higher for bowel resection patients compared with the no bowel resection patients (P = 0.05). A responder/non-responder analysis for the whole study population showed no significant differences concerning pain problems. This reduces the possible risk of (positive) bias in the results. WIDER IMPLICATIONS OF THE FINDINGS: Endometriosis is a complex condition and the focus should not be on a one-dimensional end-organ gynaecological outcome, but should take into account the role of psychological factors in pain-related outcome. To this end, more prospective data are needed on sexual functioning and psychological outcomes.

Laparoscopic treatment of endometriosis.

Endometriosis can be considered as a chronic disease which is characterized by the presence of ectopic endometrium outside the endometrial cavity and which is associated with symptoms as pelvic pain and infertility. Medical treatment is often not sufficient in patients with moderate to severe endometriosis and deep infiltrative endometriosis (DIE), therefore requiring surgical intervention. Over the past 15 years, we have built a multidisciplinary surgical team to perform a radical but fertility preserving resection of extensive endometriosis with involvement of surrounding organ systems, realizing a good clinical outcome with low complication and recurrence rate, a very good improvement of QOL and a high pregnancy rate. However, for future research evaluating surgical treatment of extensive endometriosis, it is important to reach agreement on study design and on reporting clinical outcome data. A multicenter study with clear patient identification and well defined outcome parameters needs to be set up. Moreover, prevention of DIE with colorectal extension is important, ideally by early identification and management of girls and women at risk. Years of pain and disability as well as a lot of money could be saved when patients, at risk of developing extensive forms of endometriosis could be diagnosed during adolescence.

Evaluation of a panel of 28 biomarkers for the non-invasive diagnosis of endometriosis.

BACKGROUND: At present, the only way to conclusively diagnose endometriosis is laparoscopic inspection, preferably with histological confirmation. This contributes to the delay in the diagnosis of endometriosis which is 6-11 years. So far non-invasive diagnostic approaches such as ultrasound (US), MRI or blood tests do not have sufficient diagnostic power. Our aim was to develop and validate a non-invasive diagnostic test with a high sensitivity (80% or more) for symptomatic endometriosis patients, without US evidence of endometriosis, since this is the group most in need of a non-invasive test. METHODS: A total of 28 inflammatory and non-inflammatory plasma biomarkers were measured in 353 EDTA plasma samples collected at surgery from 121 controls without endometriosis at laparoscopy and from 232 women with endometriosis (minimal-mild n = 148; moderate-severe n = 84), including 175 women without preoperative US evidence of endometriosis. Surgery was done during menstrual (n = 83), follicular (n = 135) and luteal (n = 135) phases of the menstrual cycle. For analysis, the data were randomly divided into an independent training (n = 235) and a test (n = 118) data set. Statistical analysis was done using univariate and multivariate (logistic regression and least squares support vector machines (LS-SVM) approaches in training- and test data set separately to validate our findings. RESULTS: In the training set, two models of four biomarkers (Model 1: annexin V, VEGF, CA-125 and glycodelin; Model 2: annexin V, VEGF, CA-125 and sICAM-1) analysed in plasma, obtained during the menstrual phase, could predict US-negative endometriosis with a high sensitivity (81-90%) and an acceptable specificity (68-81%). The same two models predicted US-negative endometriosis in the independent validation test set with a high sensitivity (82%) and an acceptable specificity (63-75%). CONCLUSIONS: In plasma samples obtained during menstruation, multivariate analysis of four biomarkers (annexin V, VEGF, CA-125 and sICAM-1/or glycodelin) enabled the diagnosis of endometriosis undetectable by US with a sensitivity of 81-90% and a specificity of 63-81% in independent training- and test data set. The next step is to apply these models for preoperative prediction of endometriosis in an independent set of patients with infertility and/or pain without US evidence of endometriosis, scheduled for laparoscopy.

Combined mRNA microarray and proteomic analysis of eutopic endometrium of women with and without endometriosis.

BACKGROUND: An early semi-invasive diagnosis of endometriosis has the potential to allow early treatment and minimize disease progression but no such test is available at present. Our aim was to perform a combined mRNA microarray and proteomic analysis on the same eutopic endometrium sample obtained from patients with and without endometriosis. METHODS: mRNA and protein fractions were extracted from 49 endometrial biopsies obtained from women with laparoscopically proven presence (n= 31) or absence (n= 18) of endometriosis during the early luteal (n= 27) or menstrual phase (n= 22) and analyzed using microarray and proteomic surface enhanced laser desorption ionization-time of flight mass spectrometry, respectively. Proteomic data were analyzed using a least squares-support vector machines (LS-SVM) model built on 70% (training set) and 30% of the samples (test set). RESULTS: mRNA analysis of eutopic endometrium did not show any differentially expressed genes in women with endometriosis when compared with controls, regardless of endometriosis stage or cycle phase. mRNA was differentially expressed (P< 0.05) in women with (925 genes) and without endometriosis (1087 genes) during the menstrual phase when compared with the early luteal phase. Proteomic analysis based on five peptide peaks [2072 mass/charge (m/z); 2973 m/z; 3623 m/z; 3680 m/z and 21133 m/z] using an LS-SVM model applied on the luteal phase endometrium training set allowed the diagnosis of endometriosis (sensitivity, 91; 95% confidence interval (CI): 74-98; specificity, 80; 95% CI: 66-97 and positive predictive value, 87.9%; negative predictive value, 84.8%) in the test set. CONCLUSION: mRNA expression of eutopic endometrium was comparable in women with and without endometriosis but different in menstrual endometrium when compared with luteal endometrium in women with endometriosis. Proteomic analysis of luteal phase endometrium allowed the diagnosis of endometriosis with high sensitivity and specificity in training and test sets. A potential limitation of our study is the fact that our control group included women with a normal pelvis as well as women with concurrent pelvic disease (e.g. fibroids, benign ovarian cysts, hydrosalpinges), which may have contributed to the comparable mRNA expression profile in the eutopic endometrium of women with endometriosis and controls.

Clinical outcome after CO2 laser laparoscopic radical excision of endometriosis with colorectal wall invasion combined with laparoscopic segmental bowel resection and reanastomosis.

BACKGROUND: Laparoscopic segmental bowel resection and reanastomosis for endometriosis with colorectal wall invasion can be associated with high complication rates. This study was performed to test the hypothesis that this high complication rate can be prevented and combined with a good clinical outcome, following a multidisciplinary surgical approach. METHODS: A retrospective cohort study of all patients with deep endometriosis and colorectal invasion treated by CO2 laser laparoscopic radical excision between September 2004 and September 2006 (n = 45) to document the clinical outcome: complications, recurrence and fertility (life table analysis), pain, quality of life (QOL) and sexual function. RESULTS: No immediate major post-operative complications requiring surgical reintervention were recorded. Gynaecological pain (P < 0.0001), sexual function (P < 0.03) and QOL (P< 0.0001), improved significantly after a median follow-up period of 27 (range: 16-40) months. Although five patients (11%) had a surgical reintervention, histologically proven recurrent endometriosis was observed in only two (4%), with a cumulative endometriosis recurrence rate of 2.2 and 4.4% after 1 and 3 years, respectively. Thirteen of 28 patients who wanted to become pregnant conceived after surgery. One patient delivered twice. These 14 pregnancies were achieved spontaneously (n = 9) or after IVF (n = 5). The cumulative pregnancy rate was 47% after 3 years. CONCLUSION: Pain, sexual function and QOL improved significantly and were associated with a good fertility rate and a low complication and recurrence rate after a CO2 laser laparoscopic radical excision of endometriosis with colorectal wall invasion combined with laparoscopic segmental bowel resection and reanastomosis.

Laparoscopic sigmoid resection with transrectal specimen extraction: a novel technique for the treatment of bowel endometriosis.

BACKGROUND: Multidisciplinary laparoscopic treatment is the standard of care for radical treatment of deep infiltrating pelvic endometriosis. If bowel resection is necessary, a muscle-split or Pfannenstiel incision is also required. The avoidance of any laparotomy could decrease surgical stress response, give a faster return to normal bowel function, decrease post-operative pain and reduce wound complications and incisional hernias. We assessed post-operative outcome after a full laparoscopic sigmoid resection for bowel endometriosis. PATIENTS AND METHODS: Twenty-one patients who underwent elective full laparoscopic sigmoid resection for bowel endometriosis from September 2009 to September 2010 were matched for age, American Society of Anesthesiologists class and BMI to 21 patients who underwent a conventional laparoscopic sigmoid resection. Groups were compared for peri-operative factors, complications, length of hospital stay, post-operative pain (Visual Analog Scale: VAS), analgesics consumption and inflammatory response (plasma C-reactive protein: CRP). RESULTS: Median operating time was 15 min shorter with transrectal specimen extraction (P = 0.003). VAS-scores and use of analgesics were higher in the conventional laparoscopic group (P = 0.0005). Mean CRP-level tended to be higher in the transrectal specimen extraction group (38%, P = 0.054) but there was no difference in increase in CRP level between groups (P = 0.15). There were no anastomotic leaks or reinterventions in either group, and the median hospital stay was similar. At follow-up, no wound infections or incisional hernias were observed and no patients reported anal dysfunction. CONCLUSION: Full laparoscopic sigmoid resection reduced operating times and decreased post-operative VAS-scores and analgesic requirements compared with the conventional laparoscopic sigmoid resection for bowel endometriosis.

Non-invasive diagnosis of endometriosis based on a combined analysis of six plasma biomarkers.

BACKGROUND: Lack of a non-invasive diagnostic test contributes to the long delay between onset of symptoms and diagnosis of endometriosis. The aim of this study was to evaluate the combined performance of six potential plasma biomarkers in the diagnosis of endometriosis. METHODS: This case-control study was conducted in 294 infertile women, consisting of 93 women with a normal pelvis and 201 women with endometriosis. We measured plasma concentrations of interleukin (IL)-6, IL-8, tumour necrosis factor-alpha, high-sensitivity C-reactive protein (hsCRP), and cancer antigens CA-125 and CA-19-9. Analyses were done using the Kruskal-Wallis test, Mann-Whitney test, receiver operator characteristic, stepwise logistic regression and least squares support vector machines (LSSVM). RESULTS: Plasma levels of IL-6, IL-8 and CA-125 were increased in all women with endometriosis and in those with minimal-mild endometriosis, compared with controls. In women with moderate-severe endometriosis, plasma levels of IL-6, IL-8 and CA-125, but also of hsCRP, were significantly higher than in controls. Using stepwise logistic regression, moderate-severe endometriosis was diagnosed with a sensitivity of 100% (specificity 84%) and minimal-mild endometriosis was detected with a sensitivity of 87% (specificity 71%) during the secretory phase. Using LSSVM analysis, minimal-mild endometriosis was diagnosed with a sensitivity of 94% (specificity 61%) during the secretory phase and with a sensitivity of 92% (specificity 63%) during the menstrual phase. CONCLUSIONS: Advanced statistical analysis of a panel of six selected plasma biomarkers on samples obtained during the secretory phase or during menstruation allows the diagnosis of both minimal-mild and moderate-severe endometriosis with high sensitivity and clinically acceptable specificity.

Non-steroidal targets in the diagnosis and treatment of endometriosis.

Endometriosis, a chronic gynecologic disease frequently resulting in chronic pelvic pain, severe dysmenorrhoea, and subfertility, is defined as the presence of endometrial tissue at extrauterine locations, most commonly on the peritoneum and ovaries. Conclusive diagnosis requires laparoscopic surgery followed by histological confirmation. The treatment options -at present- are limited to hormonal therapies and/or surgical ablation of the lesions, and are characterized by high recurrence rates, significant side-effects and limited duration of administration. The pathogenesis of endometriosis is still unclear and numerous immunological and inflammatory factors have been suggested to be involved in the development of the disease, including interleukin (IL)-1, IL-2, IL-6, IL-8, IL-12, tumour necrosis factor -alpha (TNF-alpha), regulated on activation, normal T-Cell expressed and secreted (RANTES) and its receptor cognate chemokine receptor 1 (CCR1), peroxisome proliferator activated receptors (PPARs), matrix metalloproteinases (MMPs) and cyclooxygenase (COX). Another crucial mechanism in endometriosis is the vascularisation of the endometriotic lesions, with a key role for vascular endothelial growth factor (VEGF). Recently, protease activated receptors (PARs), mitogen-activated protein kinases (MAPKs) and tyrosine kinases have also been associated with the pathophysiology of endometriosis. The aim of this article is to discuss molecules that have recently been found to have connections with the pathogenesis of endometriosis, as potential targets to develop new methods for noninvasive diagnosis and for novel medical management of this disease. This review also critically addresses how these molecules can be tested in basic, preclinical and clinical research, the status of this research and the importance of potential side effects.

Patient-centeredness and endometriosis: Definition, measurement, and current status.

The patient-centeredness of care is important for health care quality, especially because it was recently associated with health-related quality of life, which is increasingly being recognized as the ultimate outcome parameter of health care. Therefore, insight into the definition, measurement, and current status of the patient-centeredness of clinics is important for all health care professionals caring for patients with endometriosis. The definition of patient-centered endometriosis care is based on research into the most common preferences, needs, and values of patients with endometriosis and can be summarized in ten dimensions. One valid and reliable questionnaire exists, the ENDOCARE questionnaire, which allows measuring the patient-centeredness status of an endometriosis clinic. This questionnaire has been used to benchmark centers in different countries and has allowed the identification of ten targets for improving the patient-centeredness of endometriosis care. The next step would be to use the ENDOCARE questionnaire before and after an improvement project.