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Objectives: The objective of this study was to examine the prevalence of chronic endometritis (CE) in infertile women, its impact on reproductive outcomes, and the accuracy of hysteroscopy as a screening tool for CE. Design: This was a prospective observational study. Participants: Participants involved in this study were 514 asymptomatic patients with infertility. Setting: The review was conducted in a tertiary care center. Methods: The participants underwent a hysteroscopy and endometrial biopsy (EMB). Antibiotics were given for cases of CE. We investigated the prevalence of CE in patients starting assisted reproductive technologies (ART) as a primary outcome. Secondary outcomes were the clinical pregnancy rate (CPR) in the ART cycle after hysteroscopy, EMB, and antibiotic treatment in cases of CE; the cumulative CPR in the subsequent 2 years after hysteroscopy and EMB; the sensitivity and specificity of hysteroscopy as a screening tool compared to EMB as the “gold standard” for diagnosing CE. Results: CE was identified in 2.8% of patients starting ART (11/393). CPRs did not differ significantly between patients with CE and the entire cohort of patients without CE in the subsequent ART cycle (OR: 0.43; 95% CI: 0.09–2.02) or in the 2 years after EMB (OR: 0.56; 95% CI: 0.16–1.97). In a matched control comparison (with matching for age, basal FSH, and cause of infertility), CPR in patients with CE did not differ in the subsequent ART cycle (OR: 0.39; 95% CI: 0.09–1.61); however, their CPR in the 2 years after EMB was significantly lower (OR: 0.22; 95% CI: 0.13–0.38). The sensitivity and specificity of hysteroscopy as a screening tool for diagnosing CE were 8.3% and 90.1%, respectively. Limitations: Due to our cohort’s low CE prevalence, we could not detect significant differences in CPRs. Conclusion: CE is rare in our studied population of asymptomatic patients starting ART. Hysteroscopy cannot replace EMB for diagnosing CE.

STUDY QUESTION Can the Poor Responder Outcome Prediction (PROsPeR) score identify live birth outcomes in subpopulations of patients with poor ovarian response (POR) defined according to the ESHRE Bologna criteria (female age, anti-Müllerian hormone (AMH), number of oocytes retrieved during the previous cycle (PNO) after treatment with originator recombinant human follitropin alfa? SUMMARY ANSWER The PROsPeR score discriminated the probability of live birth in patients with POR using observational data with fair discrimination (AUC ≅ 70%) and calibration, and the AUC losing less than 5% precision compared with a model developed using the observational data. WHAT IS KNOWN ALREADY Although scoring systems for the likelihood of live birth after ART have been developed, their accuracy may be insufficient, as they have generally been developed in the general population with infertility and were not validated for patients with POR. The PROsPeR score was developed using data from the follitropin alfa (GONAL-f; Merck KGaA, Darmstadt, Germany) arm of the Efficacy and Safety of Pergoveris in Assisted Reproductive Technology (ESPART) randomized controlled trial (RCT) and classifies women with POR as mild, moderate or severe, based upon three variables: female age, serum AMH level and number of oocytes retrieved during the previous cycle (PNO). STUDY DESIGN, SIZE, DURATION The external validation of the PROsPeR score was completed using data derived from eight different centres in France. In addition, the follitropin alfa data from the ESPART RCT, originally used to develop the PROsPeR score, were used as reference cohort. The external validation of the PROsPeR score l was assessed using AUC. A predetermined non-inferiority limit of 0.10 compared with a reference sample and calibration (Hosmer–Lemeshow test) were the two conditions required for evaluation. PARTICIPANTS/MATERIALS, SETTING, METHODS The observational cohort included data from 8085 ART treatment cycles performed with follitropin alfa in patients with POR defined according to the ESHRE Bologna criteria (17.6% of the initial data set). The ESPART cohort included 477 ART treatment cycles with ovarian stimulation performed with follitropin alfa in patients with POR. MAIN RESULTS AND THE ROLE OF CHANCE The external validation of the PROsPeR score to identify subpopulations of women with POR with different live birth outcomes was shown in the observational cohort (AUC = 0.688; 95% CI: 0.662, 0.714) compared with the ESPART cohort (AUC = 0.695; 95% CI: 0.623, 0.767). The AUC difference was −0.0074 (95% CI: −0.083, 0.0689). This provided evidence, with 97.5% one-sided confidence, that there was a maximum estimated loss of 8.4% in discrimination between the observational cohort and the ESPART cohort, which was below the predetermined margin of 10%. The Hosmer–Lemeshow test did not reject the calibration when comparing observed and predicted data (Hosmer–Lemeshow test = 1.266688; P = 0.260). LIMITATIONS, REASONS FOR CAUTION The study was based on secondary use of data that had not been collected specifically for the analysis reported here and the number of characteristics used to classify women with POR was limited to the available data. The data were from a limited number of ART centres in a single country, which may present a bias risk; however, baseline patient data were similar to other POR studies. WIDER IMPLICATIONS OF THE FINDINGS This evaluation of the PROsPeR score using observational data supports the notion that the likelihood of live birth may be calculated with reasonable precision using three readily available pieces of data (female age, serum AMH and PNO). The PROsPeR score has potential to be used to discriminate expected probability of live birth according to the degree of POR (mild, moderate, severe) after treatment with follitropin alfa, enabling comparison of performance at one centre over time and the comparison between centres. STUDY FUNDING/COMPETING INTEREST(S) This analysis was funded by Merck KGaA, Darmstadt, Germany. P.L. received grants from Merck KGaA, outside of the submitted work. N.M. reports grants, personal fees and non-financial support from Merck KGaA outside the submitted work. T.D.H. is Vice President and Head of Global Medical Affairs Fertility, Research and Development at Merck KGaA, Darmstadt, Germany. P.A. has received personal fees from Merck KGaA, Darmstadt, Germany, outside the submitted work. C.R. has received grants and personal fees from Gedeon Richter and Merck Serono S.A.S., France, an affiliate of Merck KGaA, Darmstadt, Germany, outside the submitted work. P.S. reports congress support from Merck Serono S.A.S., France (an affiliate of Merck KGaA, Darmstadt, Germany), Gedeon Richter, TEVA and MDS outside the submitted work. C.A., J.P., G.P. and R.W. declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A

PURPOSE: To explore how the assisted reproductive technology (ART) laboratories can be optimized and standardized to enhance embryo culture and selection, to bridge the gap between standard practice and the new concept of shortening time to healthy singleton birth. METHODS: A Delphi consensus was conducted (January to July 2018) to assess how the ART laboratory could be optimized, in conjunction with existing guidelines, to reduce the time to a healthy singleton birth. Eight experts plus the coordinator discussed and refined statements proposed by the coordinator. The statements were distributed via an online survey to 29 participants (including the eight experts from step 1), who voted on their agreement/disagreement with each statement. Consensus was reached if ≥ 66% of participants agreed/disagreed with a statement. If consensus was not achieved for any statement, that statement was revised and the process repeated until consensus was achieved. Details of statements achieving consensus were communicated to the participants. RESULTS: Consensus was achieved for all 13 statements, which underlined the need for professional guidelines and standardization of lab processes to increase laboratory competency and quality. The most important points identified were the improvement of embryo culture and embryo assessment to shorten time to live birth through the availability of more high-quality embryos, priority selection of the most viable embryos and improved cryosurvival. CONCLUSION: The efficiency of the ART laboratory can be improved through professional guidelines on standardized practices and optimized embryo culture environment, assessment, selection and cryopreservation methodologies, thereby reducing the time to a healthy singleton delivery.

Follicle-stimulating hormone (FSH), together with luteinizing hormone (LH) and human chorionic gonadotropin (hCG), plays a fundamental role in human reproduction. The discovery of FSH and other gonadotropins was a defining moment in our understanding of reproduction and led to the development of many treatments for infertility. In this regard, exogenous FSH has been used to treat infertility in women for decades. Today, several recombinant and highly purified urinary forms of FSH are used in medically assisted reproduction (MAR). However, differences in the macro- and micro-heterogeneity of FSH result in a variety of FSH glycoforms, with glycoform composition determining the bioactivity (or potency), pharmacokinetic/pharmacodynamic (PK/PD) profiles, and clinical efficacy of the different forms of FSH. This review illustrates how the structural heterogeneity of FSH glycoforms affects the biological activity of human FSH products, and why potency does not predict effects in humans in terms of PK, PD, and clinical response.

BackgroundA Delphi consensus was conducted to evaluate the influence of single nucleotide polymorphisms (SNPs) in genes encoding gonadotropin and gonadotropin receptors on clinical ovarian stimulation outcomes following assisted reproductive technology (ART) treatment.MethodsNine experts plus two Scientific Coordinators discussed and amended statements plus supporting references proposed by the Scientific Coordinators. The statements were distributed via an online survey to 36 experts, who voted on their level of agreement or disagreement with each statement. Consensus was reached if the proportion of participants agreeing or disagreeing with a statement was >66%.ResultsEleven statements were developed, of which two statements were merged. Overall, eight statements achieved consensus and two statements did not achieve consensus. The statements reaching consensus are summarized here. (1) SNP in the follicle stimulating hormone receptor (FSHR), rs6166 (c.2039A>G, p.Asn680Ser) (N=5 statements): Ser/Ser carriers have higher basal FSH levels than Asn/Asn carriers. Ser/Ser carriers require higher amounts of gonadotropin during ovarian stimulation than Asn/Asn carriers. Ser/Ser carriers produce fewer oocytes during ovarian stimulation than Asn/Asn or Asn/Ser carriers. There is mixed evidence supporting an association between this variant and ovarian hyperstimulation syndrome. (2) SNP of FSHR, rs6165 (c.919G>A, p.Thr307Ala) (N=1 statement): Few studies suggest Thr/Thr carriers require a shorter duration of gonadotropin stimulation than Thr/Ala or Ala/Ala carriers. (3) SNP of FSHR, rs1394205 (−29G>A) (N=1 statement): Limited data in specific ethnic groups suggest that A/A allele carriers may require higher amounts of gonadotropin during ovarian stimulation and produce fewer oocytes than G/G carriers. (4) SNP of FSH β-chain (FSHB), rs10835638 (−211G>T) (N=1 statement): There is contradictory evidence supporting an association between this variant and basal FSH levels or oocyte number. (5) SNPs of luteinizing hormone β-chain (LHB) and LH/choriogonadotropin receptor (LHCGR) genes (N=1 statement): these may influence ovarian stimulation outcomes and could represent potential future targets for pharmacogenomic research in ART, although data are still very limited.ConclusionsThis Delphi consensus provides clinical perspectives from a diverse international group of experts. The consensus supports a link between some variants in gonadotropin/gonadotropin receptor genes and ovarian stimulation outcomes; however, further research is needed to clarify these findings.

This systematic review and meta-analysis determined the association between aspirated after ovarian stimulation and top/good quality embryos obtained in women undergoing ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI). MEDLINE, EMBASE, Scopus, CINAHL and Web of Science were searched for English-language publications on top/good-quality embryos at cleavage (day 2/3) and/or blastocyst (day 5/6) developmental stages, up to 18 November 2017. Twenty-eight studies (three prospective and 25 retrospective) reporting data on 291,752 assisted reproductive technology (ART) cycles were considered eligible. We confirmed a strong positive association between oocytes retrieved and top/good-quality day 2/3 embryos (weighted correlation coefficient [rw] = 0.791), day 5/6 embryos (rw = 0.901), metaphase II oocytes (rw = 0.988), oocytes exhibiting two pronuclei (rw = 0.987) and euploid embryos (rw = 0.851); P < 0.001 for all correlations (evaluated in subsets of the 17 studies). Data from 5657 cycles showed that the group with the most oocytes aspirated had the most top/good-quality day 2/3 embryos (pooled standardized mean differences (high [>15] versus low [

Both animal and human studies have demonstrated that endometriosis involves numerous levels of immune dysfunction. From aberrant cytokine signaling to shifts in immune cell populations, it is clear that endometriosis develops in the setting of an elevated pro-inflammatory state. This elevated level of inflammation could exacerbate the morbidity seen in this chronic disease. Consequently, numerous immunomodulating therapies have been tested in both animal models and limited human trials. This review seeks to summarize the in vitro and in vivo studies used to test these agents for the treatment of endometriosis. These agents include small-molecule and antibody-based disease-modifying antirheumatic drugs (DMARDs), cytokines, mTOR inhibitors, nucleotide analogs, and various other small molecules. Although many of these agents have had promising results in in vitro and animal studies, few of them have been tested in humans. For the agents that were studied in women with endometriosis-associated pain, little benefit has been seen in symptom control to date. Nevertheless, there remains the potential that these agents may offer a new pathway in the treatment of the chronic, costly, and debilitating disease.

It is essential that fertility treatment is individualized based on a thorough diagnostic work-up, with treatment tailored to the patients' requirements. This individualization should be kept in mind during the main decision points that occur before and during treatment. Treatment customization must include consideration of both the woman and her partner involved in the process together, including their collective treatment goals. Once treatment goals have been agreed and diagnostic evaluations performed, personalization based on patient characteristics, together with an understanding of treatment goals and patient preferences, enables the selection of appropriate treatments, protocols, products and their dosing. Following treatment initiation, monitoring and adaptation of product and dose can then ensure optimal outcomes. Currently, it is not possible to base treatment decisions on every characteristic of the patient and personalization is based on biomarkers that have been identified as the most relevant. However, in the future, the use of artificial intelligence coupled with continuous monitoring should enable greater individualization and improve outcomes. This review considers the current state-of-the-art related to decision points during individualized treatment of female infertility, before looking at future developments that might further assist in making individualized treatment decisions, including the use of computer-assisted decision making. ispartof: GYNECOLOGICAL ENDOCRINOLOGY vol:35 issue:12 pages:1027-1036 ispartof: location:England status: published

STUDY QUESTION: Does the GnRH antagonist, ASP1707, reduce endometriosis-associated pelvic pain? SUMMARY ANSWER: ASP1707 significantly reduced endometriosis-associated pelvic pain in a dose-related manner. WHAT IS KNOWN ALREADY: GnRH agonists are an effective therapeutic option for endometriosis that is refractory to non-steroidal anti-inflammatory drugs, oral contraceptives, and progestins. However, GnRH agonists cause complete suppression of estradiol (E2), resulting in hypoestrogenic side-effects such as bone loss that may increase the future risk of osteoporotic fractures. STUDY DESIGN, SIZE, DURATION: This was a Phase II, multicenter, double-blind, randomized, parallel-group, placebo-controlled study conducted in 540 women from 04 December 2012 to 30 July 2015 in Europe and Japan. A sample size of 504 (84 subjects per group) was calculated to provide ≥80% power to detect a dose-related treatment effect among placebo and ASP1707 doses in change from baseline in pelvic pain, assuming different dose-response curves after 12 weeks of treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of 912 women with endometriosis-associated pelvic pain screened, 540 were enrolled, and 532 received ≥1 dose of study drug (placebo, n = 88; ASP1707 3 mg, n = 86; ASP1707 5 mg, n = 91; ASP1707 10 mg, n = 90; ASP1707 15 mg, n = 88; leuprorelin, n = 89) for 24 weeks. MAIN RESULTS AND THE ROLE OF CHANCE: After 12 weeks of treatment with ASP1707, the mean (95% CI) changes in numeric rating score (NRS) for overall pelvic pain (OPP) were -1.56 (-1.91, -1.21), -1.63 (-1.99, -1.27), -1.93 (-2.27, -1.60), -2.29 (-2.64, -1.94), and -2.13 (-2.47, -1.79) for placebo, ASP1707 3 mg, ASP1707 5 mg, ASP1707 10 mg, and ASP1707 15 mg, respectively. Mean (95% CI) changes in NRS for dysmenorrhea were -1.50 (-2.00, -1.00), -2.72 (-3.22, -2.21), -2.85 (-3.33, -2.38), -3.97 (-4.46, -3.48), and -4.18 (-4.66, -3.70), respectively. Mean (95% CI) changes in NRS for non-menstrual pelvic pain (NMPP) were -1.53 (-1.88, -1.19), -1.51 (-1.87, -1.16), -1.80 (-2.14, -1.47), -2.03 (-2.37, -1.68), and -1.86 (-2.20, -1.52), respectively. Statistically significant dose-related treatment effects in reduction in NRS for OPP (P = 0.001), dysmenorrhea (P < 0.001), and NMPP (P = 0.029) were observed after 12 weeks among ASP1707 doses and were maintained through 24 weeks. Serum estradiol and bone mineral density decreased dose dependently with ASP1707 through 24 weeks, however, to a lesser extent than with leuprorelin. LIMITATIONS, REASON FOR CAUTION: This study was not powered for pairwise comparison of each ASP1707 group versus placebo. WIDER IMPLICATIONS OF THE FINDINGS: All doses of ASP1707 reduced serum E2 levels to within the target range and to a lesser extent than leuprorelin. ASP1707 is a potential alternative treatment to leuprorelin for endometriosis-associated pelvic pain with lower impact on bone health. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Astellas Pharma Inc. T.D'.H is Vice President and Head of Global Medical Affairs Fertility at Merck, Darmstadt, Germany since October 1, 2015. At the time that the TERRA study was conducted, he served as Principal Investigator in his role as Coordinator of the Leuven University Fertility Center. Since October 2015, T.D'.H has left Leuven University Hospital Gasthuisberg, but continues to serve as Professor in Reproductive Medicine and Biology at KU Leuven (University of Leuven) Belgium and at the Dept of Obstetrics, Gynecology and Reproduction at Yale University, New Haven, USA. T. Fukaya and Y. Osuga report personal consulting fees from Astellas Pharma Inc. during the conduct of the study and outside the submitted work. G.M. Holtkamp, and L. Skillern are employed by Astellas Pharma Europe B.V.; K. Miyazaki is employed by Astellas Pharma Inc.; B. López, was a biostatistician for Astellas Pharma Europe B.V. during conduct of the study; R. Besuyen was a contract Associate Director of Medical Science for Astellas during conduct of the study. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01767090. EudraCT number 2012-002791-14. TRIAL REGISTRATION DATE: 18 December 2012. DATE OF FIRST SUBJECT’S ENROLLMENT: One subject signed informed consent on 04 December 2012; the first subject was randomized on 16 April 2013. ispartof: HUMAN REPRODUCTION vol:34 issue:5 pages:813-823 ispartof: location:England status: published

Study question Can a smartphone video clip detailing the patient journey decrease the anxiety of women and men on the day of their first oocyte aspiration? Summary answer The video clip does not affect the anxiety of women but does reduce the anxiety of men on the day of couples’ first oocyte aspiration. What is known already Infertility and in vitro fertilisation (IVF) decrease the personal wellbeing of women and men. Couples shared that this contributed to their IVF discontinuation despite a good prognosis and reimbursement of IVF. Previous longitudinal studies confirmed that pre-IVF anxiety is associated with IVF discontinuation. Limiting treatment anxiety is, therefore, relevant for fertility patients and clinics. Studies from the field of reproductive medicine examining the effect of preparatory information on anxiety suggest that focussed interventions seem more effective than complex interventions. Several randomized controlled trials (RCTs) found that preparatory information movies reduce anxiety for out-patient cardiology procedures in women and men. Study design, size, duration This monocentric RCT randomized (1:1 allocation; computerized) 190 heterosexual couples about to start their first IVF cycle between care as usual (i.e. preparatory information session 1-3 months before IVF) and care as usual combined with a novel intervention during a 24 months recruitment period (2018-2020). The novel intervention is a 5-minute smartphone video clip detailing the patient journey on the day of oocyte aspiration, which was sent to both partners the day before oocyte aspiration. Participants/materials, setting, methods Upon arrival at a private fertility clinic for their first oocyte aspiration women and men independently filled out the ‘STAI-State anxiety inventory’ and the ‘infertility distress scale (IDS)’ and evaluated the novel intervention, if applicable. A minority of randomized couples didn’t comply with the standard IVF trajectory (n = 27) or didn’t fill out the questionnaires (n = 8). The data of 155 couples (76-79/group, a-priori sample size calculation requested minimally 76/group) was subjected to a modified intention-to-treat analysis. Main results and the role of chance Women and men were on average 33 and 35 years old, respectively. Couples had a mean duration of infertility of 27 months and 63 of them (41%) had tried intrauterine insemination. The background variables were equally distributed between the intervention (IG) and control group (CG). The video clip did not affect women’s anxiety on the day of oocyte aspiration (mean STAI-State score IG 42.7±8.1 vs CG 42.1±8.5, p = 0.67). However, men who watched the video clip were significantly less anxious than men who did not watch it (mean STAI-State score IG 35.8±6.4 vs CG 38.2±7.6, p = 0.04). Surprisingly, infertility-specific distress was higher among women and men who watched the video clip (mean IDS scores of 25.8±4.9 and 22.6±5.0, respectively), as compared to women (p = 0.05) and men (p = 0.02) who did not watch the video clip (mean IDS score 24.3±4.6 and 20.8±4.7, respectively). All women and men of the intervention group, except one woman, would recommend the video clip to friends and family going through IVF. The intervention and control group did not differ significantly regarding clinical pregnancy rate (31/76 vs. 29/79, p = 0.60) or miscarriage rate (2/76 vs. 3/79, p = 0.68) 12 weeks after their first oocyte aspiration. Limitations, reasons for caution Patients nor assessors were blinded and there was no attention control group. Selection bias is plausible although the participation rate was 89%. Assessing infertility-specific distress the day after watching the video clip was not optimal, as priming couples to feel infertility-specific distress short term is less problematic than longer term. Wider implications of the findings Providing additional procedural information is interesting for clinics as patients recommended the video clip and as it decreased men’s anxiety. A follow-up study should examine whether the video clip’s priming effect on infertility-specific distress lasts longer than only the day after and whether the video clip affects IVF discontinuation. Trial registration number NCT03717805

Study question Is endometriosis related to worse outcome of assisted reproductive techniques (ART)? Summary answer Cumulative incidence of live birth in patients with and without endometriosis at laparoscopy was similar, although deep endometriosis and adenomyosis were negative prognostic factors. What is known already Whether endometriosis has a negative impact on the outcome of ART is still a matter of debate. Most published data report on one fresh cycle only, usually without taking frozen embryos into account. Further, a large heterogeneity in study population has been acknowledged by several meta-analyses, as in the control groups endometriosis was not always excluded by laparoscopy, and in case of endometriosis the prior treatment history was variable or unclear. Study design, size, duration Retrospective longitudinal cohort study of 1462 patients (779 with laparoscopically treated endometriosis of any rASRM stage, and 683 without endometriosis at laparoscopy) undergoing ART treatment between July 2003 and December 2014. Primary outcome studied was time to ART live birth. Secondary outcomes include -amongst others- number of cycles needed per ART live birth, time to ART or spontaneous live birth, cycle cancellation rate, and pregnancy outcomes like miscarriage and ectopic pregnancy, and per cycle analyses. Participants/materials, setting, methods All patients with a history of laparoscopy prior to the start of their first ART were included for analysis. The ART was performed in a tertiary referral center of a large University Hospital. Primary outcome studied was the time from initiation of the first ART cycle to delivery of the first live born. Survival analysis was conducted using cumulative incidence functions and cause-specific hazards regression. Main results and the role of chance The study included 1462 patients who initiated 4537 ART cycles, of which 3672 (81%) fresh and 857 (19%) frozen cycles. The unadjusted hazard ratio (HR) of live birth was 1.01 (95% CI 0.88–1.16). After adjustment for potential confounders (age, maternal BMI, maternal smoking, secondary infertility, duration of infertility, anovulation, reduced ovarian reserve, tubal factor, male factor and therapy started before 2007) the HR was 0.99 (95% CI 0.86–1.14). Within the endometriosis population (n = 779), covariate-adjusted analyses suggested that presence of adenomyosis (HR = 0.54; 95% CI 0.34–0.86) and a history of deep endometriosis (HR = 0.74 – 95% CI 0.58–0.94) were associated with a lower cumulative incidence of live birth. In contrast, there was little support of an association with diagnosis of stage III/IV (HR = 1.15; 95% CI 0.84–1.59) or a history of ovarian endometriosis (HR = 0.97; 95% CI 0.72–1.30). Beside the effect of the different variables directly linked to endometriosis, maternal BMI (HR = 0.80; 95%CI 0.71–0.91) and smoking (HR = 0.69; 95%CI 0.52–0.92) also negatively affected live birth delivery rate per patient. Limitations, reasons for caution Practices and success rates of ART may have changed during the 11-year recruitment period. Restricting to women who underwent laparoscopy, while providing evidence of the presence or absence of endometriosis, may have induced selection bias. However, the advantage of this time period, was the high rate of pre-ART laparoscopy (+/–50%). Wider implications of the findings: As deep endometriosis and adenomyosis represent negative prognostic factors within the endometriosis population, future studies should focus on optimalisation of ART in these subgroups. Trial registration number S57393

Study question What is the impact of providing couples with their IVF-prognosis on expectations and anxiety in women and men on the day of embryo transfer? Summary answer Only couples with a less than average IVF-prognosis updated their high expectations and IVF-prognosis was negatively associated with anxiety, especially in women. What is known already Female IVF-patients are known to expect a pregnancy rate per IVF-cycle of no less than 49-55%. Qualitative interviews and a survey showed that well informed women expect unrealistically high pregnancy rates as they think that their (family’s) fertility and their clinic is better than average. Several prognostic models have recently been published. The adapted van Loendersloot model including clinical and laboratory characteristics proved performant for our clinic (AUC=0.74) and was validated internally (Devroe et al, BMJ Open, 2020). The impact of providing couples with their IVF-prognosis on expectations and wellbeing of female and male patients has yet to be studied. Study design, size, duration A prospective survey, questioning a final sample of 148 partnered individuals, completing their 2nd-6th IVF-cycle (2019-2020) in a University clinic, on the days of oocyte aspiration (OA) and fresh embryo transfer (ET). Thirty other partnered individuals declined participation (participation rate=85%) and 26 were excluded due to ET-cancellation. The IVF-prognosis (live birth rate, LBR, per completed IVF-cycle including fresh and frozen ETs from the same ovarian stimulation) was calculated with the adapted van Loendersloot model. Participants/materials, setting, methods Each partner reported their perception of their expected IVF-LBR on a visual analogue scale on the day OA. After being informed on their IVF-prognosis by gynaecologists, they re-rated their expected IVF-LBR and filled out the reliable ‘STAI-State-Anxiety Inventory’ on the day of fresh ET. Linear mixed models, taking account of partnering and assessing the association with gender, explored whether individuals updated their expected IVF-LBR after receiving their IVF-prognosis and whether IVF-prognosis and anxiety were associated. Main results and the role of chance The mean IVF-prognosis was 30.9% (±16.8). The 148 partnered individuals had a mean expected IVF-LBR of 59.1% (±20.0) on the day of OA (no gender effect; p = 0.079). After being informed on their IVF-prognosis (day of ET), women’s and men’s mean expected IVF-LBR was 50.9% (±24.5) and 58.1% (±22.1), respectively (gender effect; p = 0.002). Linear mixed models, including couple and time as random factors, did not show an effect of time on expected IVF-LBRs (p = 0.15). Although women were more likely than men to update their expected IVF-LBR (p = 0.002), the updates were not significantly different from the IVF-LBR expected on the day of OA (p = 0.10). Women were more anxious than men (41.5±10.6 and 21.9±7.2, respectively, p Limitations, reasons for caution This is an explorative study in preparation of an adequately powered randomized controlled trial, testing whether couples who are informed on their IVF-prognosis update their expected IVF-LBR and whether this causes anxiety, as compared to care as usual in which couples are not informed on their IVF-prognosis. Wider implications of the findings Men and especially women with a less than average prognosis update their IVF-expectations after having received this prognosis which may trigger anxious reactions. These findings should be re-examined in an RCT. Following up the effect of sharing IVF-prognoses on longer-term distress and IVF-discontinuation would be interesting. Trial registration number not applicable

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.

BackgroundA Delphi consensus was conducted to evaluate global expert opinions on key aspects of assisted reproductive technology (ART) treatment.MethodsTen experts plus the Scientific Coordinator discussed and amended statements plus supporting references proposed by the Scientific Coordinator. The statements were distributed via an online survey to 35 experts, who voted on their level of agreement or disagreement with each statement. Consensus was reached if the proportion of participants agreeing or disagreeing with a statement was >66%.ResultsEighteen statements were developed. All statements reached consensus and the most relevant are summarised here. (1) Follicular development and stimulation with gonadotropins (n = 9 statements): Recombinant human follicle stimulating hormone (r-hFSH) alone is sufficient for follicular development in normogonadotropic patients aged (2) Pituitary suppression (n = 2 statements): Gonadotropin releasing hormone (GnRH) antagonists are associated with lower rates of any grade ovarian hyperstimulation syndrome (OHSS) and cycle cancellation versus GnRH agonists. (3) Final oocyte maturation triggering (n=4 statements): Human chorionic gonadotropin (hCG) represents the gold standard in fresh cycles. The efficacy of hCG triggering for frozen transfers in modified natural cycles is controversial compared with LH peak monitoring. Current evidence supports significantly higher pregnancy rates with hCG + GnRH agonist versus hCG alone, but further evidence is needed. GnRH agonist trigger, in GnRH antagonist protocol, is recommended for final oocyte maturation in women at risk of OHSS. (4) Luteal-phase support (n = 3 statements): Vaginal progesterone therapy represents the gold standard for luteal-phase support.ConclusionsThis Delphi consensus provides a real-world clinical perspective on the specific approaches during the key steps of ART treatment from a diverse group of international experts. Additional guidance from clinicians on ART strategies could complement guidelines and policies, and may help to further improve treatment outcomes.

Background This study compared the effectiveness of recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa; GONAL-f®) with urinary highly purified human menopausal gonadotropin (hMG HP; Menogon HP®), during assisted reproductive technology (ART) treatments in Germany. Methods Data were collected from 71 German fertility centres between 01 January 2007 and 31 December 2012, for women undergoing a first stimulation cycle of ART treatment with r-hFSH-alfa or hMG HP. Primary outcomes were live birth, ongoing pregnancy and clinical pregnancy, based on cumulative data (fresh and frozen-thawed embryo transfers), analysed per patient (pP), per complete cycle (pCC) and per first complete cycle (pFC). Secondary outcomes were pregnancy loss (analysed per clinical pregnancy), cancelled cycles (analysed pCC), total drug usage per oocyte retrieved and time-to-live birth (TTLB; per calendar week and per cycle). Results Twenty-eight thousand six hundred forty-one women initiated a first treatment cycle (r-hFSH-alfa: 17,725 [61.9%]; hMG HP: 10,916 [38.1%]). After adjustment for confounding variables, treatment with r-hFSH-alfa versus hMG HP was associated with a significantly higher probability of live birth (hazard ratio [HR]-pP [95% confidence interval (CI)]: 1.10 [1.04, 1.16]; HR-pCC [95% CI]: 1.13 [1.08, 1.19]; relative risk [RR]-pFC [95% CI]: 1.09 [1.05, 1.15], ongoing pregnancy (HR-pP [95% CI]: 1.10 [1.04, 1.16]; HR-pCC [95% CI]: 1.13 [1.08, 1.19]; RR-pFC [95% CI]: 1.10 [1.05, 1.15]) and clinical pregnancy (HR-pP [95% CI]: 1.10 [1.05, 1.14]; HR-pCC [95% CI]: 1.14 [1.10, 1.19]; RR-pFC [95% CI]: 1.10 [1.06, 1.14]). Women treated with r-hFSH-alfa versus hMG HP had no statistically significant difference in pregnancy loss (HR [95% CI]: 1.07 [0.98, 1.17], were less likely to have a cycle cancellation (HR [95% CI]: 0.91 [0.84, 0.99]) and had no statistically significant difference in TTLB when measured in weeks (HR [95% CI]: 1.02 [0.97, 1.07]; p = 0.548); however, r-hFSH-alfa was associated with a significantly shorter TTLB when measured in cycles versus hMG HP (HR [95% CI]: 1.07 [1.02, 1.13]; p = 0.003). There was an average of 47% less drug used per oocyte retrieved with r-hFSH-alfa versus hMG HP. Conclusions This large (> 28,000 women), real-world study demonstrated significantly higher rates of cumulative live birth, cumulative ongoing pregnancy and cumulative clinical pregnancy with r-hFSH-alfa versus hMG HP.

To induce endometrial decidualization in rodents, an intrauterine oil stimulus can be delivered via the nontraumatic vagina or via the traumatic laparotomy. However, there is considerable variation in amount of decidualization using these inducing methods. Therefore, we studied which oil delivery route could achieve the highest rate of endometrial decidualization along the full length of both uterine horns.To induce decidualization, ovariectomized C57Bl/6J mice were injected with estrogen (100 ng/day; 3 days). A progesterone pellet (5 mg) was implanted subcutaneously, followed by estrogen injections (5 ng/day; 3 days). Oil (20 µL/horn) was injected in the uterus via laparotomy, laparoscopy, or vagina. Four days later, the pellet was removed, followed by hysterectomy after 4 to 6 hours. Endometrial decidualization was evaluated macroscopically and microscopically using hematoxylin and eosin and desmin staining. Furthermore, uterine weight and hormone levels were measured.The proportion of animals with macroscopic bicornuate decidualization was higher after laparoscopic (83%) and laparotomic (89%) injection than after sham injection (11%). Furthermore, macroscopic bicornuate decidualization was significantly higher after laparotomic injection (89%) compared to the vaginal injection (38%). Uterine weight and endometrial surface area were significantly higher in both laparotomy and laparoscopy groups compared to the sham group, while the relative desmin-positive endometrial surface area was only significantly different between the laparotomy and the sham animals.Methods using laparoscopic and laparotomic intrauterine oil injection resulted in a higher amount of decidualized endometrium compared to sham injection, although further optimization is needed to reach full bicornuate decidualization.

When evaluating the correlation between endometriosis and infertility with application of the evidence-based guidelines to establish causality in medicine, it becomes apparent that endometriosis causes infertility. This is supported by a strong and consistent association between the two in various settings (prevalence, natural conception, intrauterine insemination (IUI), and assisted reproductive technologies (ARTs)), evidence for a temporal relation, arguments for a dose-response gradient, and proven effects of the removal of lesions on infertility. Next to surgical treatment of endometriosis lesions, medically assisted reproduction treatments such as IUI and ART such as in vitro fertilization are cornerstones of the management of endometriosis-related infertility. Because the revised American Society for Reproductive Medicine (rASRM) staging system is poorly correlated with pregnancy rates as opposed to the Endometriosis Fertility Index (EFI), the latter should be used as the preferred clinical tool to counsel patients on their postoperative fertility management options.

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.

A noninvasive biomarker-based test could help shorten the diagnostic delay for endometriosis. The most investigated biomarker sources are peripheral blood and endometrium. Discovery of endometriosis biomarkers is often hypothesis-driven, i.e. when one or a few biomarkers are investigated based on their role in the disease pathogenesis. Alternatively, a hypothesis-generating approach has been followed using the “omics” technologies. A variety of biomarkers for endometriosis have been investigated, but no biomarker has been validated for clinical use. Many challenges lie ahead in the endometriosis biomarker field. In the future, harmonized collection and reporting methods should allow large-scale international collaboration for highly powered studies.

Ovarian stimulation with low-dose human menopausal gonadotrophin (HMG) is superior to clomiphene citrate in intrauterine insemination (IUI) cycles with respect to clinical pregnancy rate, but it is unclear whether HMG is also the more cost-effective option. The aim of this study was to compare the cost-effectiveness of ovarian stimulation with low-dose subcutaneously administred HMG (37.5–75 IU per day) to orally administred clomiphene citrate (50 mg/day from day 3–7) in an IUI programme for subfertile couples. A cost-effectiveness analysis was conducted using the results of a randomized trial, including 620 IUI cycles. The primary outcome was the incremental cost-effectiveness ratio (ICER) of using HMG versus clomiphene citrate. Results are presented from the healthcare payer perspective. The total cost per patient associated with one IUI treatment with HMG is €764, whereas it is €558 if clomiphene citrate is used, resulting in an incremental cost of €206 for HMG per treatment. The incremental clinical pregnancy rate of using HMG instead of clomiphene citrate, however, is also 5.7 percentage points higher, resulting in an ICER of HMG versus clomiphene citrate of €3615 per additional clinical pregnancy achieved. On average, HMG was found to be more cost-effective than clomiphene citrate.

Tussen maart en juni 2009 ontvingen alle meisjes, geboren in 1996 en op het moment van het onderzoek woonachtig in 8 regio’s verspreid over Vlaanderen, in het kader van het Vlaamse cohortonderzoek JOnG! een semigestructureerde vragenlijst met onder meer vragen over de leeftijd van menarche, de kenmerken van hun menstruele cyclus en de eventuele impact ervan op hun sociale activiteiten. Van de 769 respondenten (dat is 15,7 % van de doelpopulatie in de betrokken regio’s) had 47,2 % reeds menstruaties. De gemiddelde leeftijd van menarche werd geschat op 12,9 ± 1,3 jaar. Van de 363 meisjes die reeds menstruaties hadden, ervoer 41,6 % (95 % BI 36,4–47,0 %) deze als pijnlijk tijdens de afgelopen 3 maanden. Uit het onderzoek blijkt een significante correlatie tussen pijnlijke menstruatie enerzijds (dysmenorroe), en jongere menarcheleeftijd (p < .05) en meer overvloedige menstruatie (p < .001) anderzijds. Bovendien ervoer een op vier 13-jarige meisjes een negatieve impact van menstruaties op hun schoolparticipatie en deelname aan sociale activiteiten. Deze proportie is echter significant groter bij meisjes met dysmenorroe (41,3 %) dan bij meisjes die hun menstruaties hebben zonder noemenswaardige klachten (14,2 %) (RR = 2,9; 95 % BI, 2,0–4,4; p < .001). Uit de resultaten van deze studie blijkt dat menstruatie-gebonden klachten frequent voorkomen bij jonge tienermeisjes, wat aandacht verdient vanwege jeugdgezondheidszorg.

Endometriosis is a chronic oestrogen-dependent gynaecological disease present in approximately 10% of women of reproductive age and up to 30–50% of women with infertility and/or pain. It is defined as the presence of endometrial-like tissue outside the uterus. The pathogenesis remains enigmatic but the most common hypothesis is Sampson’s theory of retrograde menstruation. Over the last decade, the roles of inflammation, angiogenesis, and the immune system have been well documented. Diagnosis of endometriosis is difficult since physical examination, ultrasonography, and magnetic resonance imaging can detect but not exclude the presence of endometriosis. Therefore, the gold standard for diagnosis of endometriosis remains laparoscopic visualization with histological confirmation. Medical treatment options are combined oral contraceptives, progestogens, or gonadotropin-releasing hormone analogues. Surgical management is necessary in patients who want to become pregnant or those who are refractory to medical treatment. These complex surgical procedures, with significant risks and recurrence rates, should be performed by experienced teams only.

Objective To demonstrate the feasibility of studying exosomes directly from peritoneal fluid, we isolated exosomes from endometriosis patient samples and from controls, and characterized their cargo. Design Case-control experimental study. Setting Academic clinical center. Patient (s) Women with and without endometriosis who underwent laparoscopic surgery (n = 28 in total). Intervention (s) None. Main Outcome Measure (s) Concentration of exosomes within peritoneal fluid and protein content of the isolated exosomes. Result (s) Peritoneal fluid samples were pooled according to the cycle phase and disease stage to form six experimental groups, from which the exosomes were isolated. Exosomes were successfully isolated from peritoneal fluid in all the study groups. The concentration varied with cycle phase and disease stage. Proteomic analysis showed specific proteins in the exosomes derived from endometriosis patients that were absent in the controls. Five proteins were found exclusively in the endometriosis groups: PRDX1, H2A type 2-C, ANXA2, ITIH4, and the tubulin α-chain. Conclusion (s) Exosomes are present in peritoneal fluid. The characterization of endometriosis-specific exosomes opens up new avenues for the diagnosis and investigation of endometriosis.

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. ispartof: BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY vol:127 issue:1 pages:107-114 ispartof: location:England status: published

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. ispartof: ULTRASOUND IN OBSTETRICS & GYNECOLOGY vol:56 issue:2 pages:255-266 ispartof: location:England status: published

A noninvasive diagnostic test for endometriosis is needed to shorten the current diagnostic delay of 8–11 years. The goal of this study was to discover new biomarkers for endometriosis using an antibody array approach. A total of 103 plasma samples from patients with laparoscopically confirmed presence (n = 68) or absence (n = 35) of endometriosis were selected. Samples were pooled according to disease status, cycle phase, disease stage, and phenotype. Pooled samples were screened for possible biomarkers using the L-series 1000 and Quantibody 660 arrays from RayBiotech. Technical verification of ten markers was done using a custom-made multiplex immunoassay identifying ten proteins (10-plex) and later by single ELISA. Due to the limited reproducibility of the L-series 1000 immunoassay, the biomarker screening was performed using the Quantibody 660, a sandwich-based multiplex immunoassay, which showed that 280 proteins were upregulated, and 29 proteins downregulated in the endometriosis pool versus the control pool. In order to assess the reproducibility of these results, ten preselected proteins were analyzed using a custom 10-plex. Four proteins (CD48, DNAM-1, IL-31, and XIAP) were confirmed to be differentially expressed when comparing the endometriosis and control pool. However, only IL-31 showed a univariate statistical difference between endometriosis and control groups in individual samples that were part of the initial pools. In conclusion, discovery and verification of potential markers proved challenging using multiplex immunoassay methods, mainly due to issues with reproducibility. Only IL-31 showed potential as possible biomarker for endometriosis.

BACKGROUND: Screening hysteroscopy in infertile women with unexplained infertility, or prior to intrauterine insemination (IUI) or in vitro fertilisation (IVF) may reveal intrauterine pathology that may not be detected by routine transvaginal ultrasound. Hysteroscopy, whether purely diagnostic or operative may improve reproductive outcomes. OBJECTIVES: To assess the effectiveness and safety of screening hysteroscopy in subfertile women undergoing evaluation for infertility, and subfertile women undergoing IUI or IVF. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL CRSO, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (September 2018). We searched reference lists of relevant articles and handsearched relevant conference proceedings. SELECTION CRITERIA: Randomised controlled trials comparing screening hysteroscopy versus no intervention in subfertile women wishing to conceive spontaneously, or before undergoing IUI or IVF. DATA COLLECTION AND ANALYSIS: We independently screened studies, extracted data, and assessed the risk of bias. The primary outcomes were live birth rate and complications following hysteroscopy. We analysed data using risk ratio (RR) and a fixed-effect model. We assessed the quality of the evidence by using GRADE criteria. MAIN RESULTS: We retrieved 11 studies. We included one trial that evaluated screening hysteroscopy versus no hysteroscopy, in women with unexplained subfertility, who were trying to conceive spontaneously. We are uncertain whether ongoing pregnancy rate improves following a screening hysteroscopy in women with at least two years of unexplained subfertility (RR 4.30, 95% CI 2.29 to 8.07; 1 RCT; participants = 200; very low-quality evidence). For a typical clinic with a 10% ongoing pregnancy rate without hysteroscopy, performing a screening hysteroscopy would be expected to result in ongoing pregnancy rates between 23% and 81%. The included study reported no adverse events in either treatment arm. We are uncertain whether clinical pregnancy rate is improved (RR 3.80, 95% CI 2.31 to 6.24; 1 RCT; participants = 200; very low-quality evidence), or miscarriage rate increases (RR 2.80, 95% CI 1.05 to 7.48; 1 RCT; participants = 200; very low-quality evidence), following screening hysteroscopy in women with at least two years of unexplained subfertility.We included ten trials that included 1836 women who had a screening hysteroscopy and 1914 women who had no hysteroscopy prior to IVF. Main limitations in the quality of evidence were inadequate reporting of study methods and higher statistical heterogeneity. Eight of the ten trials had unclear risk of bias for allocation concealment.Performing a screening hysteroscopy before IVF may increase live birth rate (RR 1.26, 95% CI 1.11 to 1.43; 6 RCTs; participants = 2745; I² = 69 %; low-quality evidence). For a typical clinic with a 22% live birth rate, performing a screening hysteroscopy would be expected to result in live birth rates between 25% and 32%. However, sensitivity analysis done by pooling results from trials at low risk of bias showed no increase in live birth rate following a screening hysteroscopy (RR 0.99, 95% CI 0.82 to 1.18; 2 RCTs; participants = 1452; I² = 0%).Only four trials reported complications following hysteroscopy; of these, three trials recorded no events in either group. We are uncertain whether a screening hysteroscopy is associated with higher adverse events (Peto odds ratio 7.47, 95% CI 0.15 to 376.42; 4 RCTs; participants = 1872; I² = not applicable; very low-quality evidence).Performing a screening hysteroscopy before IVF may increase clinical pregnancy rate (RR 1.32, 95% CI 1.20 to 1.45; 10 RCTs; participants = 3750; I² = 49%; low-quality evidence). For a typical clinic with a 28% clinical pregnancy rate, performing a screening hysteroscopy would be expected to result in clinical pregnancy rates between 33% and 40%.There may be little or no difference in miscarriage rate following screening hysteroscopy (RR 1.01, 95% CI 0.67 to 1.50; 3 RCTs; participants = 1669; I² = 0%; low-quality evidence).We found no trials that compared a screening hysteroscopy versus no hysteroscopy before IUI. AUTHORS' CONCLUSIONS: At present, there is no high-quality evidence to support the routine use of hysteroscopy as a screening tool in the general population of subfertile women with a normal ultrasound or hysterosalpingogram in the basic fertility work-up for improving reproductive success rates.In women undergoing IVF, low-quality evidence, including all of the studies reporting these outcomes, suggests that performing a screening hysteroscopy before IVF may increase live birth and clinical pregnancy rates. However, pooled results from the only two trials with a low risk of bias did not show a benefit of screening hysteroscopy before IVF.Since the studies showing an effect are those with unclear allocation concealment, we are uncertain whether a routine screening hysteroscopy increases live birth and clinical pregnancy, be it for all women, or those with two or more failed IVF attempts. There is insufficient data to draw conclusions about the safety of screening hysteroscopy. ispartof: COCHRANE DATABASE OF SYSTEMATIC REVIEWS vol:4 issue:4 ispartof: location:England status: published

Background: Endometriosis in adolescent girls is often diagnosed after a long delay. This diagnostic delay can be associated with more advanced stages of endometriosis and with a higher likelihood of fertility problems at a later age. Material and Methods: A systematic review of literature and quality assessment was performed in order to identify questionnaires that were developed to identify adult women with endometriosis. Based on these questionnaires, specific questions that had been reported to be predictive for endometriosis were selected and included in a newly composed questionnaire with the aim to identify adolescents at risk of developing endometriosis. Results: Based on the literature, we identified 5 questionnaires developed to identify adult women with endometriosis; this questionnaire contained 6 questions that had been reported to be predictive for adult endometriosis. These questions query age of menarche, cycle duration, dysmenorrhea, pain descriptors, dyschezia and urinary symptoms and were combined into a new self-report questionnaire aimed to identify adolescents at risk to develop endometriosis. Conclusion: We developed a self-report questionnaire aimed to identify adolescents at risk to develop endometriosis based on questions from self-report questionnaires that have been reported to identify adult women with endometriosis.

This prospective pilot study was designed to induce endometriosis in a mouse model using laparoscopy, a less invasive and more precise approach than laparotomy. We aimed to achieve a peritoneal implant rate of at least 50% by varying both duration of anesthesia and intra-abdominal insufflation pressure.Female BALB/cANnCrl mice in metestrus or diestrus were used as donors (n = 5) or recipients (n = 20) of uterine transplant tissue. Each recipient mouse was laparoscopically inoculated with 10 uterine pieces (range: 10-12) from donor mice into the abdominal cavity. Before starting the study, recipient mice were randomly assigned to 4 groups with variable duration of anesthesia (ketamine/xylazine or pentobarbital) and variable intra-abdominal pressure (5 or 15 mm Hg). One week after laparoscopy, endometriosis incidence and peritoneal implant take rate were documented visually during laparotomy. The retrieved lesions were histologically analyzed.Laparoscopic inoculation of uterine pieces in recipient mice resulted in an endometriosis incidence of 100% (20/20 animals) and an individual peritoneal implant take rate of 60% (121/206), ranging from 17% (2/12) till 83% (10/12), without differences between the 4 subgroups, and with a histological confirmation rate of 92% (58/63).To the best our knowledge, this is the first report showing that endometriosis can be induced by laparoscopic surgery in rodents, with a 100% incidence and a median peritoneal implant take rate of 60%. This laparoscopic model offers important advantages over traditional laparotomy models that are limited by surgery-associated trauma and/or adhesion formation.

Endometriosis is a common incurable inflammatory disorder that is associated with debilitating pelvic pain in women. Macrophages are central to the pathophysiology of endometriosis: they dictate the growth and vascularization of endometriosis lesions and more recently have been shown to promote lesion innervation. The aim of this study was to determine the mechanistic role of macrophages in producing pain associated with endometriosis. Herein, we show that macrophage depletion in a mouse model of endometriosis can reverse abnormal changes in pain behavior. We identified that disease-modified macrophages exhibit increased expression of IGF-1 in an in vitro model of endometriosis-associated macrophages and confirmed expression by lesion-resident macrophages in mice and women. Concentrations of IGF-1 were elevated in peritoneal fluid from women with endometriosis and positively correlate with their pain scores. Mechanistically, we demonstrate that macrophage-derived IGF-1 promotes sprouting neurogenesis and nerve sensitization in vitro. Finally, we show that the Igf-1 receptor inhibitor linsitinib reverses the pain behavior observed in mice with endometriosis. Our data support a role for macrophage-derived IGF-1 as a key neurotrophic and sensitizing factor in endometriosis, and we propose that therapies that modify macrophage phenotype may be attractive therapeutic options for the treatment of women with endometriosis-associated pain.—Forster, R., Sarginson, A., Velichkova, A., Hogg, C., Dorning, A., Horne, A. W., Saunders, P. T. K., Greaves, E. Macrophage-derived insulin-like growth factor-1 is a key neurotrophic and nerve-sensitizing factor in pain associated with endometriosis.

Background Individualization of the follicle-stimulating hormone (FSH) starting dose is considered standard clinical practice during controlled ovarian stimulation (COS) in patients undergoing assisted reproductive technology (ART) treatment. Furthermore, the gonadotropin dose is regularly adjusted during COS to avoid hyper- or hypo-ovarian response, but limited data are currently available to characterize such adjustments. This review describes the frequency and direction (increase/decrease) of recombinant-human FSH (r-hFSH) dose adjustment reported in clinical trials. Methods We evaluated the proportion of patients undergoing ART treatment who received ≥ 1 r-hFSH dose adjustments. The inclusion criteria included studies (published Sept 2007 to Sept 2017) in women receiving ART treatment that allowed dose adjustment within the study protocol and that reported ≥ 1 dose adjustments of r-hFSH; studies not allowing/reporting dose adjustment were excluded. Data on study design, dose adjustment and patient characteristics were extracted. Point-incidence estimates were calculated per study and overall based on pooled number of cycles with dose adjustment across studies. The Clopper–Pearson method was used to calculate 95% confidence intervals (CI) for incidence where adjustment occurred in Results Initially, 1409 publications were identified, of which 318 were excluded during initial screening and 1073 were excluded after full text review for not meeting the inclusion criteria. Eighteen studies (6630 cycles) reported dose adjustment: 5/18 studies (1359 cycles) reported data for an unspecified dose adjustment (direction not defined), in 10/18 studies (3952 cycles) dose increases were reported, and in 11/18 studies (5123 cycles) dose decreases were reported. The studies were performed in women with poor, normal and high response, with one study reporting in oocyte donors and one in obese women. The median day that dose adjustment was permitted was Day 6 after the start of treatment. The point estimates for incidence (95% CI) for unspecified dose adjustment, dose increases, and dose decreases were 45.3% (42.7, 48.0), 19.2% (18.0, 20.5), and 9.5% (8.7, 10.3), respectively. Conclusions This systematic review highlights that, in studies in which dose adjustment was allowed and reported, the estimated incidence of r-hFSH dose adjustments during ovarian stimulation was up to 45%.

Endometriosis is an important gynecological disease, affecting 10% of reproductive age women, and associated with pain, infertility, reduced quality of life, and high health economic cost. Except for ultrasound detection of ovarian endometriotic cysts, the gold standard for diagnosis is laparoscopy, leading to diagnostic delays of 5–10 years. Accurate noninvasive biomarkers are needed, especially for symptomatic women with a normal gynecological ultrasound, to triage them towards medical or surgical treatment and to monitor their treatment outcome. Such biomarkers are not available today, largely because the research focus has been on discovery, not on reproducibility and validation. Academia/industry partnerships can move this field forward by validation of promising markers, consensus on endometriosis phenotypes/controls and desirable accuracy (sensitivity/specificity). Such partnerships should increase the quality and reproducibility of target discovery work and foster global consensus on the use of relevant preclinical/animal models, if they are managed with complete (financial) transparency and with the aim to translate innovation into products benefiting patients. It is essential that mutual objectives are clarified between industry and academia partners including intellectual property policy, critical decision points, funding agreements, milestones and timelines, with a clear strategy for project termination/change of strategy, a restriction on publications till new discoveries have been patented, considering that a minority of novel findings can be translated into new therapeutic targets, diagnostics, or marketed products.

Background: This study compared preference ratings of women with infertility and nurses before and after simulated injection, and handling errors, with the GONAL-f®, Bemfola®, Ovaleap® and Rekovelle® pen injectors. Research design and methods: Injector-naïve women and injector-experienced fertility nurses tested injectors with masked labels in a randomized testing order. Injections were made into a foam pad and injectors were rated before and after use. Handling errors were recorded during the study. Ratings and errors were compared between pen injectors using ordinal or Poisson linear mixed models adjusted for testing order. Results: 120 women and 60 nurses participated. All participants tested GONAL-f and Bemfola injectors. Because of their similarity, participants tested either Rekovelle (71 women; 30 nurses) or Ovaleap (49 women; 30 nurses) injectors. The ratings from women were higher for GONAL-f vs other injectors after simulated use (p < 0.001 for all comparisons). Fertility nurses rated GONAL-f injector higher than other injectors both before and after use (p < 0.01 for all comparisons). Adjusted rates of total handling errors were lower with the GONAL-f vs other injectors (p < 0.001 for all comparisons) for both groups. Conclusions: GONAL-f injector was rated significantly higher than other injectors, which may be related to less handling errors observed with the GONAL-f injector. ispartof: EXPERT OPINION ON DRUG DELIVERY vol:16 issue:9 pages:1003-1014 ispartof: location:England status: published

Endometrial disorders represent a major gynaecological burden. Current research models fail to recapitulate the nature and heterogeneity of these diseases, thereby hampering scientific and clinical progress. Here we developed long-term expandable organoids from a broad spectrum of endometrial pathologies. Organoids from endometriosis show disease-associated traits and cancer-linked mutations. Endometrial cancer-derived organoids accurately capture cancer subtypes, replicate the mutational landscape of the tumours and display patient-specific drug responses. Organoids were also established from precancerous pathologies encompassing endometrial hyperplasia and Lynch syndrome, and inherited gene mutations were maintained. Endometrial disease organoids reproduced the original lesion when transplanted in vivo. In summary, we developed multiple organoid models that capture endometrial disease diversity and will provide powerful research models and drug screening and discovery tools.

RESEARCH QUESTION: A number of live-birth predictive models are available, and despite clinical interest these are rarely used owing to poor performance. In addition, no predictive models specifically for poor ovarian responders (POR) are available. The aim of the current project was to develop a clinically applicable tool for predicting live birth for PORs receiving recombinant human FSH [r-hFSH]. DESIGN: A model was developed to predict live birth in PORs receiving r-hFSH, using data from the ESPART trial. Initially, two models were developed separately: one for patients with data from a previous assisted reproductive technology (ART) cycle and one for ART treatment-naïve patients. Subsequently, the simplified Poor Responder Outcome Prediction (PROsPeR) concept was derived. RESULTS: PROsPeR considers three predictors and categorizes PORs into three scores, with predicted the live-birth rate divided by three with each worsening category. When adequately calibrated, a discrimination score up to area under the receiver operating characteristic (AUCROC) (95% CI) of 0.84 (0.79 to 0.88) was observed, which is superior to previously published models. Lower discriminations were observed when the PROsPeR model was used to evaluate the patients who received both r-hFSH and recombinant human LH in the ESPART study (AUCROC [95% CI] 0.66 [0.61 to 0.71]) and when all the patients included in the ESPART study were evaluated (AUCROC [95% CI] 0.68 [0.61 to 0.72]). CONCLUSIONS: This model, specific to PORs receiving r-hFSH, constitutes the best compromise between precision and simplicity, and is suitable for routine practice. ispartof: REPRODUCTIVE BIOMEDICINE ONLINE vol:37 issue:1 pages:43-52 ispartof: location:Netherlands status: published

Background: Endometriosis is a common disorder that affects 6–10% of reproductive age women. In a previous study, we demonstrated that a polymorphism in let-7 microRNA-binding site in the 3' untranslated region of the KRAS gene was found in 31% of subjects with endometriosis resistant to medical therapy. This polymorphism was now tested in a large, case-control study. Methods: Peripheral blood or peritoneal biopsies from 2,077 European subjects with or without endometriosis and known infertility were tested for the presence of the variant allele using polymerase chain reaction. Results: Histologically proven endometriosis was found in 1,140 subjects, while 937 subjects were disease free. Variant allele carrier rates in subjects with and without endometriosis were 15.7 and 15.1%, respectively. No association between the variant KRAS allele and stage of the disease, age at surgery, body mass index, or type of infertility was identified. Conclusion: A germ-line single-nucleotide polymorphism in the let-7 microRNA-binding site of the KRAS gene was not associated with sporadic endometriosis in an infertile Caucasian population in this large case-control study. However, it remains possible that this gene variant may be a marker of treatment resistance. Further studies on the role of this polymorphism in endometriosis are needed.

This study aimed to investigate the characteristics of symptoms related to the menstrual cycle and their impact on social activities in young teenage girls. Between March and June 2009, all girls born in 1996 who were residents of eight regions in Flanders (Belgium) received a semi-structured questionnaire, including questions about the age of menarche, characteristics of the menstrual cycle, and its impact on social activities. Participants were 792 13-year-old girls (15.7 % of the target population). Out of 363 (47.2 % of participants) postmenarcheal girls, 41.6 % (95 % confidence interval (CI) 36.4-47.0 %) reported painful menstruations. The proportion of girls with painful menstrual periods decreased approximately 16 % with each year the age at menarche increased (relative risk (RR) = 0.84; 0.73-0.98; p 0.05) and was positively correlated with the amount of blood loss (RR = 0.33; 0.16-0.67; p 0.05 when little and 1.85; 1.49-2.31; p 0.001 when abundant, compared to average). One in four (25.4 %) postmenarcheal girls indicated a negative impact of menstruation on social activities, but this proportion was significantly higher in girls who experienced menstruation as painful (41.3 %) compared to those who did not (14.2 %).Early menstrual complaints are common in young adolescent girls and the likelihood of pain increased significantly with lower menarcheal age. What is Known? • Menstrual cycle-related symptoms may negatively interfere with school absence and social activities. • Early menarche and severe dysmenorrhea are correlated with endometriosis. What is New? • In this large population-based study on the characteristics of the menstrual cycle in young teenage girls at or shortly after menarche, painful menstruation was highly prevalent (41.7 %), but related school absenteeism was low (3.2 %). The likelihood of pain increased significantly with lower menarcheal age. • The findings support the need for a systematic evaluation of the characteristics of the menstrual cycle shortly after menarche.

Endometrial receptivity is still questioned today in women with endometriosis. The aim of this study was to assess the endometrial receptivity gene signature in patients with different stages of endometriosis by investigating transcriptomic modifications of their endometrium using the endometrial receptivity array (ERA) test. A prospective, interventional multicentre pilot trial was designed and implemented in two university-affiliated infertility units from Belgium and Spain. Gene expression microarray was used to diagnose the receptivity status by quantifying the expression of 238 specific genes directly related to human endometrial receptivity. Unsupervised hierarchical clustering showed no clustering of samples based on endometriosis stages. Two subgroups of samples clustered together corresponding on the day of the cycle in which the biopsy was taken (day 18 versus days 19-20). None of the 238 genes present in the ERA array were significantly over- or under- expressed in any of different stages of the disease compared with controls. Minimal differences were found when looking at the functional profile, suggesting that the possible effect from a clinical point of view may be meaningless. Endometrial receptivity gene signature during the implantation window does not vary significantly among patients with endometriosis even considering different stages compared with healthy women.