Human reproduction最新文献

{"title":"Human stem cell-based embryo models: innovation, ethics, and policy.","authors":"Alfonso Martinez Arias, Nicolas Rivron, Shahragim Tajbakhsh, Josephine Johnston, Cantas Alev, Laure Bally-Cuif, Elvan Böke, Tommaso Cavazza, Emma Cave, David Cyranoski, Laurent David, Miguel A Esteban, Jianping Fu, Niels Geijsen, Nienke de Graeff, Jacob H Hanna, Nick Hopwood, Maneesha S Inamdar, Fredrik Lanner, Brigitte Leeners, Zhen Liu, Maitre Jean Leon, Gabriella Minchiotti, Naomi Moris, Megan Munsie, Kathy K Niakan, Olivier Pourquie, Vincent Pasque, Martin Pera, Yaojin Peng, Sophie Petropoulos, Sharad Ramanathan, Janet Rossant, Peter Rugg-Gunn, Mitinori Saitou, Karen Sermon, Jose Silva, Thorold Theunissen, Margherita Turco, John Wallingford, Hongmei Wang, Aryeh Warmflash, Jun Wu, Leqian Yu","doi":"10.1093/humrep/deag035","DOIUrl":"https://doi.org/10.1093/humrep/deag035","url":null,"abstract":"<p><p>The aim of this White Paper is to establish a foundational framework for research, technological development, and regulation in the emerging field of stem cell-based embryo models (SCBEMs). These models, generated from Pluripotent Stem Cells, are designed to recapitulate essential events in early stages of human development. They have the potential to illuminate the early stages of embryo development and implantation and hold promise as an avenue to address global health challenges, including infertility and pregnancy loss, congenital, neonatal and adult conditions, and the need for organ transplants. While SCBEMs are not a substitute for human embryos, their tractability for large-scale analysis and their abilities to model the earliest stages of embryonic development suggest that they will have a significant impact on reproductive biology and regenerative medicine. But SCBEMs do not just raise novel scientific questions; they pose ethical and legal questions that need to be addressed. The paper stems from a meeting of a core group of researchers that met at the Institut Pasteur in Paris in November 2024 and represents the views of an extended group that has worked to elaborate the documents as a consensus for the field. Here, we provide a framework to guide research in this new field. We do this by summarizing the state of the science, assessing current SCBEM research in relation to its primary future applications and addressing the need for continued ethical and regulatory oversight associated with this new field.</p>","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147511837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heat exposure during susceptible windows of spermatogenesis and sperm epigenetic age.","authors":"Carrie Nobles, Timothy P Canty, Pauline Mendola, Lindsey M Russo, Kaniz Rabeya, Karen C Schliep, May Shaaban, Akanksha Singh, Allison M Ring, Rachael Hemmert, Neil J Perkins, Oladele A Oluwayiose, C Matthew Peterson, Karolina Nowak, J Richard Pilsner","doi":"10.1093/humrep/deag048","DOIUrl":"https://doi.org/10.1093/humrep/deag048","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Study question: &lt;/strong&gt;Does preconception exposure to outdoor heat stress during spermatogenesis alter sperm epigenetic age among men from an infertility treatment population?&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Summary answer: &lt;/strong&gt;Exposure to outdoor heat stress during the developmental stages of mitosis and meiosis during spermatogenesis was associated with accelerated sperm epigenetic age.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;What is known already: &lt;/strong&gt;Spermatogenesis is uniquely susceptible to redox stress. Age-related disruption of the blood-testes barrier is associated with changes in sperm DNA methylation linked to reduced fecundity and pregnancy complications. Preconception heat stress may cause similar disruptions in the sperm epigenome, providing a pathway through which high temperatures may impair men's reproductive health.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Study design, size, duration: &lt;/strong&gt;We evaluated exposure to high ambient temperatures and sperm epigenetic age among 1,220 men residing along the Wasatch Front in Utah in an ancillary prospective cohort study set within the Folic Acid and Zinc Supplementation Trial (FAZST; 2013-2018).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Participants/materials, setting, methods: &lt;/strong&gt;Sperm epigenetic age (SEA), the acceleration or deceleration of age-related changes in sperm DNA methylation, was calculated in semen samples collected 6 months after enrollment. Utilizing local hourly temperature data, average temperature and hours per day exceeding the 98th, 95th, 90th, and 75th percentile thresholds for dry bulb temperature (ambient air) and wet bulb temperature (relative temperature with 100% humidity) were calculated across spermatogenesis and susceptible windows of mitosis, meiosis I + II, spermiogenesis, and spermiation. Temperature was modeled using three approaches: (i) Generalized linear models (GLMs) for average temperature by warm vs. cold season, (ii) GLMs incorporating natural cubic splines for average temperature, and (iii) GLMs for temperature thresholds.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main results and the role of chance: &lt;/strong&gt;Across spermatogenesis, each additional 10% increase in proportion of time exposed to wet bulb temperatures ≥90th (16.1°C), ≥95th (17.2°C), and ≥98th (17.8°C) percentiles was associated with 0.063 (95% CI -0.001, 0.128), 0.121 (95% CI 0.022, 0.220), and 0.173 (95% CI 0.030, 0.316) years accelerated sperm epigenetic age, respectively. For spermatogenic-specific developmental windows, associations were strongest during meiosis I + II (e.g. 0.146 [95% CI 0.028, 0.264] years for ≥98th percentile) and, in spline models, both warmer and colder wet bulb temperatures during meiosis I + II were associated with accelerated sperm epigenetic age (P = 0.028). Associations for dry bulb temperatures were similar, although less precise, and no clear associations were observed when modeling average temperature by season.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Limitations, reasons for caution: &lt;/strong&gt;Due to reliance on outdoor temperatures rather than personal exposure, mis","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147511793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Periconceptional ultra-processed food consumption in women and men, fertility, and early embryonic development","authors":"Celine H X Lin, Romy Gaillard, Annemarie G M G J Mulders, Vincent W V Jaddoe, Mireille C Schipper","doi":"10.1093/humrep/deag023","DOIUrl":"https://doi.org/10.1093/humrep/deag023","url":null,"abstract":"STUDY QUESTION Is periconceptional ultra-processed food (UPF) consumption in women and men associated with fertility, embryonic growth, and yolk sac development? SUMMARY ANSWER Higher maternal UPF consumption was associated with smaller embryonic growth and yolk sac volume, and higher paternal UPF consumption was associated with reduced fertility. WHAT IS KNOWN ALREADY The periconceptional period is critical for the probability of conception, pregnancy outcomes, and long-term offspring health, and maternal dietary patterns during this period may influence fertility as well as early embryonic development. No studies have examined the combined influence of maternal and paternal UPF consumption on fertility outcomes and early development. STUDY DESIGN, SIZE, DURATION This study is embedded in a population-based prospective cohort study from preconception onwards, with follow-up into childhood. The present study included 831 women and 651 male partners. PARTICIPANTS/MATERIALS, SETTING, METHODS We assessed periconceptional dietary intake via a food frequency questionnaire at median 12+3 weeks of gestation (95% range 10+6, 18+3). Foods were categorized using NOVA classification, and UPF intake was expressed as a percentage of total food intake (grams per day). Information on time to pregnancy was obtained through questionnaires, with fecundability defined as the probability of conceiving within 1 month and subfertility as time to pregnancy ≥12 months or use of assisted reproductive technology. Crown-rump length (CRL) and yolk sac volume were measured by transvaginal ultrasound examinations at 7, 9, and 11 weeks of gestation. MAIN RESULTS AND THE ROLE OF CHANCE Median UPF intake was 22.0% of total food intake for women and 25.1% for men. UPF intake was not associated with fertility outcomes in women. In fully adjusted continuous models, higher maternal UPF intake was associated with smaller CRL at 7 weeks gestation [difference: −0.13 standard deviation score (SDS), 95% CI: −0.25, −0.01, per SDS increase in UPF intake]. Higher maternal UPF intake was also associated with smaller yolk sac volume at 7 weeks gestation in fully adjusted continuous models [difference: −0.14 SDS, 95% CI: −0.26, −0.02, per SDS increase in UPF intake]. These associations attenuated at 9 and 11 weeks gestation. In men, higher UPF intake was associated with decreased fecundability and increased subfertility risk in the continuous models (fecundability ratio: 0.90, 95% CI: 0.83, 0.99, OR: 1.36, 95% CI: 1.11, 1.67, per SDS increase in UPF intake), but not with first trimester development, after adjusting for socio-demographic, lifestyle factors, and female partner’s UPF consumption. LIMITATIONS, REASONS FOR CAUTION The inclusion of a relatively healthy population may limit the generalizability of our findings to broader or higher-risk groups. WIDER IMPLICATIONS OF THE FINDINGS These sex-specific findings underscore the importance of considering UPF intake in preconception and early ","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"18 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The World Health Organization infertility guidelines: \"Presumption of ovulation\".","authors":"Mohan S Kamath","doi":"10.1093/humrep/deag053","DOIUrl":"https://doi.org/10.1093/humrep/deag053","url":null,"abstract":"","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147511782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Depression and anxiety among women going through medically assisted reproduction: a register-based cohort study","authors":"Heidi Sonne, Sofie Egsgaard, Trine Munk-Olsen, Carolyn E Cesta, Lone Schmidt, Mette Bliddal","doi":"10.1093/humrep/deag040","DOIUrl":"https://doi.org/10.1093/humrep/deag040","url":null,"abstract":"STUDY QUESTION How do the incidence and prevalence of depression and anxiety change for women during the 3 years before and after initiation of medically assisted reproduction (MAR)? SUMMARY ANSWER Women initiating MAR experienced a decline in depression and anxiety before treatment initiation, followed by an increase after initiation, returning to pre-treatment levels 3 years later. WHAT IS KNOWN ALREADY Infertility and its treatment are associated with psychological distress, and previous research has examined mental health trajectories shortly before, during, and after treatment. Studies suggest that emotional adjustment varies across treatment phases and outcomes, but population-based evidence on clinical depression and anxiety patterns in a longer period before treatment initiation is lacking. STUDY DESIGN, SIZE, DURATION Nationwide register-based cohort study including all women in Denmark initiating MAR from 2006 to 2018 (n = 64 611) and a matched comparison group of women without MAR (n = 64 611), matched on the date of the first MAR treatment. Depression and anxiety were examined from 3 years before to 3 years after MAR initiation. PARTICIPANTS/MATERIALS, SETTING, METHODS Women were identified from the Danish National Register of Assisted Reproductive Technology and matched on age, calendar year, parity, and psychiatric history. Depression and anxiety were defined as hospital diagnoses or filled prescriptions for antidepressants or anxiolytics. Incidence rates were defined as new registrations of depression or anxiety, requiring no registration in the preceding 12 months. Prevalence was defined as the proportion of person-time affected by depression or anxiety based on diagnoses or prescriptions within the preceding 12 months. MAIN RESULTS AND THE ROLE OF CHANCE Among women undergoing MAR, the incidence rate of depression and anxiety declined from 19 to 11 per 1000 persons per half-year before treatment and rose to 17 three years after, forming a U-shaped pattern. In the comparison group, rates remained stable at about 25 per 1000 half-years. Results were consistent across subgroups defined by psychiatric history, age, and parity, and when restricting outcomes to hospital-based diagnoses. LIMITATIONS, REASONS FOR CAUTION The study relied on registry data and did not capture untreated or subclinical cases. Information on partnership status, socioeconomic characteristics, and parenthood intentions was unavailable and may differ between groups, potentially influencing both MAR initiation and mental health outcomes. WIDER IMPLICATIONS OF THE FINDINGS The findings suggest that women undergoing MAR experience a temporary period of improved mental health before treatment, followed by an increased risk afterwards. These descriptive patterns suggest that mental health varies across phases of fertility treatment and may help identify periods of particular relevance for mental health support in women undergoing MAR. STUDY FUNDING/COMPETING INTEREST","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"17 2 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply: Endometriotic cystectomy as an unaccounted mediator of early menopause and adverse health outcomes in later life.","authors":"Hsin-Fang Chung,Gita D Mishra","doi":"10.1093/humrep/deag043","DOIUrl":"https://doi.org/10.1093/humrep/deag043","url":null,"abstract":"","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"27 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147495005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endometriotic cystectomy as an unaccounted mediator of early menopause and adverse health outcomes in later life.","authors":"Johnny S Younis,Hugh S Taylor","doi":"10.1093/humrep/deag042","DOIUrl":"https://doi.org/10.1093/humrep/deag042","url":null,"abstract":"","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"1 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147495003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ovarian and reproductive hormone characteristics and risk of cycle cancellation in immediate versus postponed modified natural cycle frozen embryo transfer (mNC-FET) cycles.","authors":"Sara Bergenheim,Amalie Somuncu Johansen,Clara Colombo,Marte Saupstad,Tine Vrist Dam,Jeanette Wulff Bogstad,Nina la Cour Freiesleben,Lisbeth Prætorius,Ida Behrendt-Møller,Birgitte Oxlund-Mariegaard,Bugge Nøhr,Merete Husth,Negjyp Sopa,Ellen Løkkegaard,Anja Pinborg,Kristine Løssl","doi":"10.1093/humrep/deag039","DOIUrl":"https://doi.org/10.1093/humrep/deag039","url":null,"abstract":"STUDY QUESTIONDo ovarian and reproductive hormone characteristics and risk of cycle cancellation differ between immediate and postponed modified natural cycle (mNC) frozen embryo transfer (FET) cycles?SUMMARY ANSWEROvarian morphology, early follicular phase levels of progesterone and LH, and follicular phase length differed significantly between immediate and postponed mNC-FET. Cancellation rates differed numerically.WHAT IS KNOWN ALREADYThe optimal timing of mNC-FET following ovarian stimulation and oocyte retrieval is heavily debated. Concerns about suboptimal ovarian and hormonal conditions in the NC immediately following ovarian stimulation have led to the widespread practice of postponing FET for at least 1 month. However, emerging evidence suggests that reproductive outcomes in immediate programmed FET cycles are comparable, or even superior, to those achieved in postponed cycles. Studies of the NC immediately following ovarian stimulation and oocyte retrieval are lacking, leaving a limited understanding of its functionality, cycle characteristics, hormonal profiles, and ovarian morphology.STUDY DESIGN, SIZE, DURATIONThis descriptive study is based on data from a recently completed Danish multicentre randomised controlled non-inferiority trial (RCT) evaluating the optimal timing of FET following ovarian stimulation and oocyte retrieval. Women were randomised 1:1 to mNC-FET in the cycle immediately following ovarian stimulation and oocyte retrieval, or after a 1-month delay. Data from 468 women, collected from March 2021 to May 2025, were included in this study.PARTICIPANTS/MATERIALS, SETTING, METHODSWomen with a regular menstrual cycle, aged 18-40 years, and undergoing autologous single blastocyst mNC-FET were eligible for inclusion. The presence of cystic intraovarian structures &gt; 10 mm and plasma levels of FSH, LH, estradiol, and progesterone from cycle initiation to blastocyst transfer were assessed, as were the length of the follicular phase and cancellation rates between groups.MAIN RESULTS AND THE ROLE OF CHANCEThe number of cystic ovarian structures was significantly higher in the immediate group than in the postponed group on Days 2-5 of the treatment cycle (median, 3 [IQR, 1-6] vs 0 [IQR, 0-1]; P &lt; 0.001) as well as on the day of ovulation trigger (median, 1 [IQR, 0-2] vs 0 [IQR, 0-1]; P &lt; 0.001). In the early follicular phase, plasma progesterone levels were higher (median, 1.2 [IQR, 0.7-1.7] vs 0.8 [IQR, 0.6-1.5] nmol/L; P &lt; 0.001) in the immediate compared to postponed cycles, and plasma LH levels were lower (median, 4.1 [IQR, 2.7-6.1] vs 5.9 [IQR, 4.7-7.5] IU/L; P &lt; 0.001), as were FSH levels (median, 6.6 [IQR, 5.0-8.2] vs 6.9 [IQR, 5.9-7.9] IU/L; P = 0.047). The time to ovulation trigger was longer in the immediate than in the postponed group (mean, 15.0 [SD, 3.9] vs 13.0 [SD, 3.0] days; P &lt; 0.001): an effect driven by freeze-all cycles. As a natural consequence of the increased time to ovulation trigger, more follicular scans","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"8 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147495004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From tablets to targeted therapy: the APHRODITE era in male infertility","authors":"Sandro C Esteves, Peter Humaidan","doi":"10.1093/humrep/deag041","DOIUrl":"https://doi.org/10.1093/humrep/deag041","url":null,"abstract":"Treatment of idiopathic male infertility has traditionally relied on the empirical use of oral agents such as clomiphene citrate and aromatase inhibitors, often prescribed without rigorous endocrine phenotyping. The newly proposed APHRODITE criteria (Addressing male Patients with Hypogonadism and/or infeRtility Owing to altereD, Idiopathic TEsticular function) introduce a biologically rational framework for stratifying infertile men and tailoring hormonal therapy. This opinion article draws a conceptual parallel with the evolution of ovarian stimulation in IVF, in which exogenous gonadotropins supplanted oral agents due to their superior physiological control and better outcomes. Similarly, the APHRODITE system may catalyze a paradigm shift in male infertility treatment—from empirical, tablet-based regimens to biology-driven gonadotropin therapy. Here, we revisit the hormonal regulation of spermatogenesis, critically appraise the limited efficacy of selective estrogen receptor modulators and aromatase inhibitors, and summarize evidence supporting gonadotropin therapy. We further highlight the potential impact of FSH and LH/hCG genetic polymorphisms on treatment responsiveness. While clomiphene citrate and aromatase inhibitors retain a role in specific endocrine profiles, the new positioning of exogenous gonadotropins—LH/hCG and FSH–as targeted, earlier-line interventions holds promise to improve outcomes and efficacy in male fertility care. Future progress will depend on prospective trials that apply the APHRODITE criteria and on comparative analyses of oral agents versus injectable gonadotropin regimens in well-defined patient phenotypes.","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"12 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147489743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A clinical protocol for the detection of comorbidities associated with monogenic causes of male infertility","authors":"G W van der Heijden, D Westra, M C S van Olden, W Hobo, M S Oud, R M Smits, Ö Baysal, H Bogers, K D’Hauwers, M J E Kempers, J F M Jacobs, J A Veltman, M F Stokman, L Ramos","doi":"10.1093/humrep/deag038","DOIUrl":"https://doi.org/10.1093/humrep/deag038","url":null,"abstract":"STUDY QUESTION How can comorbidities associated with monogenic forms of male infertility systematically be identified? SUMMARY ANSWER Via a framework that consists of seven sequential steps, gene-specific phenotyping protocols can be generated for all monogenic causes of male infertility. WHAT IS KNOWN ALREADY Infertility negatively impacts men’s health. When loss of a single gene is causal for infertility (i.e. monogenic), the associated comorbidities are largely unknown. STUDY DESIGN, SIZE, DURATION A framework was developed that allows the generation of gene-specific phenotyping protocols. The framework was applied to generate such protocols for two men, each with a different monogenic cause for their infertility. PARTICIPANTS/MATERIALS, SETTING, METHODS A multidisciplinary medical team formulated seven sequential steps to develop gene-specific phenotyping protocols. Gene-specificity was obtained by using a gene’s expression pattern in the human body to identify tissues/cell types that show high levels of expression, as well as a literature search on the gene of interest, for potential morbidities. With these insights, tailored questionaries and tests are designed. We applied this framework to generate gene-specific protocols for two men in whom infertility was caused by the respective disruption of the genes MEI1 and DNAH17. These genes respectively show very high levels of expression in various types of immune cells and retinal cells. With gene-specific phenotyping protocols, we assessed the functionality of these cells in these men. MAIN RESULTS AND THE ROLE OF CHANCE Our framework facilitated the generation of two gene-specific phenotyping protocols that were used to systematically identify potential comorbidities associated with two forms of monogenic male infertility. Analyses of the gene expression in the human body identified immune cells (MEI1) and retinal cells and oligodendrocytes (DNAH17) as somatic cell types with high expression. Gene-specific phenotyping protocols contained targeted questions as well as clinical tests for these tissues/cell types. The questionnaires indicated no increased susceptibility to infections, allergies nor autoimmune disease (MEI1) or visual problems (DNAH17). The clinical tests comprised extensive immune profiling for the MEI1-participant and functional evaluation and imaging of the retinal cells of the DNAH17-participant. None of the test results indicated clinically relevant alterations at present. To identify true comorbidities, or lack thereof, more men with the same monogenic cause should be phenotyped. LARGE SCALE DATA Not applicable. LIMITATIONS, REASONS FOR CAUTION The Human Protein Atlas database was used to assess the expression pattern of the causal gene. This database only contains expression data in adult tissues. Potential comorbidities due to a developmental function of a gene can therefore be missed. In addition, comorbidities might develop later in life and might not be present during ","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"57 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147489742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}