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The constant decline in fertility and older reproductive age is the major cause of low clinical pregnancy rates in industrialised countries. Epigenetic mechanisms impact on proper embryonic development in women undergoing in vitro fertilisation (IVF) protocols. Here, we describe the main epigenetic modifications that may influence female reproduction and could affect IVF success. Graphical Abstract

Object: To assess the impact of endometriosis on health-related quality of life (HRQoL) and work productivity. Design: Multicentre cross-sectional study with prospective recruitment. Setting: Sixteen clinical centers in ten countries. Patient(s): A total of 1,418 premenopausal women, aged 18-45 years, without a previous surgical diagnosis of endometriosis, having laparoscopy to investigate symptoms or to be sterilized. Intervention(s): None. Main Outcome Measure(s): Diagnostic delay, HRQoL, and work productivity. Result(s): There was a delay of 6.7 years, principally in primary care, between onset of symptoms and a surgical diagnosis of endometriosis, which was longer in centers where women received predominantly state-funded health care (8.3 vs. 5.5 years). Delay was positively associated with the number of pelvic symptoms (chronic pelvic pain, dysmenorrhoea, dyspareunia, and heavy periods) and a higher body mass index. Physical HRQoL was significantly reduced in affected women compared with those with similar symptoms and no endometriosis. Each affected woman lost on average 10.8 hours (SD 12.2) of work weekly, mainly owing to reduced effectiveness while working. Loss of productivity translated into significant costs per woman/week, from US$4 in Nigeria to US$456 in Italy. Conclusion(s): Endometriosis impairs HRQoL and work productivity across countries and ethnicities, yet women continue to experience diagnostic delays in primary care. A higher index of suspicion is needed to expedite specialist assessment of symptomatic women. Future research should seek to clarify pain mechanisms in relation to endometriosis severity. (Fertil Steril 2011; 96:366-73.)

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.

This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field. (C) 2018 by American Society for Reproductive Medicine.

In 2007, the WHO initiated an organizational structure for the 11th revision of the International Classification of Diseases (ICD). Effective deployment of ICD-derived tools facilitates the use and collection of health information in a variety of resource settings, promoting quantitatively informed decisions. They also facilitate comparison of disease incidence and outcomes between different countries and different health care systems around the world. The Department of Reproductive Health and Research (RHR) coordinates the revision of chapters 14 (diseases of the genitourinary system), 15 (pregnancy, childbirth, and puerperium), and 16 (conditions originating in the perinatal period). RHR convened a technical advisory group (TAG), the Genito-Urinary Reproductive Medicine (GURM) TAG, for the ICD revision. The TAG’s work reflects the collective understanding of sexual and reproductive health and is now available for review within the ICD-11 revision process. Copyright © 2012 S. Karger AG, Basel

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.

Item does not contain fulltext STUDY QUESTION: Can the differences in patients' and professionals' perspective regarding essential endometriosis care be accommodated in one set of key recommendations? SUMMARY ANSWER: Consensus between patients and professions on a key set of recommendations for essential endometriosis care was achieved. WHAT IS KNOWN ALREADY: Guideline development alone will not lead to healthcare improvement. Quality indicators are needed to monitor actual care and guideline adherence. These can help with better implementation of the ESHRE guidelines in European hospitals and thereby improve the quality of endometriosis care. The first step in the development of quality indicators is to select a compact set of key recommendations. STUDY DESIGN, SIZE AND DURATION: Using a RAND modified Delphi method, this study reports the systematic selection of key recommendations based on the ESHRE guideline 'Management of Women with Endometriosis' by an international expert panel of both patients and professionals during the study period of September 2015 and December 2015. PARTICIPANTS, SETTING, METHODS: An international panel of patients (n = 10) and medical professionals (n = 11) rated and prioritized the 83 recommendations extracted from the ESHRE guideline for relevance in three rounds. A strict consensus methodology was used to select key recommendations. The main outcome measure was one set of key recommendations for endometriosis care. MAIN RESULTS AND THE ROLE OF CHANCE: A representative set of 17 key recommendations was selected from the preliminary set of 83 recommendations. This selection covers all dimensions of endometriosis care, including diagnosis, treatment of endometriosis-associated pain, treatment of endometriosis-associated infertility and miscellaneous topics such as prevention, menopause and relationship with cancer. Of the 21 experts, 17 participated in at least one round while 16 (76.2%) participated in all 3 rounds. LIMITATIONS, REASONS FOR CAUTION: The feasibility of the selected key recommendations was not assessed in this study. As not all panel members took part in all three rounds, some response bias may have occurred. WIDER IMPLICATIONS OF THE FINDINGS: This set of key recommendations is the first step in the development of quality indicators for monitoring and improving endometriosis care. The set is generic and can be used in hospitals internationally. A practice test should be conducted to assess the feasibility of our key recommendations in clinical practice. STUDY FUNDING/COMPETING INTERESTS: No funding was received for the conduct of this study. Members of the EndoKey study group did not receive payment. The authors and members of the EndoKey study group have no conflict of interest.

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

BackgroundA Delphi consensus was conducted to evaluate 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.

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