STUDY QUESTION What are the current national medically assisted reproduction (MAR) data collection systems across EU Member States, and how can these countries contribute to a unique, cycle-by-cycle registry for the European Monitoring of Medically Assisted Reproduction (EuMAR) project? SUMMARY ANSWER The study identified significant variation in MAR data collection practices across Member States, with differences in data types, collection methods, and reporting requirements; the EuMAR project emerges as an opportunity to enhance data standardization and improve MAR data collection in the EU. WHAT IS KNOWN ALREADY There is a need for new approaches in MAR data collection that include long-term and cross border follow-up. The EuMAR project intends to establish a unified, cycle-by-cycle registry of data on MAR treatments in EU countries, from which accurate cumulative outcomes can be calculated. STUDY DESIGN, SIZE, DURATION This cross-sectional study involved a survey and interviews with stakeholders from 26 EU Member States conducted in 2023 over a period of seven months. PARTICIPANTS/MATERIALS, SETTING, METHODS Representatives from national competent authorities and professional associations involved in MAR data collection in EU countries were invited to complete the survey and interviewed to assess current data flows, information requirements, and their interest in the EuMAR project. MAIN RESULTS AND THE ROLE OF CHANCE Half of the participating countries reported having a national MAR registry with cycle-by-cycle data (n = 13), while 31% reported having a national registry with aggregated data (n = 8) and 19% reported having no national registry (n = 5). Of the countries with a national cycle-by-cycle registry, eight countries collect identifiable data, five countries collect pseudonymized data, and one country collects fully anonymized data. Informed consent is required in 10 countries. The main advantages that participants expected from a European registry like EuMAR were the possibility of obtaining national statistics in the absence of a national registry and improving the calculation of cumulative outcomes. LIMITATIONS, REASONS FOR CAUTION The results of the study are based on self-reported data, which may be subject to bias, however, the validity of the collected information was verified with different means, including follow-up calls for clarifications and sharing final transcript reports. The feasibility of the proposed data flow models will be tested in a pilot study. WIDER IMPLICATIONS OF THE FINDINGS Despite the heterogeneity of data collection practices across EU countries, the results show that stakeholders have high expectations of the benefits that the EuMAR registry can bring, namely the improvement of data consistency, cross-border comparability, and cumulative live birth rates, leading to better information for patients, health care providers and policy makers.

The major purpose of a couple at the first infertility appointment is to get a healthy baby as soon as possible. From diagnosis and decision on which assisted reproduction technique (ART) and controlled ovarian stimulation, to the selection of which embryo to transfer, the dedicated team of physicians and embryologists puts all efforts to shorten the time to pregnancy and live birth. Time seems thus central in assisted reproduction, and we can conveniently use it as a measure of treatment efficiency. How can we measure time to live birth? What timelines do we need to consider to evaluate efficiency? In this paper, we will discuss the importance of "Time" as a fundamental parameter for measuring ART success.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age, which in some case leads to infertility. This disorder is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Infertile PCOS women that need in vitro fertilization (IVF) have greater risk of ovarian hyperstimulation syndrome (OHSS) if conventional ovarian stimulation is used. In vitro oocyte maturation (IVM) is an alternative technique that prevents OHSS in infertile PCOS women. In the last decade, IVM protocols have improved, particularly with the development of biphasic IVM culture accounting for better pregnancy and live birth rates. This technique has been extended to other treatments like, fertility preservation, when patients have no time, or a contra-indication for ovarian stimulation, and poor responders. In this review, we will discuss IVM as a viable option for PCOS infertile patients. This article is categorized under: Reproductive System Diseases > Molecular and Cellular Physiology Reproductive System Diseases > Environmental Factors Reproductive System Diseases > Genetics/Genomics/Epigenetics.

Abstract Study question Which are the main factors on first oocyte retrievals influencing the time to achieve a live birth? Summary answer The number of oocytes collected on the first retrieval is the most important factor to decrease time to live birth. What is known already The goal of infertile couples when they attend a fertility clinic is to obtain a healthy baby as soon as possible. Cumulative live birth rate is today considered the most reliable estimate of ART success. However, the time used to achieve such goal is still not clear both to health professionals and patients. Although there is a general idea of which factors predict ART success, both clinicians and embryologists are still not aware of which variables can effectively influence the time to a live birth. Study design, size, duration We analyzed retrospectively 333 couples who performed their first fresh IVF/ICSI cycles from January 2015 to December 2018, along with their eventual subsequent FET and/or IVF/ICSI cycles, leading to 146 live births. The aim of this study was to use “Time” as an additional measure of ART success, and to identify which variable of the first oocyte retrieval has a major influence on time to live birth. Participants/materials, setting, methods We included in total 430 oocyte retrievals and 147 FET cycles. Oocyte donation cycles were excluded. Data were studied cumulatively until the childbirth (couples at risk) or until the last treatment record (censored couples). Cox Regression Model for survival analysis was used to study the variables that may influence the time to live birth, in order to take both confounding and collinearity into account. Main results and the role of chance We considered the date of the first oocyte retrieval as the starting point and the date of the first childbirth as the ending point to determine the time to live birth. The mean age of the woman at the first oocyte retrieval was 36.8±4.67, the cumulative pregnancy rate 43.5% (95%CI:41.77%;45.23%) and the live birth rate 34.0%(95%CI:32.32%;35.63%). As variables for the Cox Regression Model we selected the woman’s age and number of collected oocytes from the first oocyte retrieval. We also considered the number of frozen embryo transfers (FET). We have found a positive association between the number of oocytes collected at the first oocyte retrieval and the period until obtaining a healthy singleton (HR = 1.20;95%CI:1.105–1.297;p>0.001). Conversely, a negative association concerning the number of FET and time to live birth (HR = 0.32;95%CI:0.18–0.562;p>0.001) was demonstrated. Importantly, woman’s age, was not found to have a significant effect on time to live birth. Our results indicated that the number of oocytes collected at the first cycle, but not woman’s age, mostly affect time to live birth. Poor prognosis patients were found to be associated with several embryo transfers. Limitations, reasons for caution This is a retrospective study with a small number of cycles and freeze-all procedures were not included. Additional inclusion of freeze-all procedures in a larger study will be needed to confirm our preliminary results. Wider implications of the findings: This study identified oocyte number at first collection as a major influence on time to live birth. Increased attention to the “Time” parameter will be helpful for health professionals and patients, to further personalize reproductive treatment procedures, potentially decreasing psychological burdens associated with ART treatments. Trial registration number Not applicable

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. 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. 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. 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.

Mammalian females are born with a finite reserve of ovarian follicles, the functional units of the ovary. Building an ovarian follicle involves a complex interaction between multiple cell types, of which the oocyte germ cell and the somatic granulosa cells play a major role. Germ–somatic cell interactions are modulated by factors of different cell origins that influence ovarian development. In early development, failure in correct germ–somatic cell communication can cause abnormalities in ovarian development. These abnormalities can lead to deficient oocyte differentiation, to a diminished ovarian follicle reserve, and consequently to early loss of fertility. However, oocyte–granulosa cell communication is also extremely important for the acquisition of oocyte competence until ovulation. In this paper, we will visit the establishment of follicle reserve, with particular emphasis in germ–somatic cell interactions, and their importance for human fertility.

STUDY QUESTION: What has the ESHRE programme 'ESHRE Certification for Clinical Embryologists' achieved after 10 years? SUMMARY ANSWER: The post-exam analysis showed a pass rate of 60% for Clinical and 50% for Senior Clinical Embryologists and a high level of internal consistency of all exams, leading to a total of 773 certified Clinical and 493 Senior Clinical Embryologists over the decade. WHAT IS KNOWN ALREADY: In an ESHRE survey on the educational and professional status of Clinical Embryology in Europe, it was found that education of laboratory personnel working in the field of assisted reproduction is highly variable between countries. In 2008, ESHRE introduced a programme, curriculum and certification in the field of Clinical Embryology. Knowledge gained by postgraduate study of recommended literature, following a clear curriculum, is verified by a written two-level exam for obtaining a certificate for Clinical (basic) or Senior Clinical (advanced) Embryologists. With a total of 1266 certificates awarded over a period of 10 years and recognition by the Union Europeenne des Medecins Specialistes and their Council for European Specialists Medical Assessment, the ESHRE Clinical Embryology exams have become an internationally recognized educational standard in the field of Clinical Embryology. STUDY DESIGN, SIZE, DURATION: A retrospective analysis of all applications for ESHRE Clinical (2009-2018) and Senior Clinical Embryologist Certification (2008-2018) and exam results of the first decade was carried out by the Steering Committee for Clinical Embryologist Certification. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 2894 applications for ESHRE Certification for Clinical Embryologists and the results of 10 exams for the Clinical (1478 candidates) and 11 exams for Senior Clinical (987 candidates) levels were analysed. A detailed post-exam retrospective analysis was performed regarding difficulty, discrimination and reliability levels of 1600 multiple-choice questions (MCQs) with a single best answer among four options, from eight different curriculum topics (Basic cell biology, Genetics, Developmental biology, Female reproduction, Male reproduction, IVF laboratory, Cryopreservation and Laboratory management), representing the core theoretical knowledge of Clinical Embryology. Difficulty levels of the MCQs were subsequently compared regarding each topic and each yearly exam. The participation and success rates in the ESHRE Clinical Embryology exams were also assessed in terms of the educational and geographic backgrounds of candidates. MAIN RESULTS AND THE ROLE OF CHANCE: Over the 10 years studied, the mean pass rate for the Clinical Embryologist exam was 60% (range 41-86%), and for the Senior Clinical Embryologist exam was 50% (range 34-81%). On average, 63% European candidates and 35% non-European candidates passed the Clinical Embryologist exam, while 52% European candidates and 31% non-European candidates passed the Senior Clinical Embryologist exam. The candidates' educational level impacted on the success of the Clinical Embryologist exam but not of the Senior Clinical Embryologist exam. The mean difficulty indices by study topic showed that in the period of 10 years, there were no statistically significant differences between topics, for either the Clinical or Senior Clinical Embryologist exams. However, the overall exam difficulty varied between years. Reassuringly, the exam MCQ discrimination and reliability indices always showed a high level of internal consistency in all exams. LIMITATIONS, REASONS FOR CAUTION: Some data from the initial ESHRE certification programme were not obtained electronically, in particular data for education, implying tables and figures reflect the specified valid data periods. Several countries exhibit different study profiles for those working in ART laboratories, such that laboratory technicians/technologists predominate in some countries, while in others only biologists and medical doctors are allowed to work with human embryos. Such differences could consequently affect the exam performance of candidates from specific countries. WIDER IMPLICATIONS OF THE FINDINGS: The ESHRE exams on Clinical Embryology are the most widely, internationally accepted tests of knowledge in the rapidly growing area of human reproduction. Clinical Embryology is increasingly recognized as a specific discipline for scientific staff who are collaborating closely with clinicians in managing human infertility through medically assisted reproduction. The analysis of the first 10 years of application of a two-level exam for Clinical Embryology shows a consistent high quality and reliability of the exam and MCQs used. These results represent an important follow-up of the quality of the ESHRE Certification programme for Clinical Embryologists, and convincingly position Clinical Embryology in the wider group of health disciplines that are harmonized through professional bodies such as ESHRE and European Board & College of Obstetrics and Gynaecology. The exams provide a clear step towards the increasing professional recognition and establishment of Clinical Embryology within health systems at both European and international level.

STUDY QUESTION Which recommendations can be provided by the European Society of Human Reproduction and Embryology Special Interest Group (ESHRE SIG) Embryology to support laboratory specialists in the organization and management of IVF laboratories and the optimization of IVF patient care? SUMMARY ANSWER Structured in 13 sections, the guideline development group formulated recommendations for good practice in the organization and management of IVF laboratories, and for good practice of the specific procedures performed within the IVF laboratory. WHAT IS KNOWN ALREADY NA. STUDY DESIGN, SIZE, DURATION The guideline was produced by a group of 10 embryologists representing different European countries, settings and levels of expertise. The group evaluated the document of 2008, and based on this assessment, each group member rewrote one or more sections. Two 2-day meetings were organized during which each of the recommendations was discussed and rewritten until consensus within the guideline group was reached. After finalizing the draft, the members of the ESHRE SIG embryology were invited to review the guideline. PARTICIPANTS/MATERIALS, SETTING, METHODS NA. MAIN RESULTS AND THE ROLE OF CHANCE The guideline provides recommendations on the general organization of an IVF laboratory (staffing and direction, quality management, laboratory safety), and on the specific aspects of the procedures performed in IVF laboratories (Identification of patients and traceability of their reproductive cells, consumables, handling of biological material, oocyte retrieval, sperm preparation, insemination of oocytes, scoring for fertilization, embryo culture and transfer, and cryopreservation). A last section provides recommendations regarding an Emergency plan for IVF laboratories. LIMITATIONS, REASONS FOR CAUTION Evidence on most of the issues described is scarce, and therefore it was decided not to perform a formal search for and assessment of scientific evidence. However, recommendations published in the EUTCD and relevant and recent documents, manuals and consensus papers were taken into account when formulating the recommendations. WIDER IMPLICATIONS OF THE FINDINGS Despite the limitations, the guideline group is confident that this document will be helpful to directors and managers involved in the management and organization of IVF laboratories, but also to embryologists and laboratory technicians performing daily tasks. STUDY FUNDING/COMPETING INTERESTS The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings. The guideline group members did not receive payment. Dr Coticchio reports speaker's fees from IBSA and Cook, outside the submitted work; Dr Lundin reports grants from Vitrolife, personal fees from Merck Serono, non-financial support from Unisense, outside the submitted work; Dr. Rienzi reports personal fees from Merck Serono, personal fees from MSD, grants from GFI, outside the submitted work; the other authors had nothing to disclose. TRIAL REGISTRATION NUMBER NA.

In the present study, fertilization and developmental potential of mouse oocytes matured in different conditions were tested. The efficiency of in vitro fertilization (IVF), pre-implantation development and some important aspects of cytokinesis during early cleavages are discussed.In vivo matured (IVO), in vitro matured (IVM) and roscovitine-treated (IVM-Rosco) mouse oocytes were subjected to IVF under identical conditions. Three replicates per group were analyzed. Fertilization was identified by the presence of two pronuclei at 6-8 h post-fertilization. Evaluation of pre-implantation embryonic development was done daily from day 2 to day 5 and embryos were processed for analyses of chromatin, nuclear lamina, microtubules and centrosomal proteins by conventional and confocal fluorescence microscopy.Both IVM groups displayed lower fertilization rates when compared to in vivo controls. While IVO-derived embryos exhibit efficient and synchronous progression to the blastocyst stage, both IVM-derived embryos exhibit a delay in embryonic progression, and a lower blastocyst rate. Interestingly, IVM-Rosco M-II oocytes exhibited more blastomere symmetries and higher number of cells at the blastocyst stage than the IVM group with the most notable influence being on the centrosome-microtubule complex of blastomeres.Our study strongly indicates that when compared to spontaneously in vitro matured oocytes, treatment with roscovitine may partially enhance developmental competence by maintaining coordination between nuclear and cytoplasmic events. Further evidence is given of cytoskeletal biomarkers that can be identified during in vitro oocyte maturation conditions.

STUDY QUESTIONWhat is the recognition of clinical embryology and the current status of clinical embryologists in European countries, regarding educational levels, responsibilities and workload, and need for a formal education in assisted reproductive technology (ART)?SUMMARY ANSWERIt is striking that the profession of clinical embryology, almost 40 years after the introduction of IVF, is still not officially recognized in most European countries.WHAT IS KNOWN ALREADYReproductive medicine has developed into a sophisticated multidisciplinary medical branch since the birth of Louise Brown 37 years ago. The European Board & College of Obstetrics and Gynaecology (EBCOG) has recognized reproductive medicine as a subspeciality and has developed a subspeciality training for gynaecologists in collaboration with the European Society for Human Reproduction and Embryology (ESHRE). However, nothing similar exists for the field of clinical embryology or for clinical embryologists.STUDY DESIGN, SIZE, DURATIONA questionnaire about the situation in clinical embryology in the period of 2012-2013 in the respective European country was sent to ESHRE National representatives (basic scientists only) in December 2013. At this time, 28 European countries had at least one basic scientist in the ESHRE Committee of National Representatives.PARTICIPANTS/MATERIALS, SETTING, METHODSThe survey consisted of 46 numeric, dichotomous (yes/no) or descriptive questions. Answers were obtained from 27 out of 28 countries and the data were tabulated. Data about the numbers of 'ESHRE Certified Embryologists' were taken from the ESHRE Steering Committee for Embryologist Certification.MAIN RESULTS AND THE ROLE OF CHANCEIn 2012, more than 7000 laboratory staff from 1349 IVF clinics in 27 European countries performed over 700 000 fresh and frozen ART cycles. Despite this, clinical embryology is only recognized as an official profession in 3 out of 27 national health systems. In most countries clinical embryologists need to be registered under another profession, and have limited possibilities for organized education in clinical embryology. Mostly they are trained for practical work by senior colleagues. ESHRE embryologist certification so far constitutes the only internationally recognized qualification; however this cannot be considered a subspecialization.LIMITATIONS, REASONS FOR CAUTIONData were obtained through different methods, by involving national embryologist societies and cycle registers, collecting information from centre to centre, and in some cases by individual assessment of the situation. For these reasons, the results should be interpreted with caution.WIDER IMPLICATIONS OF THE FINDINGSThis paper presents the current status of clinical embryology and clinical embryologists in Europe and is an important step towards implementation of clinical embryology as an officially recognized profession.STUDY FUNDING/COMPETING INTERESTSNone.TRIAL REGISTRATION NUMBERNo.

Cellular interactions are known to be essential not only in mammalian developing tissues and organs, but also during steady-state maintenance phases. In the mammalian ovary, cellular interactions are particularly important since follicle development is continuously initiated, during childhood and adulthood, until the follicle pool drops below a poorly understood threshold in menopause. In this context, the germ cell–soma interface is of major relevance since it is at this level that a fine tuning must take place to allow for correct ovarian follicle development and the full oocyte functionality, known as oocyte competence acquisition. This includes complex differentiation processes of the somatic cells, fine tuning in response to growth factors and hormones, and the regulation of meiotic arrest and metabolism to the demand of the growing and maturing oocyte.

Successful production of high quality blastocysts depends on the use of a culture system that ensures the acquisition of developmental competence by the maturing oocyte followed by an efficient in vitro fertilization. In the present work the effect of FSH and pyruvate in an EGF containing medium for ovine oocyte maturation prior to insemination with fresh (F) or frozen–thawed (FT) semen on embryo developmental competence and cryosurvival was determined. Sheep oocytes were matured in two culture media (M1 and M2, respectively; M1=CM+EGF, n=836 and M2=CM+EGF+pyruvate+FSH, n=850) for 22h and then fertilized using FT or F spermatozoa (M1×FT=371, M2×FT=359, M1×F=353 and M2×F=372, 9 replicates) from Merino rams (n=3). After embryo culture and evaluation, good quality blastocysts (grade 1) were vitrified in OPS. Post-thawed embryo integrity, re-expansion and number of total and viable cells were assessed. Oocyte maturation rates presented no differences (P>0.05) between treatments (M1=87.0±4.1 and M2=86.7±3.9%) as well as embryo developmental rates either for maturation media or semen status. However, fresh semen improved blastocyst quality (grade 1 embryos F=52.5±4.8% and FT=39.0±4.4%, P=0.01). Grade 1 blastocysts presented similar post-thawed integrity and re-expansion rates. After 3h of culture, expansion rates were higher (P=0.05) for M2×F warmed embryos (80.0±8.3%) than for M1×F (54.3±10.4%). Results seem to confirm the existence of a synergistic effect between FSH, EGF and pyruvate upon cytoplasmic maturation of ovine oocytes. Moreover, in vitro fertilization by fresh semen clearly improves ovine embryo developmental competence by enhancing morphological blastocyst quality. The beneficial effect of M2 on cryosurvival was only observed in embryos derived from fresh semen. Therefore these combined strategies enhance embryo cryosurvival.

Apart from freezing/thawing related cryodamage, several additional factors have been identified as major players in the reduction of success rates after frozen embryo transfers. The post-thaw culture is particularly relevant as it may amplify environmental influences over a stressed embryo. In the present study the influence of the post-thaw culture duration on the implantation and developmental potential of cleavage stage embryos was evaluated.In this retrospective evaluation, that spanned an 8-year period, 631 frozen-thawed embryos were allocated to one of two study groups, depending on their post-thaw culture period: 1) the long (18-24 h), or 2) the short (2-5 h) culture group. Groups were compared regarding implantation rate and live birth rate per embryo transferred. This comparison was corrected for the most common confounding factors such as maternal age at oocyte pick-up, number of transferred embryos, developmental day at freezing, blastomere survival after thawing, catheter used for transfer and year of procedure.Implantation and live birth rate per embryo transferred were inversely related to the duration of the post-thaw culture, as diminishing this period significantly increased both rates. Moreover, no advantage could be found for a long post-thaw culture period, even for embryos with observed mitotic activity.This retrospective analysis indicates that a short post-thaw culture period is associated with higher implantation and live birth rates per embryo. This study supports selection of frozen-thawed embryos strictly based on blastomere cryosurvival and raises the hypothesis that environmental factors may have an important role on embryo implantation and developmental potential during post-thaw culture.

Objective: The aim of this paper is to apply an informatics tool for dealing with a medical decision aiding problem to help infertile couples to become parents, when using assisted reproduction.Methods: A multiple criteria decision aiding method for sorting or ordinal classification problems, called ELECTRE TRI-C, was chosen in order to assign each couple to an embryo-transfer category. The set of categories puts in evidence a way for increasing the single pregnancy rate, while minimizing multiple pregnancies. The decision aiding sorting model was co-constructed through an interaction process between the decision aiding analysts and the medical experts.Results: According to the sample used in this study, the ELECTRE TRI-C method provides a unique category in 86% of the cases and it achieves a sorting accuracy of 61%. Retrospectively, the medical experts do agree that some of their judgments concerning the number of embryos to transfer back to the uterus of the woman could be different according to these results. The current ART methodology achieves a single pregnancy rate of 47% and a twin pregnancy rate of 14%. Thus, this informatics tools may play an important role for supporting ART medical decisions, aiming to increase the single pregnancy rate, while minimizing multiple pregnancies.Limitations: Building the set of criteria comprises a part of arbitrariness and imperfect knowledge, which require time and expertise to be refined. Among them, three criteria are modeled by means of a holistic classification procedure by the medical experts. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Heterochromatin: the hidden epigenetic geography of the Y chromosome Sir, We read with great interest the systematic review and meta-analysis of Stouffs et al. (2010), which aimed to characterize the association between gr/gr deletions and male infertility. The authors present evidence supporting that the strength of the association depends on the ethnicity and geographic region of the tested population. Such observation is concurrent with our previously published data (Navarro-Costa et al., 2010) and further highlights the role population differences can play in determining the phenotypical outcome of a genetic risk factor. As discussed in both manuscripts, the genetic constitution of the Y chromosome is central to this effect, since gr/gr deletions are fixed in several Y haplogroups with no discernible consequences on spermato-genic function. Due to the well-defined geographical distribution of these Y haplogroups, they represent the basis of the population-specific differences. Nevertheless, it remains unknown how different evolutionary lineages of a single gene-poor chromosome can modulate, to such an extent, the spermatogenic phenotype. Interestingly, a recent study on Y-linked genetic variance in Drosophila has provided a most promising lead. The study from Lemos et al. (2010) has demonstrated that heterochromatic variation in the Drosophila Y chromosome can result in significant differences in terms of global expression patterns. Seeing that the recorded gene-expression changes arose from whole genome alterations in the balance between euchromatin and heterochromatin, it was proposed that DNA-binding chromatin regulators were sequestered to the lengthy Y chromosome heterochromatic domains. Therefore, given the variation in heterochro-matin length in the tested Y chromosomes, the recorded expression differences were bound to reflect a titration effect of the DNA-binding regulators in the Y heterochromatin. A similar mechanism can be envisaged in our species when considering the phenotypical variability associated with gr/gr deletions. Just like in Drosophila, the human Y is characterized by extensive heterochromatin stretches, the size of which has been shown to be variable between Y haplogroups (Repping et al., 2006). Perhaps, evolution conserved a similar role for these domains between fly and primates. If indeed human Y heterochromatin can sequester chromatin regulators, the significant size polymorphism associated with this region can ultimately lead to the establishment of different transcription-permissive states. These may vary in terms of their resilience to the genetic disruption introduced by gr/gr deletions, ultimately explaining the variability of the spermatogenic phenotype. Testing this hypothesis in humans will be a daunting technical challenge , yet one that …

Successful gametogenesis requires the establishment of an appropriate epigenetic state in developing germ cells. Nevertheless, an association between abnormal spermatogenesis and epigenetic disturbances in germline-specific genes remains to be demonstrated.In this study, the DNA methylation pattern of the promoter CpG island (CGI) of two germline regulator genes-DAZL and DAZ, was characterized by bisulphite genomic sequencing in quality-fractioned ejaculated sperm populations from normozoospermic (NZ) and oligoasthenoteratozoospermic (OAT) men.OAT patients display increased methylation defects in the DAZL promoter CGI when compared with NZ controls. Such differences are recorded when analyzing sperm fractions enriched either in normal or defective germ cells (P < 0.001 in both cases). Significant differences in DNA methylation profiles are also observable when comparing the qualitatively distinct germ cell fractions inside the NZ and OAT groups (P= 0.003 and P= 0.007, respectively). Contrastingly, the unmethylation pattern of the DAZ promoter CGI remains correctly established in all experimental groups.An association between disrupted DNA methylation of a key spermatogenesis gene and abnormal human sperm is described here for the first time. These results suggest that incorrect epigenetic marks in germline genes may be correlated with male gametogenic defects.