What is the optimal GnRH antagonist protocol for ovarian stimulation during ART treatment? A systematic review and network meta-analysis.

BACKGROUND: Several GnRH antagonist protocols are currently used during COS in the context of ART treatments; however, questions remain regarding whether these protocols are comparable in terms of efficacy and safety. OBJECTIVE AND RATIONALE: A systematic review followed by a pairwise and network meta-analyses were performed. The systematic review and pairwise meta-analysis of direct comparative data according to the PRISMA guidelines evaluated the effectiveness of different GnRH antagonist protocols (fixed Day 5/6 versus flexible, ganirelix versus cetrorelix, with or without hormonal pretreatment) on the probability of live birth and ongoing pregnancy after COS during ART treatment. A frequentist network meta-analysis combining direct and indirect comparisons (using the long GnRH agonist protocol as the comparator) was also performed to enhance the precision of the estimates. SEARCH METHODS: The systematic literature search was performed using Embase (Ovid), MEDLINE (Ovid), Cochrane Central Register of Trials (CENTRAL), SCOPUS and Web of Science (WOS), from inception until 23 November 2021. The search terms comprised three different MeSH terms that should be present in the identified studies: GnRH antagonist; assisted reproduction treatment; randomized controlled trial (RCT). Only studies published in English were included. OUTCOMES: The search strategy resulted in 6738 individual publications, of which 102 were included in the systematic review (corresponding to 75 unique studies) and 73 were included in the meta-analysis. Most studies were of low quality. One study compared a flexible protocol with a fixed Day 5 protocol and the remaining RCTs with a fixed Day 6 protocol. There was a lack of data regarding live birth when comparing the flexible and fixed GnRH antagonist protocols or cetrorelix and ganirelix. No significant difference in live birth rate was observed between the different pretreatment regimens versus no pretreatment or between the different pretreatment protocols. A flexible GnRH antagonist protocol resulted in a significantly lower OPR compared with a fixed Day 5/6 protocol (relative risk (RR) 0.76, 95% CI 0.62 to 0.94, I2 = 0%; 6 RCTs; n = 907 participants; low certainty evidence). There were insufficient data for a comparison of cetrorelix and ganirelix for OPR. OCP pretreatment was associated with a lower OPR compared with no pretreatment intervention (RR 0.79, 95% CI 0.69 to 0.92; I2 = 0%; 5 RCTs, n = 1318 participants; low certainty evidence). Furthermore, in the network meta-analysis, a fixed protocol with OCP resulted in a significantly lower OPR than a fixed protocol with no pretreatment (RR 0.84, 95% CI 0.71 to 0.99; moderate quality evidence). The surface under the cumulative ranking (SUCRA) scores suggested that the fixed protocol with no pretreatment is the antagonist protocol most likely (84%) to result in the highest OPR. There was insufficient evidence of a difference between fixed/flexible or OCP pretreatment/no pretreatment interventions regarding other outcomes, such as ovarian hyperstimulation syndrome and miscarriage rates. WIDER IMPLICATIONS: Available evidence, mostly of low quality and certainty, suggests that different antagonist protocols should not be considered as equivalent for clinical decision-making. More trials are required to assess the comparative effectiveness of ganirelix versus cetrorelix, the effect of different pretreatment interventions (e.g. progestins or oestradiol) or the effect of different criteria for initiation of the antagonist in the flexible protocol. Furthermore, more studies are required examining the optimal GnRH antagonist protocol in women with high or low response to ovarian stimulation.

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.

Reduced FSH and LH action: implications for medically assisted reproduction.

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) play complementary roles in follicle development and ovulation via a complex interaction in the hypothalamus, anterior pituitary gland, reproductive organs, and oocytes. Impairment of the production or action of gonadotropins causes relative or absolute LH and FSH deficiency that compromises gametogenesis and gonadal steroid production, thereby reducing fertility. In women, LH and FSH deficiency is a spectrum of conditions with different functional or organic causes that are characterized by low or normal gonadotropin levels and low oestradiol levels. While the causes and effects of reduced LH and FSH production are very well known, the notion of reduced action has received less attention by researchers. Recent evidence shows that molecular characteristics, signalling as well as ageing, and some polymorphisms negatively affect gonadotropin action. These findings have important clinical implications, in particular for medically assisted reproduction in which diminished action determined by the afore-mentioned factors, combined with reduced endogenous gonadotropin production caused by GnRH analogue protocols, may lead to resistance to gonadotropins and, thus, to an unexpected hypo-response to ovarian stimulation. Indeed, the importance of LH and FSH action has been highlighted by the International Committee for Monitoring Assisted Reproduction Technologies (ICMART) in their definition of hypogonadotropic hypogonadism as gonadal failure associated with reduced gametogenesis and gonadal steroid production due to reduced gonadotropin production or action. The aim of this review is to provide an overview of determinants of reduced FSH and LH action that are associated with a reduced response to ovarian stimulation.

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.

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.

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.

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.

Terms, definitions and measurements to describe sonographic features of myometrium and uterine masses: a consensus opinion from the Morphological Uterus Sonographic Assessment (MUSA) group.

The MUSA (Morphological Uterus Sonographic Assessment) statement is a consensus statement on terms, definitions and measurements that may be used to describe and report the sonographic features of the myometrium using gray-scale sonography, color/power Doppler and three-dimensional ultrasound imaging. The terms and definitions described may form the basis for prospective studies to predict the risk of different myometrial pathologies, based on their ultrasound appearance, and thus should be relevant for the clinician in daily practice and for clinical research. The sonographic features and use of terminology for describing the two most common myometrial lesions (fibroids and adenomyosis) and uterine smooth muscle tumors are presented.

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.

Pain during Fallopian-tube patency testing by hysterosalpingo-foam sonography.

OBJECTIVES: To evaluate perception of pain during Fallopian-tube patency testing by hysterosalpingo-foam sonography (HyFoSy). METHODS: In this cross-sectional study, 216 consecutive women presenting at a university fertility clinic for HyFoSy examination were included. Patients were instructed to take ibuprofen 1 hour before the procedure. Immediately after the procedure, patients filled in a questionnaire concerning discomfort or pain experienced during the process, including a visual analog scale (VAS) score for perception of pain. RESULTS: The median VAS score for perception of pain during transvaginal ultrasound examination and during HyFoSy examination was 1.5 (95% CI, 1.2-1.7) and 3.6 (95% CI, 3.0-4.0), respectively. One-third of women reported that the level of discomfort or pain during HyFoSy examination was similar to that during the preceding transvaginal ultrasound examination and 48% of women considered HyFoSy examination to be neutral/unpleasant, but not painful. There was an inverse association between both patients' age and parity and the pain experienced. CONCLUSIONS: HyFoSy examination is tolerated well and allows for reliable tubal patency testing without exposing the patient to ionizing radiation in an outpatient setting with a low technical failure rate.

ESHRE guideline: management of women with endometriosis.

STUDY QUESTION: What is the optimal management of women with endometriosis based on the best available evidence in the literature? SUMMARY ANSWER: Using the structured methodology of the Manual for ESHRE Guideline Development, 83 recommendations were formulated that answered the 22 key questions on optimal management of women with endometriosis. WHAT IS KNOWN ALREADY: The European Society of Human Reproduction and Embryology (ESHRE) guideline for the diagnosis and treatment of endometriosis (2005) has been a reference point for best clinical care in endometriosis for years, but this guideline was in need of updating. STUDY DESIGN, SIZE, DURATION: This guideline was produced by a group of experts in the field using the methodology of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included papers up to January 2012 and consensus within the guideline group on all recommendations. To ensure input from women with endometriosis, a patient representative was part of the guideline development group. In addition, patient and additional clinical input was collected during the scoping and review phase of the guideline. PARTICIPANTS/MATERIALS, SETTING, METHODS: NA. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 83 recommendations on diagnosis of endometriosis and on the treatment of endometriosis-associated pain and infertility, on the management of women in whom the disease is found incidentally (without pain or infertility), on prevention of recurrence of disease and/or painful symptoms, on treatment of menopausal symptoms in patients with a history of endometriosis and on the possible association of endometriosis and malignancy. LIMITATIONS, REASONS FOR CAUTION: We identified several areas in care of women with endometriosis for which robust evidence is lacking. These areas were addressed by formulating good practice points (GPP), based on the expert opinion of the guideline group members. WIDER IMPLICATIONS OF THE FINDINGS: Since 32 out of the 83 recommendations for the management of women with endometriosis could not be based on high level evidence and therefore were GPP, the guideline group formulated research recommendations to guide future research with the aim of increasing the body of evidence. STUDY FUNDING/COMPETING INTEREST(S): The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the implementation of the guideline. The guideline group members did not receive payment. All guideline group members disclosed any relevant conflicts of interest (see Conflicts of interest). TRIAL REGISTRATION NUMBER: NA.

The significant effect of endometriosis on physical, mental and social wellbeing: results from an international cross-sectional survey.

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.

Prevalence of endometriosis diagnosed by laparoscopy in adolescents with dysmenorrhea or chronic pelvic pain: a systematic review.

BACKGROUND Endometriosis associated with pain symptoms in adolescents has been extensively reported, but the exact prevalence is unclear because pain symptoms may be atypical and endometriosis can only be diagnosed by laparoscopy. The aim of this paper is to provide a systematic review of the prevalence of endometriosis diagnosed by laparoscopy in adolescents. METHODS A systematic literature search was carried out for relevant articles published between 1980 and 2011 in the databases PUBMED and EMBASE, based on the keywords 'endometriosis', 'laparoscopy', 'adolescents' and 'chronic pelvic pain (CPP)'. In addition, the reference lists of the selected articles were examined. RESULTS Based on 15 selected studies, the overall prevalence of visually confirmed endometriosis was 62% (543/880; range 25-100%) in all adolescent girls undergoing laparoscopic investigation, 75% (237/314) in girls with CPP resistant to treatment, 70% (102/146) in girls with dysmenorrhea and 49% (204/420) in girls with CPP that is not necessarily resistant to treatment. Among the adolescent girls with endometriosis, the overall prevalence of American Society of Reproductive Medicine classified moderate-severe endometriosis was 32% (82/259) in all girls, 16% (17/108) in girls with CPP resistant to treatment, 29% (21/74) in girls with dysmenorrhea and 57% (44/77) in girls with CPP that is not necessarily resistant to treatment. Due to the quality of the included papers an overestimation of the prevalence and/or severity of endometriosis is possible. CONCLUSIONS About two-thirds of adolescent girls with CPP or dysmenorrhea have laparoscopic evidence of endometriosis. About one-third of these adolescents with endometriosis have moderate-severe disease. The value of early detection of endometriosis in symptomatic adolescents and the indications for laparoscopic investigation in adolescents require more research.

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.

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.

Semi-automated morphometric analysis of human embryos can reveal correlations between total embryo volume and clinical pregnancy.

STUDY QUESTION: Is there a link between morphometric characteristics measured by a computer-assisted scoring system and clinical pregnancy outcome? SUMMARY ANSWER: The results confirm that computer-assisted assessment of the total embryo volume is associated with clinical pregnancy outcome and can be used to complement current procedures of embryo selection. WHAT IS KNOWN ALREADY: Morphometric analysis of a large group of embryos has revealed the potential to optimize algorithms for image-analysis systems for the grading of embryos and predicting pregnancy outcomes. STUDY DESIGN, SIZE, DURATION: Oocytes and embryos were obtained from 458 patients who underwent single embryo transfer on Day 3 after IVF/ICSI, between September 2006 and December 2010 at the Leuven University Fertility Center, Belgium. In total, the data set contained 2796 embryos including 458 embryos that were transferred on Day 3. Ongoing pregnancy was defined as the presence of at least one intrauterine gestational sac at 20 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients included in this study were younger than 36 years, entering their first (n = 375) or second (n = 83) IVF/ICSI cycle and were only included once. Patients were excluded if the cycle included biopsy for PGD or if donor sperm/donor oocytes were used. Based on the 26 sequential images of the same embryo taken at one time point in different planes, the software calculates the total cytoplasmic volume for each time point, from which any reduction or change in the volume with time can be assessed (which helps interpret the degree of fragmentation) and the size of blastomeres. The diameter of the smallest and largest blastomere and the total volume of each embryo were extracted from the computer-assisted scoring system database and the coefficient of diversity was calculated for Days 1, 2 and 3. A logistic regression analysis was performed to determine the range of embryo volume associated with an increased chance of pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: On Day 3, blastomeres of 8-cell stage embryos were less divergent in size than those of 6-, 7-, 9-cell stage embryos. Although, the coefficients of diversity (ratio of the largest:smallest blastomeres) of implanted embryos tended to be lower than for non-implanted embryos, the difference was only significant for 6-cell stage embryos (P = 0.02). After logistic regression, an association between total embryo volume and pregnancy was observed which had a quadratic nature: both lower and higher volumes were associated with a lower probability of successful pregnancy. A significant association was identified between total embryo volume and pregnancy rate on both Days 2 (P = 0.003) and 3 (P = 0.0003). Diagnostic measures (sensitivity, specificity, positive predictive value, accuracy and c-statistics) of the defined volume range were relatively poor. However, results showed a good negative predictive value [76.86% (95% confidence interval 71.03-82.02) on Day 3]. LIMITATIONS, REASONS FOR CAUTION: A general disadvantage of studies evaluating the impact of a characteristic on the implantation potential of an embryo is the fact that the best embryo is chosen for transfer. No comparisons can therefore be made with the other embryos. Moreover, the decision process is currently based on a non-automated, standard scoring system, which means that a 'bias' in the selection process is always present. WIDER IMPLICATIONS OF THE FINDINGS: Our results are an important step towards the development of an automated computer-assisted scoring system for the morphological characteristics of human embryos to improve embryo selection for optimizing implantation potential. Total embryo volume appears to be one of the objective characteristics that should be included. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: Not applicable.

Replication of endometriosis-associated single-nucleotide polymorphisms from genome-wide association studies in a Caucasian population.

STUDY QUESTION: Is it possible to replicate the previously identified genetic association of four single-nucleotide polymorphisms (SNPs), rs12700667, rs7798431, rs1250248 and rs7521902, with endometriosis in a Caucasian population? SUMMARY ANSWER: A borderline association was observed for rs1250248 and endometriosis (P = 0.049). However, we could not replicate the other previously identified endometriosis-associated SNPs (rs12700667, rs7798431 and rs7521902) in the same population. WHAT IS KNOWN ALREADY: Endometriosis is considered a complex disease, influenced by several genetic and environmental factors, as well as interactions between them. Previous studies have found genetic associations with endometriosis for SNPs at the 7p15 and 2q35 loci in a Caucasian population. STUDY DESIGN, SIZE, DURATION: Allele frequencies of SNPs were investigated in patients with endometriosis and controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood samples and peritoneal biopsies were taken from a Caucasian female population consisting of 1129 patients with endometriosis and 831 controls. DNA was extracted for genotyping. The study was performed at a University hospital and research laboratories. MAIN RESULTS AND THE ROLE OF CHANCE: A weak association with endometriosis (all stages) was observed for rs1250248 (P = 0.049). No significant associations were observed for the SNPs rs12700667, rs7798431 and rs7521902. A non-significant trend towards the association of rs1250248 with moderate/severe endometriosis was observed (odds ratio 1.18, 95% confidence interval 0.97-1.44). LIMITATIONS, REASONS FOR CAUTION: The inability to confirm all previous findings may result from differences between populations and type II errors. WIDER IMPLICATIONS OF THE FINDINGS: Our result demonstrates the difficulty of identifying common genetic variants in complex diseases. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by grants from the Karolinska Institutet and Stockholm City County/Karolinska Institutet (ALF), Stockholm, Sweden, Swedish Medical Research Council (K2007-54X-14212-06-3, K2010-54X-14212-09-3), Stockholm, Sweden, Leuven University Research Council (Onderzoeksraad KU Leuven), the Leuven University Hospitals Clinical Research Foundation (Klinisch onderzoeksfonds) and by the National Scientific Foundation (Fonds voor Wetenschappelijk Onderzoek, FWO). The authors have no conflict of interest.