Human reproduction最新文献

{"title":"Nanomolar vanillin, an e-cigarette flavorant, appears to disrupt pluripotency and promote endodermal differentiation in human embryonic stem cells via TRPV4 activation.","authors":"Shabnam Etemadi, Prue Talbot","doi":"10.1093/humrep/deag126","DOIUrl":"10.1093/humrep/deag126","url":null,"abstract":"<p><strong>Study question: </strong>Does vanillin, at concentrations relevant to maternal exposures during vaping, disrupt gastrulation-related processes in human embryonic stem cells (hESCs) by activating TRPV4 channels?</p><p><strong>Summary answer: </strong>Activation of TRPV4 channels by nanomolar concentrations of vanillin promoted an exit from pluripotency and a shift toward endodermal gene expression, while micromolar concentrations induced developmental toxicity, identifying a concentration-dependent mechanism by which vanillin, a flavoring agent in electronic cigarette (EC) aerosols, may pose risks to embryonic development during pregnancy.</p><p><strong>What is known already: </strong>The use of ECs during pregnancy is increasing, potentially driven by perceptions of reduced harm and the appeal of flavoring agents, such as vanillin. However, vanillin activates transient receptor potential (TRP) channels, raising concerns about its impact on early embryonic development.</p><p><strong>Study design, size, duration: </strong>hESCs, which model the epiblast stage of development, were treated in vitro for various times with vanillin, a TRPV4 antagonist, a TRPV4 function-blocking antibody, or vanillin combined with either the antagonist or antibody. All experiments were done three times with different passages of stem cells.</p><p><strong>Participants/materials, setting, methods: </strong>After variable periods of exposure, the hESC colonies were evaluated for activation of TRPV4 channels and calcium influx, colony growth, colony detachment, increased cell death, mitochondrial dysfunction, colony morphology, gap formation, downregulation of EpCAM, loss of pluripotency, and initiation of differentiation.</p><p><strong>Main results and the role of chance: </strong>We demonstrate that vanillin, at concentrations relevant to maternal EC exposure, significantly (P < 0.05) disrupted gastrulation-related processes in hESCs. hESCs, which model the epiblast during Weeks 2-3 of human development, exhibited TRPV4 channel expression and showed a significant increase in intracellular calcium upon nanomolar-to-micromolar vanillin exposure, as detected by the Fluo-8 calcium dye. Time-lapse imaging and quantitative analysis indicated that micromolar vanillin impaired colony expansion, induced colony detachment, and increased cell death over 72 h, while concurrently reducing mitochondrial reductase activity in the MTT assay. At nanomolar concentrations, vanillin promoted TRPV4 activation, an exit from pluripotency, downregulation of EpCAM cell adhesion protein, intercellular gap formation, and a shift toward endodermal gene expression. All effects were blocked by a TRPV4 antagonist (HC067047), identifying activation of this channel as a critical mediator of vanillin-induced toxicity.</p><p><strong>Large scale data: </strong>N/A.</p><p><strong>Limitations, reasons for caution: </strong>Our data are derived from in vitro experiments, as direct investigation of e","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":"1688-1702"},"PeriodicalIF":6.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148726104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A proteomic signature of oocyte quality from models of varying oocyte developmental competence.","authors":"Emily R Frost, Dulama Richani, Anne Poljak, Ananya Vuyyuru, Xiuhua Liao, Elise Georgiou, J M Binuri Gunasekara, Bettina P Mihalas, Irene E Sucquart, Kaushiki Kadam, Lindsay E Wu, Robert B Gilchrist","doi":"10.1093/humrep/deag134","DOIUrl":"10.1093/humrep/deag134","url":null,"abstract":"<p><strong>Study question: </strong>Which proteins underpin oocyte developmental competence, as modelled by oocytes of variable competence matured in vivo or matured in vitro under different conditions (capacitation in vitro maturation (CAPA-IVM) or standard IVM)?</p><p><strong>Summary answer: </strong>Significant differences in the global proteome were observed in both oocytes and their corresponding cumulus cells depending on the mode of oocyte maturation, with key variations in eukaryotic translation, autophagy, and endocytosis pathways within oocytes, and changes in reactive oxygen species detoxification and serine biosynthesis in cumulus cells.</p><p><strong>What is known already: </strong>Within the ovarian follicle, mammalian oocytes must acquire the necessary molecular machinery to support successful fertilization and embryonic development. Close contact with the surrounding cumulus cells ensures coordinated nuclear and cytoplasmic maturation of the oocyte, along with the accumulation of proteins stored within the oocyte in cytoplasmic lattices and endo-lysosomal vesicular assemblies.</p><p><strong>Study design, size, duration: </strong>This basic science study utilized a mouse model to assess proteomic changes across three oocyte competence models. Key proteins identified in mouse oocytes were also assessed in discarded immature human germinal vesicle (GV) oocytes and MII oocytes following rescue-IVM. Three oocyte maturation methods were tested: (i) in vivo maturation, (ii) CAPA-IVM, and (iii) standard IVM. In vivo maturation served as a positive control group, whereby metaphase II (MII) mature oocytes were collected from mice stimulated with pregnant mare serum gonadotropin (PMSG) and triggered with hCG, simulating full ovarian stimulation. For the IVM groups, immature cumulus-oocyte complexes (COCs) were collected from mildly stimulated (23 h PMSG) mice. For the standard IVM group, immature COCs were matured in media containing amphiregulin and epiregulin for 18 h. For the CAPA group, COCs were held for 24 h in pre-IVM conditions in the presence of c-type natriuretic peptide (CNP), oestradiol, insulin, and FSH, and then matured via IVM in media containing FSH, amphiregulin, and epiregulin. Four biological replicates were performed for mouse proteomics experiments; three biological replicates were performed for mouse immunocytochemistry experiments; and six replicates were performed for embryology experiments.</p><p><strong>Participants/materials, settings, methods: </strong>Four- to six-week-old C57BL/6JAusb mice were used for all mouse experiments. Embryology outcomes were used to confirm the variation in oocyte developmental competence between the three maturation groups. For the in vivo, CAPA and IVM groups, mature MII COCs were collected and separated into oocytes and cumulus cells. Oocytes and cumulus cells were subjected to mass spectrometry and bioinformatic analysis was performed using Proteome Discoverer and Ingenuity Pathway ","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":"1741-1761"},"PeriodicalIF":6.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal lifestyle risk factors and human embryonic morphologic development using 3D ultrasound: a population-based prospective cohort study.","authors":"Naomi Graafland, Anke G Posthumus, Annemarie G M G J Mulders, Romy Gaillard, Anton H J Koning, Vincent W V Jaddoe, Eric A P Steegers, Melek Rousian","doi":"10.1093/humrep/deag125","DOIUrl":"10.1093/humrep/deag125","url":null,"abstract":"<p><strong>Study question: </strong>Are periconception maternal modifiable lifestyle factors (i.e. smoking, alcohol consumption, caffeine intake, folic acid supplement use, and physical activity) associated with embryonic morphologic development and growth in a large population-based cohort study?</p><p><strong>Summary answer: </strong>Inadequate folic acid supplement use and insufficient serum folate levels were associated with delayed embryonic morphologic development and reduced growth, while no associations were observed for smoking, alcohol, caffeine intake, or physical activity.</p><p><strong>What is known already: </strong>Modifiable maternal lifestyle factors during the periconception period may influence embryonic growth and development. Prior studies suggest associations between smoking, folic acid use, and first trimester growth, but evidence on morphologic development remains limited.</p><p><strong>Study design, size, duration: </strong>This study was embedded in the Generation R Next Study, a population-based periconception cohort in Rotterdam, the Netherlands, conducted between 2017 and 2021. Of the 2173 included spontaneous singleton pregnancies, 993 had reliable pregnancy dating, 3D ultrasound data up to 10 + 2 weeks of gestation, and available information on periconception lifestyle risk factors.</p><p><strong>Participants/materials, setting, methods: </strong>Embryonic development and growth were assessed in vivo at 7 and 9 weeks of gestation using 3D transvaginal ultrasound and virtual reality techniques. Morphologic development was determined using the Carnegie staging system based on limb position, embryonic curvature, and brain morphology; crown-rump length (CRL) was used to assess growth. Periconception lifestyle factors, including smoking, alcohol and caffeine intake, physical activity, and folic acid supplement use, were assessed using early pregnancy questionnaires. Linear mixed models were used to examine the association between lifestyle factors and embryonic Carnegie stages and CRL. Analyses were adjusted for gestational age at ultrasound, maternal age, ethnicity, education level, parity, fetal sex, and the other lifestyle factors.</p><p><strong>Main results and the role of chance: </strong>Inadequate folic acid supplement use was associated with a 0.51-day delay in embryonic development and a 0.72-mm reduction in CRL (-1.6%) at 10 + 2 weeks of gestation. Insufficient serum folate levels (<25.5 nmol/l) were associated with a 1.01-day developmental delay and a 1.24-mm reduction in CRL (-3.7%). No significant associations were observed for smoking, alcohol or caffeine intake, or physical activity. Results remained robust after adjustment for confounders.</p><p><strong>Limitations, reasons for caution: </strong>Lifestyle exposures were self-reported, which may have introduced recall or social desirability bias. Gestational age determination was based on the last menstrual period, which can result in dating discrepancies ","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":"1703-1714"},"PeriodicalIF":6.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148761153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Western-style diet exacerbates male infertility in M1ap knockout mice.","authors":"Brendan J Houston, Joseph Nguyen, Nadja Rotte, Frank Tüttelmann, Corinna Friedrich, D Jo Merriner, Anne E O'Connor, Moira K O'Bryan, Jessica E M Dunleavy","doi":"10.1093/humrep/deag130","DOIUrl":"10.1093/humrep/deag130","url":null,"abstract":"<p><strong>Study question: </strong>What are the individual and combined effects of a common genetic cause of human male infertility (loss of M1AP function) and a negative lifestyle factor (a Western diet) on male fertility, spermatogenesis, and sperm quality in mice?</p><p><strong>Summary answer: </strong>The loss of M1AP and a Western diet separately led to subfertility (a form infertility) in male mice and in combination subfertility was worsened.</p><p><strong>What is known already: </strong>Genetics and lifestyle factors individually play important roles in male infertility aetiology. How lifestyle factors influence common genetic causes of infertility are unknown.</p><p><strong>Study design, size, duration: </strong>We generated knockout M1ap mice (M1ap-/--) and investigated the effects of genotype (wild type or knockout) and diet (control or Western diet) or genotype and age (young or aged) on male fertility and sperm parameters.</p><p><strong>Participants/materials, settings, methods: </strong>C57BL6/J mice: wild type (M1ap+/+) and M1ap knockout (M1ap-/-) at 10-12 (young) weeks or 26-28 weeks old (aged), on a control of Western (high-fat and high-sugar) diet and age. We evaluated male fertility, testis and epididymis histology, and sperm quality (motility, morphology, and count).</p><p><strong>Main results and the role of chance: </strong>Compared to the individual gene deletion or diet treatments, the combined M1ap-/- and Western diet group had more abnormal germ cells, sloughed germ cells and resulted in fewer pups per litter. In accordance, sperm motility and morphology in the combination group were more significantly compromised compared to individual experimental groups.</p><p><strong>Large scale data: </strong>N/A.</p><p><strong>Limitations, reasons for caution: </strong>While the mutant mouse mimics the genetic variants seen in many infertile men, this is a mouse model study, meaning findings should be validated in a human cohort where possible.</p><p><strong>Wider implications of the findings: </strong>Taken together, our data highlight that genetic and lifestyle factors can interact to exacerbate male infertility. This study sets a precedent for an improved consideration of how genetic, lifestyle and environmental factors contribute to infertility aetiology. These data inform a clinical foundation for lifestyle interventions for men presenting at infertility clinics prior to medically assisted reproduction.</p><p><strong>Funding: </strong>This project was supported by a Society for Reproductive Biology Career Development Award to B.J.H., National Health and Medical Research Council project grant (APP1120356) awarded to M.K.O.B., an Australia-Germany Joint Research Co-operation Scheme (UA-DAAD) grant (57511796) awarded to M.K.O.B., J.E.M.D., and F.T., and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) within the Clinical Research Unit 'Male Germ Cells' (CRU326, project number 329621271) awarded to F.T. and C","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":"1633-1642"},"PeriodicalIF":6.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148864757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of unilateral endometriomas on ovarian response to stimulation: a systematic review and meta-analysis.","authors":"D R Kalaitzopoulos, M Zografou, A Daniilidis, E Somigliana, P Viganò, N Salmeri, M Casalechi, B Leeners, S Makieva, S Mackens, M Soares, C Blockeel, N Samartzis","doi":"10.1093/humrep/deag137","DOIUrl":"10.1093/humrep/deag137","url":null,"abstract":"<p><strong>Study question: </strong>How do unoperated ovarian endometriomas affect ovarian response during ovarian stimulation cycles?</p><p><strong>Summary answer: </strong>Ovaries affected by unoperated ovarian endometriomas show similar outcomes to unaffected ovaries following controlled ovarian stimulation.</p><p><strong>What is known already: </strong>Ovarian endometriomas are estimated to affect between 17% and 44% of women with endometriosis. The heterogeneity of the published literature from IVF/ICSI cycles aggregated in meta-analyses has shown both lower and similar reproductive outcomes in women with ovarian endometriomas compared with control women. To overcome these problems in studying reproductive outcomes in presence of ovarian endometriomas, some observational studies have been performed, comparing the affected unoperated ovary with the unaffected contralateral ovary in women with unilateral disease. This approach allows to investigate both the quantitative and qualitative aspects of the ovarian response in presence of a unilateral ovarian cyst.</p><p><strong>Study design, size, duration: </strong>A systematic search for all eligible studies in the PubMed and Cochrane databases until 1 May 2025 was conducted. Eligible studies met the following criteria: (i) original studies comparing unoperated unilateral endometriomas with contralateral healthy ovaries in the same patients, (ii) clear description of diagnostic methods for ovarian endometriosis, and (iii) available data on ovarian response, oocyte collection, and reproductive outcomes following ART from each ovary.</p><p><strong>Participants/materials, setting, methods: </strong>Studies were screened, data were extracted, and the risk of bias was assessed independently by two investigators. The main outcome was the number of oocytes retrieved per ovary. Secondary outcomes included the number of MII oocytes, fertilization rate, the number of embryos formed, the number of good-quality embryos, and implantation rates.</p><p><strong>Main results and the role of chance: </strong>Two thousand nine hundred and three studies were identified and 13 observational studies met the inclusion criteria and were included in this systematic review and meta-analysis. The meta-analysis of the number of oocytes retrieved showed comparable results between affected and unaffected ovaries in women with unilateral ovarian endometrioma (MD -0.72, 95% CI -1.45 to 0.02; I² = 97%; 11 studies, 560 patients). Similarly, the number of MII oocytes and good-quality embryos were comparable between affected and unaffected ovaries (MD -0.60, 95% CI -1.86 to 0.66; I² = 81%; 6 studies, 149 patients and MD -0.18, 95% CI -0.53 to 0.18; I² = 0%; 3 studies, 74 affected vs 74 unaffected ovaries, respectively). Conversely, the number of embryos formed was significantly lower in affected ovaries (MD -0.72, 95% CI -1.39 to -0.05; I² = 68%; 4 studies, 192 affected vs 193 unaffected ovaries, respectively).</p><p><strong>Limitat","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":"1715-1724"},"PeriodicalIF":6.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148864680","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":"Pre-treatment AMH levels suggesting PCOM do not prevent chemotherapy-induced ovarian damage despite higher long-term ovarian reserve: a longitudinal study in 467 women treated with alkylating agents.","authors":"C Decanter, C Legrand, H Behal, A Mailliez, D Cavalieri, E D'Orazio, P Pigny","doi":"10.1093/humrep/deag131","DOIUrl":"10.1093/humrep/deag131","url":null,"abstract":"<p><strong>Study question: </strong>Are young women with anti-Müllerian hormone (AMH) levels suggesting polycystic ovarian morphology (PCOM) at baseline better protected against chemo-induced ovarian damages?</p><p><strong>Summary answer: </strong>Compared with women with lower baseline AMH levels, women with pre-treatment AMH levels suggesting PCOM experienced a similar degree of follicular loss and only partial recovery of baseline values after treatment but maintained significantly higher AMH levels at 12 and 24 months of follow-up and had a faster menstrual function resumption.</p><p><strong>What is known already?: </strong>Longitudinal studies on AMH variations in women treated by chemotherapy have shown that pre-treatment AMH levels is one of the factors influencing the degree of the ovarian recovery. Recombinant AMH administration recently demonstrated a protective effect on ovarian follicles exposed to alkylating agents in mouse models. High AMH levels in women with polycystic ovaries have been associated with decreasing apoptosis of granulosa cells in small follicles and altered initial follicular growth.</p><p><strong>Study design, size, duration: </strong>This retrospective analysis of prospective collected data was carried out at the OncoFertility Observatory of the Lille University Hospital from January 2012 to February 2022. All women eligible for chemotherapy are prospectively recruited for ovarian function indicators follow-up until 24 months after the end of treatment.</p><p><strong>Participants/materials, setting, methods: </strong>467 women treated by alkylating agents for breast cancer (BC) or hematological malignancies (HM) were included in our Onco-Fertility Observatory and benefited from an onco-fertility consultation with discussion on fertility preservation options. The study population was divided into two groups according to basal AMH level at time of diagnosis: PCOM-like AMH levels ≥35 pmol/l before 2016 and ≥ 30 pmol/l after 2026 (PCOM group), and 8 ≥ AMH <35 pmol/l (non-PCOM group). Serial AMH measurements were performed at baseline before chemotherapy initiation (AMH0), 15 days after the start of chemotherapy (AMH1), 15 days before the last chemotherapy cycle (AMH2), and at time 3, 6, 12, 18, and 24 months from the end of chemotherapy. Menstrual function was assessed in parallel and antral follicle count (AFC) was performed at baseline, 12- and 24-month post-treatment. Serum AMH levels were measured using the second-generation enzyme immunoassay EIA AMH/MIS kit from 2012 to 2016, and by an automated AMH immunoassay on an Access Dxi analyzer thereafter. Results were secondarily homogenized using a validated conversion formula.</p><p><strong>Main results and the role of chance: </strong>261 BC women aged 31.4 years, and 206 HM patients aged 24.4 years eligible for alkylating regimen were included before commencing treatment. Sixty-six women in the BC population were excluded from this study (death n = 4, recurrence n ","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":"1780-1789"},"PeriodicalIF":6.8,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148758651","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":"Granular assessment of paediatric and adolescent ovaries following low levels of alkylating treatment reveals significant morphologic differences in early stage follicles.","authors":"Hannah B McDowell, Shravya Pant, Beatrice Piras, Claire Joswiak, Monica M Laronda","doi":"10.1093/humrep/deag149","DOIUrl":"https://doi.org/10.1093/humrep/deag149","url":null,"abstract":"<p><strong>Study question: </strong>Are subtle changes in the paediatric adolescent/young adult ovarian follicles and microenvironment following low-dose acute alkylating chemotherapy detectable by granular assessment tools?</p><p><strong>Summary answer: </strong>Low-dose alkylating agents impact the ovaries of pre- and post-pubertal participants with significant alterations to the follicle and oocyte area, number of granulosa cells (GCs) per follicle, and number of immature vessels, when compared to ovaries from untreated participants.</p><p><strong>What is known already: </strong>The metric known as cyclophosphamide equivalent dose (CED) was developed to counsel patients on the risk of acute and long-term adverse outcomes following exposure to alkylating agents. Likewise, CED is used to evaluate the risk of developing premature ovarian insufficiency and can support decisions to undergo fertility preservation. It is well known that high levels of alkylating agents significantly impact the ovarian reserve and extrafollicular microenvironment. However, there is limited data on the impact of low levels of CED on the human ovary.</p><p><strong>Study design, size, duration: </strong>This is a retrospective study of 75 participants aged from 0.53 to 22.82 years, all of whom had undergone ovarian tissue cryopreservation (OTC) at a children's hospital. We assessed the short-term effects of low-dose alkylating agents (CED ≤8 g/m2) on the paediatric and adolescent ovary using immunohistochemical assessments and a comprehensive morphological assessment of ovarian follicles. The median time from first alkylating treatment to tissue collection was 1.35 months. The pre-pubertal cohort consisted of 50 participants; 4 had non-alkylating treatments (NA), 23 participants had alkylating treatments (A), and 23 were untreated (U). The post-pubertal cohort consisted of 25 participants: 5 with NA, 10 with A, and 10 who were U.</p><p><strong>Participants/materials, setting, methods: </strong>Biopsies for routine pathology were obtained during a unilateral oophorectomy performed for OTC. Formalin-fixed paraffin-embedded ovarian tissue was analyzed retrospectively. The extrafollicular environment was analyzed for collagen density, stromal fibre architecture, vascularity and vessel maturity, apoptosis, proliferation, and DNA damage. Digital scans of hematoxylin and eosin-stained pathology slides were used to classify and morphologically assess follicles in adjacent sections.</p><p><strong>Main results and the role of chance: </strong>We first determined the effect of acute low-dose alkylating agents on the extrafollicular environment. Collagen was significantly more abundant in pre-pubertal ovarian tissue compared to post-pubertal (20.97 ± 3.30 vs. 7.11 ±1.82%, P ≤ 0.0008), but there was no significant difference in collagen abundance within either group based on exposure. Interestingly, collagen fibres in the cortex of post-pubertal ovaries exposed to non-alkylating agen","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080808","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":"Virulent bacterial pathogens disassemble the epididymal amyloid matrix to evade host defense.","authors":"Caitlyn Myers, Gail A Cornwall","doi":"10.1093/humrep/deag146","DOIUrl":"https://doi.org/10.1093/humrep/deag146","url":null,"abstract":"<p><strong>Study question: </strong>Does the functional epididymal amyloid matrix have host defense functions against the bacterial pathogens Staphylococcus aureus and Neisseria gonorrhoeae which are known to be exceedingly adept at evading host defense responses?</p><p><strong>Summary answer: </strong>While the monomeric and preformed amyloids of cystatin-related epididymal spermatogenic (CRES), a component of the epididymal amyloid matrix, exhibited antimicrobial activity against S. aureus and N. gonorrhoeae in vitro, the epididymal amyloid matrix did not.</p><p><strong>What is known already: </strong>The mouse epididymal amyloid matrix is an extracellular matrix-like structure with antimicrobial activity against Escherichia coli, the most common cause of human epididymal infections. The epididymal amyloid matrix exhibits distinct host defense responses depending on the bacterial strain mimicking what occurs in men and may explain why the pathogen dictates the characteristics and severity of epididymal infections.</p><p><strong>Study design, size, duration: </strong>Control versus treatment with increasing doses of CRES amyloid and epididymal amyloid matrix.</p><p><strong>Participants/materials, setting, methods: </strong>Increasing concentrations of recombinant mouse CRES/CRES amyloids and amyloid matrix isolated from the mouse caput and cauda epididymis were incubated with S. aureus and N. gonorrhoeae and the percentage of growth and viability measured using colony-forming unit (CFU) and live/dead assays, respectively. Transmission electron microscopy was used to assess structural changes in CRES/CRES amyloid and the epididymal amyloid matrix following incubation with bacteria while various mutant strains were used to identify the virulence factor contributing to epididymal amyloid matrix disassembly and bacterial survival.</p><p><strong>Main results and the role of chance: </strong>Preformed CRES amyloids reduced the ability of S. aureus and N. gonorrhoeae to grow in CFU assays. In contrast, both bacterial strains disassembled the epididymal amyloid matrix effectively evading its host defense responses. Mutant S. aureus strains showed that nucleases targeting the eDNA backbone and not proteases or phenol-soluble modulins were the likely mechanisms for amyloid matrix disassembly by S. aureus.</p><p><strong>Large scale data: </strong>N/A.</p><p><strong>Limitations, reasons for caution: </strong>The assays were carried out in vitro using biochemically enriched populations of epididymal amyloid matrix. We cannot rule out that altered structure or disruption of the native composition and physiochemical environment of the epididymal amyloid matrix hindered its host defense functions against S. aureus and N. gonorrhoeae. We also have not established the presence of a functional amyloid matrix in the human epididymis.</p><p><strong>Wider implications of the findings: </strong>Our studies provide insight of the interactions between mammalian and bact","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074477","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":"Endometrial scratching in patients with unexplained infertility who have a good prognosis for natural conception: a randomized controlled trial (SCRaTCH-OFO).","authors":"E E Preesman, B Bui, P M Vd Ven, M van Wely, B Mossink, K C E Drechsel, F J M Broekmans, S L Broer, W Verpoest","doi":"10.1093/humrep/deag153","DOIUrl":"https://doi.org/10.1093/humrep/deag153","url":null,"abstract":"<p><strong>Study question: </strong>Does endometrial scratching improve live birth rates in patients with unexplained infertility who have a good prognosis for natural conception (Hunault score ≥ 30%)?</p><p><strong>Summary answer: </strong>The cumulative live birth rate per intention-to-treat (ITT) was 64% and 57% in the endometrial scratch and control group, respectively (not statistically significant).</p><p><strong>What is known already: </strong>Endometrial injury (also called endometrial scratching) improves embryo implantation in patients undergoing medically assisted reproduction (MAR). Due to the low quality of evidence in the currently available literature, it is not clear whether endometrial scratching will improve live birth rates in patients with unexplained infertility who have a good prognosis for natural conception.</p><p><strong>Study design, size, duration: </strong>A multicentre open-label, randomized controlled trial was conducted at 31 hospitals in the Netherlands between November 2017 and May 2023. A total of 593 patients were randomized to endometrial scratch (intervention group) versus no intervention (control group) at the start of a period of minimum 6 months of natural conception. Follow-up continued 12 months after randomization and subsequently until live birth in the event of a pregnancy.</p><p><strong>Participants/materials, setting, methods: </strong>Patients with unexplained infertility with a good prognosis for natural conception (Hunault score ≥ 30%) were eligible. Scratching was performed using an endometrial biopsy catheter (Pipelle de Cornier or similar catheter) covering the entire endometrial cavity. Analyses were performed according to the ITT and the per-protocol (PP) principle, the latter excluding participants who did not receive the allocated intervention. Inverse probability weighting (IPW) was used to account for differences in baseline factors when comparing the subgroups of women in the intervention arm who received the scratch in the follicular phase or the luteal phase with the control arm. As women receiving scratch in the mid-luteal phase were instructed not to become pregnant in the scratch cycle, an additional landmark analysis using IPW was performed where pregnancies in the first cycle were excluded. The primary outcome was pregnancy occurring within 12 months follow-up, leading to live birth.</p><p><strong>Main results and the role of chance: </strong>In total, 593 participants were randomized and assigned to the scratch group or the control group (n = 296 in scratch, n = 297 in control). Two participants were secondarily excluded, and three participants were lost to follow-up (2 withdrew consent; 1 lost to follow-up). After 12 months of follow-up, in the ITT analysis 188/294 (64%) and 168/294 (57%) pregnancies leading to live birth were observed in the scratch and control group, respectively (relative risk (RR): 1.12 [95% CI 0.98-1.28], P = 0.09; risk difference (RD): +6.8% [95% CI -1.1% ","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074480","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 two-shot protocol. A randomized controlled trial of a novel two-injection ovarian stimulation strategy.","authors":"Valeria Donno, Noemie Sachs-Guedj, Marta Devesa, Sandra García-Martinez, Ignacio Rodriguez, Nikolaos P Polyzos","doi":"10.1093/humrep/deag142","DOIUrl":"https://doi.org/10.1093/humrep/deag142","url":null,"abstract":"<p><strong>Study question: </strong>Is the number of MII (metaphase II) oocytes comparable in the two-shot protocol versus the conventional corifollitropin alfa (CFA) followed by follitropin-beta protocol?</p><p><strong>Summary answer: </strong>Although the mean number of MII oocytes did not differ significantly between the two-shot protocol and the control group, non-inferiority was not statistically met.</p><p><strong>What is known already: </strong>Controlled ovarian stimulation (COS) protocols are often associated with significant side effects, largely due to the burden of multiple daily injections. Efforts to develop more patient-friendly protocols include the shift from GnRH-agonist to antagonist protocols and the introduction of progestin protocol for pituitary suppression (PPS). While such patient-friendly approaches benefit infertile patients, they are even more appealing for women undergoing COS for elective fertility preservation. The current study aims to compare a novel ovarian stimulation protocol involving two sequential CFA injections (two-shot protocol) with a conventional approach using CFA and follitropin-beta in elective fertility preservation.</p><p><strong>Study design, size, duration: </strong>Phase III, randomized, controlled, single-center, non-inferiority clinical trial conducted at a Fertility Unit within a University-Affiliated Hospital between December 2023 and July 2025. A total of 194 women were enrolled with a 1:1 allocation. Eligible participants were ≤40, with antral follicular count <20, and anti-Mullerian hormone (AMH) ≤ 3 ng/ml. Participants were randomized to receive either two sequential shots of CFA (150 mcg on Day 1 + 100 mcg on Day 5) or CFA (150 mcg) on Day 1, followed by recombinant FSH (200 IU/day) from Day 8.</p><p><strong>Participants/materials, setting, methods: </strong>In both groups, the LH surge was suppressed using a PPS protocol with daily oral desogestrel 75 mcg from the beginning of stimulation until the trigger day. Final oocyte maturation was triggered with GnRH-agonist (triptorelin 0.2 mg). The primary outcome was to compare the two ovarian stimulation protocols in terms of the number of MII oocytes. Comparisons will be made using the estimated mean difference (MD) and corresponding 95% CI.</p><p><strong>Main results and the role of chance: </strong>A total of 194 patients were assessed for eligibility and randomized into two groups: 97 patients were assigned to the two-shot protocol (Group A), while 97 patients followed the conventional protocol involving CFA followed by rFSH (Group B). No statistically significant differences were found in the mean number of oocytes nor MII oocytes between the two-shot protocol and the control group, respectively, 8.09 ± 5.87 vs 9.11 ± 6.86; MD -1.02 [95% CI: -2.83; 0.79] and 6.14 ± 4.59 vs 7.19 ± 5.67, MD -1.04 [95% CI: -2.27; 0.18]. However, because the lower bound of the CI for the primary endpoint (-2.27) exceeded the pre-specified non-inferiority m","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038263","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}