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

Background: Specific polymorphisms might influence controlled ovarian stimulation in women undergoing assisted reproductive technologies (ARTs). Data regarding possible interactions of these polymorphisms are still scanty. The aim of this analysis was to evaluate the effect of polymorphisms of gonadotropins and their receptors in women undergoing ART. Methods: A total of 94 normogonadotropic patients from three public ART units were enrolled. Patients underwent a gonadotropin releasing hormone (GnRH) long down-regulation protocol with a starting dose of 150 IU of recombinant follicular stimulating hormone (FSH) daily. Eight polymorphisms were genotyped. Results: A total of 94 women (mean age 30.71 ± 2.61) were recruited. Fewer fertilized and mature oocytes were retrieved in homozygous carriers of luteinizing hormone/choriogonadotropin receptor (LHCGR) 291 (T/T) than in heterozygous C/T carriers (p = 0.035 and p = 0.05, respectively). In FSH receptor (FSHR) rs6165 and FSHR rs6166 carriers, the ratio between total gonadotropin consumption and number of oocytes retrieved differed significantly among three genotypes (p = 0.050), and the ratio was lower in homozygous A/A carriers than in homozygous G/G and heterozygous carriers. Women who co-expressed allele G in FSHR-29 rs1394205 and FSHR rs6166 and allele C LHCGR 291 rs12470652 are characterized by an increased ratio between total FSH dosage and number of oocytes collected after ovarian stimulation (risk ratio: 5.44, CI 95%: 3.18–7.71, p < 0.001). Conclusions: Our study demonstrated that specific polymorphisms affect the response to ovarian stimulation. Despite this finding, more robust studies are required to establish the clinical utility of genotype analysis before ovarian stimulation.

Various preparations of follicle-stimulating hormone (FSH) are commercially available; however, they differ in glycoforms composition and purity owing to their respective sources. Additional chemical/physical changes can also be introduced during manufacturing and can impact their biological activity (biopotency), which is routinely assessed using an in vivo bioassay (Steelman–Pohley). This study aimed to determine whether an in vitro bioassay could assess biopotency by distinguishing between r-hFSH chemical/physical variants with similar ability to the in vivo bioassay. The specific activity (units of biological activity per mg of product) of variants of r-hFSH generated through enrichment (acidic/basic), stress (oxidative/acidic pH) and enzymatic treatment (desialylation and desialylation/degalactosylation) was compared using the in vivo and in vitro bioassays. The in vitro bioassay reliably detected potential chemical/physical modifications in r-hFSH variants that may impact biopotency. Overall, the methods demonstrated a comparable ability to detect changes in specific activities due to chemical/physical differences in r-hFSH variants. These data indicate that the in vitro bioassay is suitable to replace the in vivo bioassay.

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.

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

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.

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

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

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

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

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

Study question How can cycle monitoring using a urine-based hormonal assay device improve current clinical practice in medically assisted reproduction (MAR)? Summary answer A urine-based hormonal assay has the potential to overcome the inconvenience of blood tests and reduce the frequency of appointments, waiting times and patient burden. What is known already Cycle monitoring via ultrasound and serum-based hormonal assays during MAR can provide information on the ovarian response and assist in optimising treatment strategies and reducing complications, such as ovarian hyperstimulation syndrome (OHSS). However, blood tests may cause inconvenience to patients due to repeated venepuncture and the need for frequent clinic appointments. Urine-based assays have been historically used by fertility specialists in clinics, but since got replaced by more practical and automated serum-based assays. Novel technology utilising rapid chromatographic immunoassay to test urinary reproductive hormones in a home setting could provide an alternative to current serum-based testing at clinics. Study design, size, duration A questionnaire was disseminated among 24 fertility specialists (2019–2020) on the use of ultrasound and serum-based hormone monitoring in clinical practice. In addition, the literature on the reliability of urine-based hormonal assays compared to serum-based hormonal assays during MAR was reviewed in order to examine if urine-based hormonal monitoring could be re-introduced in clinical practice using novel state-of-the-art technology. Participants/materials, setting, methods All 24 surveyed fertility specialists responded, representing 10 countries from across Europe, Asia and Latin America. Questions assessed the frequency and role of hormonal monitoring, the hormones tested and the drawbacks of blood tests. The PubMed search engine was used to search the Medline database for publications between 1960–2020 with (MeSH-) search terms related to cycle monitoring (e.g. fertility monitoring, controlled ovarian stimulation, ovulation confirmation) and hormonal assays (e.g. estrone–3-glucuronide or E1–3G). Main results and the role of chance The survey confirmed that many fertility practitioners (n = 22/24) routinely conducted hormone monitoring during MAR, primarily for guiding dose adjustments (n = 20/24) and indicating risk of OHSS (n = 20/24). The reported drawbacks of blood tests included validity of results from different service providers, long waiting times and discomfort to patients due to travelling to clinics for tests and repeated venepunctures. The hormones routinely checked were E2 (n = 22/22), P4 (n = 18/22) and LH (n = 15/22). The literature review revealed a relatively high correlation (correlation coefficients 0.85–0.95) between serum E2 and urinary E1–3G in gonadotrophin stimulated cycles (Lessing 1987, Catalan 1989, Rapi 1992 and Alper 1994). No studies assessed the correlation between serum P4 and urinary PdG or between serum LH and urinary LH in stimulated cycles. In natural cycles, the correlation coefficients between serum P4 and urinary PdG seemed to be slightly higher than those between serum E2 and urinary E1–3G (0.73–0.94 vs. 0.54–0.88) (Denari 1981, Munro 1991, Roos 2015, Stanczyk 1980). One study reported a moderate correlation coefficient (0.72) between serum and urinary LH in natural cycles (Roos 2015). Limitations, reasons for caution There is risk of selection-bias for fertility specialists included in survey, however, the 100% response rate is reassuring. The correlation coefficients between serum- and urine-based hormonal assay and the cost-effectiveness and time-efficiency of urinary assay should be confirmed in further clinical studies using a novel state-of-the-art remote urinary monitoring device. Wider implications of the findings: Remote hormonal monitoring can be part of a novel digital health solution that includes remote ultrasound and tele-counselling to link clinics and patients at home. Especially during the unprecedented times of the COVID–19 pandemic, the prospect of remote monitoring system has the potential to improve patient experience during fertility treatment. Trial registration number Not applicable

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

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

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

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.

ispartof: GYNECOLOGIC AND OBSTETRIC INVESTIGATION vol:85 issue:6 pages:451-453 ispartof: location:Switzerland status: published

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

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.

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

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