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Background Ovarian stimulation during medically assisted reproduction treatment should be individualized to optimize outcomes and reduce complications. This study assessed whether use of the recombinant human follicle-stimulating hormone (r-hFSH) pen injector allowing small 12.5 IU dose increments resulted in lower r-hFSH dose per oocyte retrieved in a subgroup of patients at risk of OHSS, compared with r-hFSH injection devices allowing only 37.5 IU increments. Methods This multicenter, comparative, observational study evaluated patients from a prospective (study group) and historical (control group) cohort. The study group enrolled 1783 patients using the redesigned r-hFSH pen injector (GONAL-f®, Merck Healthcare KGaA, Darmstadt, Germany) from a prospective phase IV, non-interventional, open-label study, conducted in Korea, Vietnam, Indonesia, and China. The control group consisted of 1419 patients from a historical study using r-hFSH devices allowing 37.5 IU increments. In the study group, 397 patients were considered at risk of OHSS; this information was unavailable for the control group, so biomarkers and patient characteristics were used to match 123 patients from the study group and control group. Each center adhered to standard practice; starting dose and intra-cycle dose adjustments were allowed at any point. The primary endpoint, amount of r-hFSH (IU) administered per oocyte retrieved, was assessed in matched patients only. Additional outcomes and safety were assessed in the overall populations. Results Baseline characteristics were comparable between groups. Mean (SD) total dose of r-hFSH administered per oocyte retrieved in patients at risk of OHSS, was significantly lower in the study group compared with the control group (132.5 [85.2] vs. 332.7 [371.6] IU, P < 0.0001, n = 123). Implantation rate, clinical pregnancy rate, and live birth rates in the overall study and control groups were 30.0 vs. 20.6%, 50.3 vs. 40.7%, and 43.8 vs. 34.0%, respectively. OHSS incidence was significantly lower in the study group compared with the control group (27/1783 [1.5%] vs. 57/1419 [4.0%] patients, P < 0.0001). AEs were reported by 5.0% of patients in the study group. Conclusions A significantly lower r-hFSH dose per oocyte retrieved and lower OHSS incidence were observed in patients using the redesigned injector compared with patients using other injection devices.

A high ovarian response to conventional ovarian stimulation (OS) is characterized by an increased number of follicles and/or oocytes compared with a normal response (10-15 oocytes retrieved). According to current definitions, a high response can be diagnosed before oocyte pick-up when >18-20 follicles ≥11-12 mm are observed on the day of ovulation triggering; high response can be diagnosed after oocyte pick-up when >18-20 oocytes have been retrieved. Women with a high response are also at high risk of early ovarian hyper-stimulation syndrome (OHSS)/or late OHSS after fresh embryo transfers. Women at risk of high response can be diagnosed before stimulation based on several indices, including ovarian reserve markers (anti-Müllerian hormone [AMH] and antral follicle count [AFC], with cutoff values indicative of a high response in patients with PCOS of >3.4 ng/mL for AMH and >24 for AFC). Owing to the high proportion of high responders who are at the risk of developing OHSS (up to 30%), this educational article provides a framework for the identification and management of patients who fall into this category. The risk of high response can be greatly reduced through appropriate management, such as individualized choice of the gonadotropin starting dose, dose adjustment based on hormonal and ultrasound monitoring during OS, the choice of down-regulation protocol and ovulation trigger, and the choice between fresh or elective frozen embryo transfer. Appropriate management strategies still need to be defined for women who are predicted to have a high response and those who have an unexpected high response after starting treatment. ispartof: BEST PRACTICE & RESEARCH CLINICAL OBSTETRICS & GYNAECOLOGY vol:86 ispartof: location:Netherlands status: published

Two observational studies in the Russian Federation described patient demographics/clinical decision for treatment with recombinant human follicle-stimulating hormone:recombinant human luteinizing hormone (r-hFSH:r-hLH) 2:1 combination for ovarian stimulation (OS) during assisted reproductive technology (ART) and outcomes, respectively. The first (prospective) study enrolled 500 patients. After post-hoc regrouping to assign patients to discrete groups, 378 (75.6%) met the local Russian label for an r-hFSH:r-hLH 2:1 combination, 105 (21%) were treated according to other physician preference, and 17 (3.4%) met only the ESHRE Bologna criteria for a poor ovarian response. The clinical pregnancy rate per cycle was 30.4%. A total of 158/175 (90.3%) women achieving clinical pregnancy in the prospective study participated in the second (retrospective) study. The live birth rate per cycle was 25.8%. No new safety concerns were reported. These results support the use of the r-hFSH:r-hLH 2:1 combination in patients with a poor/suboptimal response to OS for ART treatment in the Russian Federation. ispartof: BEST PRACTICE & RESEARCH CLINICAL OBSTETRICS & GYNAECOLOGY vol:85 issue:Pt B pages:134-148 ispartof: location:Netherlands status: published

Various interventions have been proposed to improve embryo implantation in IVF. Among these, intrauterine injections of human chorionic gonadotropin seem to have promising results. Consequently, we conducted a review and meta-analysis to assess IVF outcomes by comparing couples who underwent intrauterine hCG injection transfer versus those who underwent embryo transfer with intrauterine injection of placebo, or without any additional intervention. The primary outcome was the clinical pregnancy rate. Secondary outcomes were the implantation rate, miscarriage rate, and live birth rate. A meta-analysis was conducted using the random effects model, while bias within studies was detected using the Cochrane risk of bias tool. Ectopic pregnancies and stillbirths were also assessed. The clinical pregnancy (RR 1.38, 95% CI 1.17−1.62, p < 0.0001) and implantation rate (RR 1.40, 95% CI 1.12−1.75, p = 0.003) were significantly higher in women who underwent hCG injection than in the control group. These significant effects persisted only in women who underwent cleavage-stage embryo transfer. No significant differences between groups were observed in the other secondary outcomes. In conclusion, our systematic review and meta-analysis demonstrate that intrauterine injection of hCG could be a valuable approach in women who undergo cleavage-stage embryo transfer. Given the lack of data about the live birth rate, caution should be exercised in interpreting these data. ispartof: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES vol:23 issue:20 ispartof: location:Switzerland status: published

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

Although the full primary structures of the alfa and beta subunits of reference r-hFSH-alfa and its biosimilars are identical, cell context-dependent differences in the expressing cell lines and manufacturing process can lead to variations in glycosylation profiles. In the present study, we compared the structural features of reference r-hFSH-alfa with those of five biosimilar preparations approved in different global regions outside Europe (Primapur®, Jin Sai Heng®, Follitrope®, Folisurge®, and Corneumon®) with respect to glycosylation, macro- and microheterogeneity, and other post-translational modifications and higher order structure. The mean proportion of N-glycosylation-site occupancy was highest in reference r-hFSH-alfa, decreasing sequentially in Primapur, Jin Sai Heng, Corneumon, Follisurge and Follitrope, respectively. The level of antennarity showed slightly higher complexity in Corneumon, Primapur and Follitrope versus reference r-hFSH-alfa, whereas Jin Sai Heng and Folisurge were aligned with reference r-hFSH-alfa across all N-glycosylation sites. Sialylation level was higher in Corneumon and Follitrope, but small differences were detected in other biosimilar preparations compared with reference r-hFSH-alfa. Jin Sai Heng showed higher levels of N-glyconeuramic acid than the other preparations. Minor differences in oxidation levels were seen among the different products. Therefore, in summary, we identified var ious differences in N-glycosylation occupancy, antennarity, sialylation and oxidation between reference r-hFSH-alfa and the biosimilar preparations analyzed. ispartof: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES vol:23 issue:12 ispartof: location:Switzerland status: published

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.

Background Recombinant human follitropin alfa (r-hFSH) is used for ovarian stimulation as part of medically assisted reproduction. There is a risk for ovarian hyperstimulation syndrome (OHSS) with r-hFSH treatment, and an increased risk for thromboembolic events in the presence of pregnancy with OHSS. Objectives To report the frequency of OHSS and thromboembolism with originator follitropin alfa (GONAL-f) based on the Global Safety Database of Merck KGaA, Darmstadt, Germany and a systematic review of published data. Data Sources Reports of OHSS and thromboembolism were obtained from the Global Safety Database of Merck KGaA, Darmstadt, Germany from 20 October 1995 to 19 October 2018. The systematic review was based on MEDLINE and Embase searches from inception to 19 October 2018. Study Eligibility Criteria Patients receiving GONAL-f for ovulation induction or ART, with a starting dose within the range included in the prescribing information and providing information on the occurrence of OHSS and/or thromboembolism. Study Appraisal and Synthesis Matches In the Global Safety Database of Merck KGaA, Darmstadt, Germany there were an estimated 16,525,975 treatment cycles since 20 October 1995; 1110 reported cases of OHSS and 80 reported cases of thromboembolic events (reporting rates 6.7 and 0.48 per 100,000 treatment cycles, respectively). The systematic review identified 45 studies (5186 patients exposed to GONAL-f; 5240 treatment cycles). There were 272 reports of OHSS (5190 [5.19%] per 100,000 treatment cycles), including 10 cases of severe OHSS (191 [0.19%] per 100,000 treatment cycles). Limitations There may be the potential for under-reporting of safety outcomes in the literature, and under-reporting is a well-known phenomenon in spontaneous reporting databases. Conclusion and Implications of Key Findings Our analyses demonstrate low rates of OHSS and thromboembolism with GONAL-f. Electronic Supplementary Material The online version of this article (10.1007/s12325-020-01512-w) contains supplementary material, which is available to authorized users.

Randomized controlled trials (RCTs) are the cornerstone of evidence-based medicine. In this series in Fertility and Sterility, several aspects of RCTs are discussed, with contributions on multicenter RCTs, different international settings, and integrity of RCTs. The present contribution deals with methodologic issues. We discuss different types of RCTs based on null hypothesis (superiority vs. noninferiority vs. equivalence) as well as frequentist versus Bayesian interpretation. We also discuss the use of RCTs in the era of personalized medicine and RCTs to address diagnostic and prognostic questions. Finally, we address the use of big data compared with the use of RCTs.

Cycle monitoring via ultrasound and serum-based hormonal assays during medically assisted reproduction (MAR) can provide information on ovarian response and assist in optimizing treatment strategies in addition to reducing complications such as ovarian hyperstimulation syndrome (OHSS). Two surveys conducted in 2019 and 2020, including overall 24 fertility specialists from Europe, Asia and Latin America, confirmed that the majority of fertility practitioners routinely conduct hormone monitoring during MAR. However, blood tests may cause inconvenience to patients. The reported drawbacks of blood tests identified by the survey included the validity of results from different service providers, long waiting times and discomfort to patients due to travelling to clinics for tests and repeated venepunctures. Historically, urine-based assays were used by fertility specialists in clinics but were subsequently replaced by more practical and automated serum-based assays. A remote urine-based hormonal assay could be an alternative to current serum-based testing at clinics, reducing the inconvenience of blood tests and the frequency of appointments, waiting times and patient burden. Here we provide an overview of the current standard of care for cycle monitoring and review the literature to assess the correlation between urine-based hormonal assays and serum-based hormonal assays during MAR. In addition, in this review, we discuss the evidence supporting the introduction of remote urine-based hormonal monitoring as part of a novel digital health solution that includes remote ultrasound and tele-counselling to link clinics and patients at home. Supplementary Information The online version contains supplementary material available at 10.1007/s43032-021-00754-5.

PurposeTo determine the pattern of dose adjustment of recombinant human follicle-stimulating hormone alfa (r-hFSH-alfa) during ovarian stimulation (OS) for assisted reproductive technology (ART) in a real-world setting.MethodsThis was an observational, retrospective analysis of data from an electronic de-identified medical records database including 39 clinics in the USA. Women undergoing OS for ART (initiated 2009–2016) with r-hFSH-alfa (Gonal-f® or Gonal-f RFF Redi-ject®) were included. Assessed outcomes were patients’ baseline characteristics and dosing characteristics/cycle.ResultsOf 33,962 ART cycles, 13,823 (40.7%) underwent dose adjustments: 23.4% with ≥1 dose increase, 25.4% with ≥1 dose decrease, and 8.1% with ≥1 increase and ≥1 decrease. Patients who received dose adjustments were younger (mean [SD] age 34.8 [4.58] years versus 35.9 [4.60] years, p2 versus 25.5 [5.45] kg/m2, pConclusionsDose adjustment during OS is common in clinical practice in the USA and occurred more often in younger versus older patients, those with a high versus non-normal ovarian reserve or those with ovulation disorders/polycystic ovary syndrome versus other primary diagnoses of infertility.

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

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. ispartof: HUMAN REPRODUCTION vol:36 issue:6 pages:1469-1480 ispartof: location:England status: published

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.

STUDY QUESTION Is the microRNA (miRNA) expression pattern of cumulus oophorus cells (COCs) in women undergoing medically assisted reproduction (MAR) procedures differentially modulated according to patient age and gonadotropin treatment strategy? SUMMARY ANSWER Maternal age is an independent factor impacting miRNA expression in COCs while gonadotropin treatment may affect follicular miRNA expression and IVF efficacy. WHAT IS KNOWN ALREADY Epigenetic mechanisms in female infertility are complex and poorly studied. DNA methylation, histone modifications, miRNAs and nucleosome positioning influence cellular machinery through positive and negative feedback mechanisms either alone or interactively. miRNAs are important regulators during oogenesis, spermatogenesis and early embryogenesis, and are reported to play a role in regulating crosstalk between the oocyte and COCs. Although miRNome analysis has been performed in female human reproductive tissues (endometrium, myometrium, cervix and ovaries), epigenetic modifications in women with infertility have not been explored in detail. In addition, the impact of gonadotropin treatments during MAR on miRNA expression in COCs has not been fully investigated. STUDY DESIGN, SIZE, DURATION This study was carried out in 53 COC samples obtained from mature metaphase II (MII) oocytes in 53 women undergoing MAR treatment. A total of 38 samples for assay development were pooled by maternal age and gonadotropin treatment into four predetermined subgroups: ≥36 years and recombinant human FSH (r-hFSH), n = 10; ≥36 years and r-hFSH+ recombinant human-luteinizing hormone (r-hLH), n = 10; ≤35 years and r-hFSH, n = 9; ≤35 years and r-hFSH+r-hLH, n = 9. miRNome profiles were determined and compared between subgroups. Expression of defined miRNAs was validated in the remaining fifteen samples, representative of each subgroup, by quantitative polymerase chain reaction (PCR). PARTICIPANTS/MATERIALS, SETTING, METHODS COCs were processed for miRNA-enriched total RNA extraction and pooled in homogeneous subgroups to obtain a sufficient amount and quality of starting material to perform the analysis. Each pooled sample underwent miRNA profiling using PCR assay system to examine expression of 752 human miRNAs without pre-amplification. Data were analyzed using the delta-delta Ct method for relative quantitation and prediction of target genes (with at least four algorithms predicting the same miRNA-gene interaction pair (HIT)>4). The miRSystem database provided functional annotation enrichment (raw P-value MAIN RESULTS AND THE ROLE OF CHANCE We found distinctive miRNA expression profiles in each subgroup correlating with age and MAR stimulation. In addition, a number of selective and co-expressed miRNAs were revealed by comparative analysis. A cluster of 37 miRNAs were commonly but differentially expressed in all four pools. Significant differences were observed in expression regulation of 37 miRNAs between age groups (≤35 or ≥36) in women receiving r-hFSH+r-hLH compared to those receiving r-hFSH alone. Higher concentrations and increased numbers of miRNAs were recorded in younger than in older patients, regardless of treatment. Functional and expression studies performed to retrieve common miRNome profiles revealed an enrichment of biological functions in oocyte growth and maturation, embryo development, steroidogenesis, ovarian hyperstimulation, apoptosis and cell survival, glucagon and lipid metabolism, and cell trafficking. The highest scored pathways of target genes of the 37 common miRNAs were associated with mitogen-activated protein kinase (MAPK) signaling pathways, G alpha signaling, transcription regulation, tight junctions, RNA polymerase I and III, and mitochondrial transcription. We identified a potential age- and MAR stimulation-dependent signature in the miRNA landscape of COCs. LIMITATIONS, REASONS FOR CAUTION We cannot rule out the possibility that other unknown individual genetic or clinical factors may have interfered with the reported results. Since miRNA profiling was conducted with a predefined array of target probes, other miRNA molecules, potentially modulated by age and hormonal stimulation, may have been missed in this study. WIDER IMPLICATIONS OF THE FINDINGS miRNA expression in COCs is modulated by gonadotropin treatment and correlates strongly with age. A better understanding of the expression patterns and functions of miRNAs may lead to the development of novel therapeutics to treat ovarian dysfunction and improve fertility in older women. STUDY FUNDING/COMPETING INTEREST This study was funded by Merck KGaA, Darmstadt, Germany. All authors declared no competing interest, except SL and TD who are fully employed by Merck KGaA. TRIAL REGISTRATION NUMBER N/A

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.

Time taken to achieve a live birth is an important consideration that is central to managing patient expectations during infertility treatment. However, time-related endpoints are not reported as standard in the majority of fertility-related clinical studies and there is no internationally recognized consensus definition for such endpoints. There is, therefore, a need for meaningful discussions around the selection of appropriate time-related treatment outcome measures for studies evaluating fertility treatments that will be relevant to diverse stakeholders (e.g. patients, healthcare professionals, clinical scientists, authorities and industry). Here, we provide a proposal for the evaluation of time-related outcome measures in fertility-related clinical studies, alongside associated definitions. ispartof: HUMAN REPRODUCTION vol:35 issue:8 pages:1732-1739 ispartof: location:England status: published

Several hormonal fertility medications have comparable effectiveness. A literature review was conducted into patients' assessments regarding seven medication characteristics including ‘side effects' and ‘ease of use'. Medline, CINAHL and PsycINFO were searched for female fertility patients' written assessments of a hormonal medication. The tools used were appraised and common (i.e. ≥10%) unpleasant consequences were distinguished from rare ones. The 35 eligible studies did not rely on valid and reliable tools and did not provide patient assessments regarding all seven medication characteristics for any of the globally used medications. Evidence on medications for oocyte triggering was absent and for induction of pituitary quiescence it was scarce. Regarding medications for ovarian stimulation and luteal support, evidence on general side effects (mostly headache), local side effects (mostly pain), ‘interference with home life' and ‘impact on psychological wellbeing' was found. Evidence on ‘ease of use' and ‘required education' was only identified for medication for ovarian stimulation. Evidence on ‘interference with work life' and ‘compliance worry' was absent. This review calls for randomized controlled trials questioning patients with valid and reliable tools. In the meantime, this review's summary of the best available evidence can be integrated in decision aids facilitating personalized and informed medication choices.

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.

Although most medical treatments are designed for the average patient with a one-size-fits-all-approach, they may not benefit all. Better understanding of the function of genes, proteins, and metabolite, and of personal and environmental factors has led to a call for personalized medicine. Personalized reproductive medicine is still in its infancy, without clear guidance on treatment aspects that could be personalized and on trial design to evaluate personalized treatment effect and benefit-harm balance. While the rationale for a personalized approach often relies on retrospective analyses of large observational studies or real-world data, solid evidence of superiority of a personalized approach will come from randomized trials comparing outcomes and safety between a personalized and one-size-fits-all strategy. A more efficient, targeted randomized trial design may recruit only patients or couples for which the personalized approach would differ from the previous, standard approach. Multiple monocenter studies using the same study protocol (allowing future meta-analysis) might reduce the major center effect associated with multicenter studies. In certain cases, single-arm observational studies can generate the necessary evidence for a personalized approach. This review describes each of the main segments of patient care in assisted reproductive technologies treatment, addressing which aspects could be personalized, emphasizing current evidence and relevant study design. ispartof: FERTILITY AND STERILITY vol:109 issue:6 pages:968-979 ispartof: location:United States status: published

Background Morphometric and morphokinetic evaluation of in vitro cultured human embryos allows evaluation without time restriction and reduces intra- and inter-observer variability. Even though these technologies have been reported to improve the quality of cleavage stage embryo evaluation during fresh culture, possible advantages in the evaluation of cryopreserved embryos have been scarcely explored. This study aims to compare morphometric and morphokinetic parameters between slow frozen and vitrified embryos and to determine their relationship to embryo survival and implantation rate (IR) after thawing/warming. Methods During fresh culture, morphometric characteristics (Total Cell Volume (TCV), symmetry, fragmentation and number of blastomeres) were measured in 286 thawed/warmed embryos. Likewise, after thawing/warming, similar morphometric characteristics were measured in 135 survived embryos. Moreover, morphokinetic parameters (time to mitosis resumption and time to compaction) were measured in 90 embryos after thawing/warming. Then, using linear regression, we investigated the differences between vitrified and slow frozen embryos and the relation of the measured characteristics to embryo survival and IR. Statistical corrections were applied to account for data clustering and for multiple testing. Results Vitrified embryos resume mitosis and start compaction significantly earlier than slow frozen embryos. Mitosis resumption rate was 82% for vitrified and 63% for slow frozen embryos and median time to mitosis resumption was 7.6 h and 13.1 h (p = 0.02), respectively. Compaction rate was 62% in vitrified and only 23% in slow frozen embryos. Median time to compaction was 18.1 h for vitrified embryos but, for slow frozen could not be computed since less than half of the slow frozen embryos reached compaction (p = 0.0001). Moreover, intact embryos resume mitosis significantly earlier than not intact ones regardless of the freezing method (rate: 79% vs. 66%, median time: 7.6 h vs 14.6 h, respectively, p = 0.03). Regarding morphometrics, slow frozen embryos showed lower TCV and higher blastomere symmetry after thawing than vitrified embryos despite having similar blastomere number. IR was related to blastomere number at cryopreservation in slow frozen embryos, but not in vitrified ones. Conclusions Interestingly, vitrified/warmed embryos undergo mitosis resumption and compaction significantly earlier than slow frozen/thawed embryos. However, the clinical use of this morphokinetic parameters still remains to be investigated in larger studies. Trial registration Retrospectively registered on December 15, 2015 NCT02639715 .

STUDY QUESTION Are progesterone vaginal pessaries 400 mg twice a day (bid) non-inferior to progesterone vaginal gel (90 mg) once a day (od) in the primary endpoint of clinical pregnancy rate after 38 days of luteal phase support in women undergoing in vitro fertilisation (IVF)? SUMMARY ANSWER Non-inferiority of progesterone vaginal pessaries 400 mg bid to progesterone 8% vaginal gel (90 mg od) was shown for clinical pregnancy rate after 38 days of luteal phase support. WHAT IS KNOWN ALREADY To maximise successful embryo transfer after IVF, additionally administered progesterone is used for proper endometrium transformation in the luteal phase. Vaginally administered progesterone results in adequate secretory transformation of the endometrium. STUDY DESIGN, SIZE, DURATION This multicentre, multinational, open, randomised, two-parallel group, non-inferiority Phase 3 clinical trial was carried out at 17 study sites in five European countries (Belgium, Bulgaria, Czech Republic, Hungary and Serbia) between October 2013 and August 2014. An interactive web response system (IWRS) was implemented for treatment allocation at the sites. Power analysis, based on the assumptions of a non-inferiority margin of −9%, a significance level of α 2.5% (one-sided), power 90%, at a reference pregnancy rate for the progesterone vaginal gel group of 30%, as well as applying a dropout rate of 10%, yielded a total number of 766 patients to be randomised. PARTICIPANTS/MATERIALS, SETTING, METHODS Women aged between 18 and 40 years with a clinical indication for IVF/intracytoplasmic sperm injection (ICSI) and embryo transfer were eligible to participate. The clinical pregnancy rate was assessed by fetal heart movement measured by transvaginal ultrasound at day 38 (D38) (primary endpoint) and D70. Also assessed were biochemical pregnancy rate (assessed by serum β-hCG ≥25 IU/L), clinical implantation rates at D38, patient evaluation of vaginal bleeding and discharge (assessed by diary) and adverse event (AE) incidence, severity and relationship to study medication. MAIN RESULTS AND THE ROLE OF CHANCE A total of 769 female patients were randomised to progesterone 400 mg vaginal pessaries bid (n = 385, 50.1%) or progesterone 90 mg vaginal gel od (n = 384, 49.9%). Patients receiving progesterone vaginal pessaries and progesterone vaginal gel were comparable in demographics, baseline characteristics and number of retrieved oocytes. In the full analysis set (FAS; n = 369 progesterone vaginal pessaries and n = 368 progesterone vaginal gel), clinical pregnancy rates on D38 were 38.3% for progesterone vaginal pessaries and 39.9% for progesterone vaginal gel. In the per protocol analysis set (PP; n = 357 progesterone vaginal pessaries and n = 356 progesterone vaginal gel), clinical pregnancy rates on D38 were 38.1% for progesterone vaginal pessaries and 40.4% for progesterone vaginal gel. For the differences in pregnancy rates between the progesterone vaginal pessaries group and the progesterone vaginal gel, the lower limit of the 97.5% CI was −8.6 and −9.5% for the FAS and PP datasets, respectively. The original prespecified non-inferiority margin of −9% was thus met in the FAS dataset but was marginally below this in the PP dataset. However, the pregnancy rate of the comparator was higher than the anticipated rate of 30%, and a predetermined logistic regression model including treatment group, country and age group effects without interaction terms showed non-inferiority of progesterone vaginal pessaries to progesterone vaginal gel for both the FAS and PP populations, in that the lower limits of the 95% CIs were above 0.7 for both analyses. As a result of this, the relevant authorities accepted to widen the acceptable non-inferiority margin to −10%, and as such both the FAS and PP populations succeeded in showing non-inferiority. Biochemical pregnancy and clinical implantation rates were comparable for both treatments. Both treatment groups showed similar high compliance throughout the study, and the safety profiles were also comparable between the groups. Drug-related AEs occurred with frequencies of 15.1% with progesterone vaginal pessaries and 14.4% with progesterone vaginal gel. LIMITATIONS, REASONS FOR CAUTION Clinical pregnancy rate is a surrogate for the outcome of live birth rate. WIDER IMPLICATIONS OF THE FINDINGS Progesterone 400 mg pessaries bid for luteal phase support is an effective, safe and tolerable treatment option for women undergoing IVF during ART. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by Actavis Group PTC ehf., Iceland, part of Teva Pharmaceuticals, and by L.D. Collins & Co. Ltd. Gedeon Richter plc has recently entered into a license and distribution agreement to commercialise the vaginal pessaries in the European Union (except Ireland/UK). The progesterone vaginal pessaries studied are now marketed as Cyclogest®, Amelgen®, Cyclovita®, Luteum and Cygest® throughout the EU, Asia and Middle East & North Africa. The competing interests are as follows. H.S.: employee of Gedeon Richter plc/PregLem S.A. C.K.: consultant to L.D. Collins & Co. Ltd and received consulting fees for work performed. T.D.H.: at the initiation and completion of this study, full professor at KU Leuven and Head of Leuven University Fertility Center at the University Hospital Gasthuisberg, Leuven, Belgium. In October 2015, T.D.H. became vice president of Global Medical Affairs Fertility at the pharmaceutical company Merck—marketing authorisation holder of the Progesterone vaginal gel (Crinone®)—and has remained a part-time professor at KU Leuven (Belgium) and adjunct professor at Yale University (New Haven, CT, USA). T.B.M.: at the initiation and completion of this study, employee of Actavis Group PTC ehf. I.K.: consultant to Actavis, later TEVA and received consulting fees for work performed. S.H.: at the initiation and completion of this study, employee of Actavis Group PTC ehf. Trial registration number EudraCT number 2013-001105-81 Trial registration date 2 July 2013 Date of first patient’s enrolment 9 October 2013

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.

There is a great need for a noninvasive diagnosis for endometriosis. Several biomarkers and biomarker panels have been proposed. Biomarker models consisting of CA-125, VEGF, Annexin V, and glycodelin/sICAM-1 were previously developed by our group. The objective of our current study was to assess the impact of technical and biological variability on the performance of those previously developed prediction models in a technical verification and a validation setting. The technical verification cohort consisted of peripheral blood plasma samples from a subset of the patients included in the original study of Vodolazkaia et al. (99 women with and 37 women without endometriosis). The validation study was done in plasma samples of an independent patient cohort (170 women with and 86 women without endometriosis). Single immunoassays were used for CA-125, VEGF-A, sICAM-1, Annexin V, and glycodelin. Statistical analyses were done using univariate and multivariate (logistic regression) approaches. The previously reported prediction models for endometriosis had a low performance in both the technical verification and validation setting. New prediction models were developed, which included CA-125, Annexin V, and sICAM-1, but CA-125 was the only marker that was retained in the models across the technical verification and validation study. Overall, successful validation of a biomarker model depends on several factors such as patient selection, collection methods, assay selection/handling, stability of the marker, and statistical analysis and interpretation. There is a need for standardized studies in large, well-defined patient cohorts with robust assay methodologies. ispartof: BIOMED RESEARCH INTERNATIONAL vol:2019 ispartof: location:United States status: published

Research question How much do patients with severe infertility and their gynaecologists value genetic parenthood relative to other key treatment characteristics? Design A discrete choice experiment included the following treatment characteristics: genetic parenthood, pregnancy rate, curing infertility, maternal health, child health and costs. The questionnaire was disseminated between 2015 and 2016 among Dutch and Belgian patients with severe infertility and their gynaecologists. Results The questionnaire was completed by 173 patients and 111 gynaecologists. When choosing between treatments that varied in safety, effectiveness and costs, the treatment's ability to lead to genetic parenthood did not affect the treatment preference of patients with severe infertility (n = 173). Genetic parenthood affected the treatment preference of gynaecologists (n = 111) less than all other treatment characteristics. Patients indicated that they would switch to a treatment that did not enable genetic parenthood in return for a child health risk reduction of 3.6%, a cost reduction of €3500, an ovarian hyperstimulation risk reduction of 4.6%, a maternal cancer risk reduction of 2.7% or a pregnancy rate increase of 18%. Gynaecologists made similar trade-offs. Conclusions While awaiting replication of this study in larger populations, these findings challenge the presumed dominant importance of genetic parenthood. This raises questions about whether donor gametes could be presented as a worthy alternative earlier in treatment trajectories and whether investments in novel treatments enabling genetic parenthood, like in-vitro gametogenesis, are proportional to their future clinical effect.

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.

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.

Study question Can a valid and reliable questionnaire be developed to assess patients' experiences with all of the characteristics of hormonal fertility medication valued by them? Summary answer The FertiMed questionnaire is a valid and reliable tool that assesses patients' experiences with all medication characteristics valued by them and that can be used for all hormonal fertility medications, irrespective of their route of administration. What is known already Hormonal fertility medications cause emotional strain and differ in their dosage regime and route of administration, although they often have comparable effectiveness. Medication experiences of former patients would be informative for medication choices. A recent literature review showed that there is no trustworthy tool to compare patients' experiences of medications with differing routes of administration, regarding all medication characteristics which patients value. Study design, size, duration The items of the new FertiMed questionnaire were generated by literature review and 23 patient interviews. In 2013, 411 IVF-patients were asked to retrospectively complete the FertiMed questionnaire to assess 1 out of the 8 different medications used for ovarian stimulation, induction of pituitary quiescence, ovulation triggering or luteal support. Participants/materials, setting, methods In total, 276 patients (on average 35 per medication) from 2 university fertility clinics (Belgium, the Netherlands) completed the FertiMed questionnaire (67% response rate). The FertiMed questionnaire questioned whether items were valued by patients and whether these items were experienced while using the assessed medication. Hence, the final outcome 'Experiences with Valued Aspects Scores' (EVAS) combined importance and experience ratings. The content and face validity, reliability, feasibility and discriminative potential of the FertiMed questionnaire were tested and changes were made accordingly. Main results and the role of chance Patient interviews defined 51 items relevant to seven medication characteristics previously proved to be important to patients. Item analysis deleted 10 items. The combined results from the reliability and content validity analysis identified 10 characteristics instead of 7. The final FertiMed questionnaire was valid (Adapted Goodness of Fit Index = 0.95) and all but one characteristic ('ease of use: disturbance') could be assessed reliably (Cronbach's α > 0.60). The EVAS per characteristic differed between the medications inducing pituitary quiescence (P = 0.001). Limitations, reason for caution As all eight medications prescribed in the recruiting clinics were questioned, sample sizes per medication were rather small for presenting EVAS per medication and for testing the discriminative potential of the FertiMed questionnaire. Wider implication of the findings The FertiMed questionnaire can be used for all hormonal fertility medications to assess in a valid and reliable way whether patients experience what they value regarding 10 medication characteristics (e.g. side effects and ease of use). Future randomized controlled trials (RCT) comparing medications could include the FertiMed questionnaire as a Patient Reported Experience Measure (PREM). Insights from these RCTs could be used to develop evidence-based decision aids aiming to facilitate shared physician-patient medication choices. Study funding/competing interests Funding was received from the University of Leuven and Amsterdam University Medical Centre. E.A.F.D. holds a postdoctoral fellowship of the Research Foundation of Flanders. T.D. was appointed Vice-President and Head Global Medical Affairs Fertility at Merck (Darmstadt, Germany) on 1 October 2015. The reported project was initiated and finished before this date. The other authors had no conflicts of interest to declare.

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.

Fetal microchimerism has been implicated in the etiology of autoimmune diseases. This study was done to test the hypothesis that male fetal microchimerism is present in eutopic and ectopic endometrium (EM) obtained from women with endometriosis but not in eutopic EM from women without endometriosis.A total of 31 patients were selected, including women with endometriosis (paired eutopic and ectopic EM; n = 19) and women without endometriosis (eutopic EM; n = 12). Tricolor interphase fluorescence in situ hybridization analysis was performed by cohybridization of CEP Y SpectrumAqua and CEP X SpectrumGreen (SG)/CEP Y SpectrumOrange probes.Ectopic EM from women with endometriosis had 75% XX chromosomes (double SG signals) and 25% X chromosomes (single SG signal). Y chromosomes were not observed in any of the eutopic/ectopic endometrial tissues from cases or controls.We were unable to confirm our hypothesis that male fetal microchimerism is present in eutopic and/or ectopic EM obtained from women with endometriosis.