Human reproduction最新文献

{"title":"Single-step warming for blastocysts: a clinically validated alternative to conventional multi-step protocols.","authors":"Stefanie De Gheselle, Lobke De Vuyst, Sylvie Lierman, Ilse De Croo, Frauke Vanden Meerschaut, Dominic Stoop, Kelly Tilleman","doi":"10.1093/humrep/deag021","DOIUrl":"10.1093/humrep/deag021","url":null,"abstract":"<p><strong>Study question: </strong>Can a single-step warming protocol for vitrified blastocysts provide comparable or superior outcomes to a conventional multi-step warming approach in a clinical IVF setting?</p><p><strong>Summary answer: </strong>Single-step warming resulted in higher blastocyst survival, intactness, and transfer rates compared to the conventional multi-step protocol, with comparable ongoing pregnancy rates and a consistent trend toward lower miscarriage rates across all subgroups.</p><p><strong>What is known already: </strong>While vitrification has become the gold standard for embryo cryopreservation, the warming process remains critical to embryo survival and implantation potential. Traditional warming relies on multi-step dilution protocols to minimize osmotic stress. Preliminary studies have suggested that single-step rehydration protocols may be equally effective, but data on clinical validation remain scarce.</p><p><strong>Study design, size, duration: </strong>A three-phase validation study was conducted at a single university-based IVF centre including (i) risk analysis, (ii) preclinical validation (n = 246 blastocysts), and (iii) a clinical comparison of outcomes over one year (March 2024-March 2025) between single-step warming (n = 1925 cycles) and the conventional multi-step protocol (n = 1744 cycles, March 2023-March 2024).</p><p><strong>Participants/materials, setting, methods: </strong>In the preclinical phase, vitrified surplus and PGT blastocysts were rewarmed using the single-step protocol and compared to historical controls. Survival (≥50% intact cells), intactness (100% intact), and transfer suitability were assessed. Single-step warmed blastocysts were monitored for 24 h post-warming in a time-lapse incubator, and viability was further evaluated using live/dead fluorescent staining to quantify cell damage. In the clinical phase, outcomes (survival, transfer rate, pregnancy, ongoing pregnancy, miscarriage) were retrospectively compared across protocols, stratified by PGT status and day of vitrification.</p><p><strong>Main results and the role of chance: </strong>In the preclinical phase, blastocyst survival was ≥50% in 99.1% of cases after single-step warming versus 96.8% after multi-step warming (P = 0.0924). Fully intact blastocysts were significantly more frequent in the single-step group (85.4% vs. 76.3%, P = 0.0058), and transfer suitability at 2 h post-warming was also higher (96.7% vs. 91.2%, P = 0.0076). Time-lapse monitoring confirmed a high re-expansion rate (93.9%) with a mean re-expansion time of 3.3 ± 2.7 h. Fluorescent viability staining showed that 90.5% of blastocysts exhibited no or minimal cell damage. In the clinical cohort, significantly higher survival rates were seen in the single-step group across multiple subgroups, including non-PGT Day 5 (98.5% vs. 96.1%, P = 0.0003) and PGT Day 5 (100% vs. 98.2%, P = 0.0407) blastocysts. Fully intact rates were significantly higher in all subgroups","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":"531-540"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146213019","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":"Role of extracellular vesicles in fertility preservation before gonadotoxic exposures to the ovaries and testes.","authors":"Esra Cetin, Leen Oyoun Alsoud, Yassine El Mahi, Hang-Soo Park, Begum Mathyk, Mervat M Omran, Sana M Salih, Ayman Al-Hendy, Farzana Begum Liakath Ali","doi":"10.1093/humrep/deag004","DOIUrl":"10.1093/humrep/deag004","url":null,"abstract":"<p><p>Fertility preservation remains a significant concern for individuals undergoing gonadotoxic treatments. While traditional fertility preservation techniques are well-established, these methods can be time-consuming and limited by various medical or logistical barriers. In recent years, the potential of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) has emerged as a promising, paradigm-shifting approach in fertility preservation. Preclinical studies have demonstrated the protective and regenerative properties of EVs in chemotherapy-induced ovarian and testicular damage in animal models. EVs provide a cell-free therapy that can potentially preserve ovarian function in females and spermatogenesis in males without the need for surgery or delay in cancer treatment. Additionally, using MSC-derived EVs offers advantages over traditional stem cell therapies, such as a reduced risk of immune rejection, targeted treatment, and avoidance of safety concerns associated with stem cell-based therapies. Future directions include enhancing the therapeutic potential of MSC-derived EVs through genetic engineering or cell priming techniques to target specific tissues and further optimize their utilization in fertility preservation. Given the potential of MSC-derived EVs to protect fertility in both females and males, this approach could revolutionize treatment in oncofertility. Further research, including clinical trials, is necessary to confirm the safety and efficacy of MSC-derived EVs, focusing on premature ovarian insufficiency. Looking ahead, MSC-derived EVs could revolutionize fertility preservation, offering hope for cancer patients and individuals exposed to various environmental risks affecting reproduction, including in space exploration, where protection from cosmic radiation is essential.</p>","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":"488-497"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112899","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":"ESHRE guideline: ovarian stimulation for IVF/ICSI: an update in 2025†.","authors":"B Ata, E Bosch, S Broer, G Griesinger, M Grynberg, E Kolibianakis, M Kunicki, A La Marca, G Lainas, N Le Clef, N Massin, N P Polyzos, S K Sunkara, T Timeva, M Töyli, J Urbancsek, F Broekmans","doi":"10.1093/humrep/deag018","DOIUrl":"10.1093/humrep/deag018","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Study question: &lt;/strong&gt;What is the recommended management of ovarian stimulation, based on the best available evidence in the literature?&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Summary answer: &lt;/strong&gt;This updated ESHRE guideline on ovarian stimulation for IVF/ICSI provides 121 recommendations, answering 21 key questions on ovarian stimulation for IVF/ICSI.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;What is known already?: &lt;/strong&gt;Before the ESHRE guideline on ovarian stimulation for IVF/ICSI was published in 2019, ovarian stimulation for IVF/ICSI had only been discussed briefly in the National Institute for Health and Care Excellence guideline on fertility problems and in a statement by the Royal Australian and New Zealand College of Obstetricians and Gynaecologists.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Study design, size, duration: &lt;/strong&gt;The guideline was developed according to the structured methodology for ESHRE guidelines. The 18 key questions from the 2019 version of the guideline were revised by the Guideline Development Group (GDG). This resulted in the addition of one new key question, the splitting of the key question on fertility preservation in three separate key questions (fertility preservation for women facing gonadotoxic treatment, elective oocyte cryopreservation, and oocyte donation) and several new interventions being added to the existing key questions. Papers published between 31 October 2018 and 2 February 2025 and written in English were included. The critical outcomes for this guideline were efficacy in terms of cumulative live birth rate per started cycle or live birth rate per started cycle, as well as safety in terms of the rate of occurrence of moderate and/or severe ovarian hyperstimulation syndrome (OHSS).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Participants/materials, setting, methods: &lt;/strong&gt;Based on the available evidence, recommendations were formulated and discussed until consensus was reached within the GDG. Following stakeholder review of the initial draft, the final version was approved by the GDG and ultimately by the ESHRE Executive Committee.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main results and the role of chance: &lt;/strong&gt;The guideline provides a total of 121 recommendations: 42 recommendations remained unchanged in 2019, 4 recommendations were reworded for better understanding, 29 recommendations were updated in view of new evidence, and 46 new recommendations for 2025 have been formulated. The guideline provides 4 recommendations on pre-stimulation evaluation, 7 recommendations on pre-treatment therapies, 50 recommendations on pituitary suppression and ovarian stimulation, 17 recommendations on monitoring, 18 recommendations on triggering of final oocyte maturation and luteal support, and 8 recommendations on the prevention of OHSS. In addition, the guideline provides 17 recommendations on fertility preservation, both oncologic and elective, and oocyte donation. These include 90 evidence-based recommendations, of which only 42 were formulated as strong recommendations and 48 as conditional, as well as 29 g","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":" ","pages":"498-514"},"PeriodicalIF":6.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13061131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147275505","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":"Endometrial organoids to model benign disorders affecting the endometrium.","authors":"Marie-Madeleine Dolmans,Chloé Beaussart","doi":"10.1093/humrep/deag050","DOIUrl":"https://doi.org/10.1093/humrep/deag050","url":null,"abstract":"The endometrium is a highly dynamic and complex tissue lining the uterus, playing a central role in reproductive health. Despite its importance, the pathogenesis of many benign endometrial disorders remains poorly understood, largely due to limitations in current experimental models. Traditional in vivo models like murine and primate models fail to replicate key human-specific features like menstruation or spontaneous disease development. Similarly, conventional 2-dimensional in vitro cultures using cell lines or primary cells lack the structural and functional complexity of native endometrium, often losing physiological relevance over time. To address these challenges, endometrial epithelial organoids (EEOs), 3-dimensional self-organizing epithelial structures derived from endometrial biopsies, have emerged as a promising in vitro model. EEOs mimic many aspects of in vivo endometrial glands, including apical-basal polarity, hormone responsiveness, long-term preservation of epithelial identity, and retention of patient-specific genetic and molecular signatures. Their ability to reproduce cellular interactions and tissue architecture makes them an invaluable tool for studying endometrial physiology and disease. This review explores the application of EEOs in modeling various benign conditions affecting the endometrium, including endometriosis, adenomyosis, uterine fibroids, implantation failure, endometrial aging, endometritis, and endometrial hypoplasia, as well as systemic diseases and exposure to environmental or pharmacological agents. While EEOs do not yet fully replicate functional human endometrium, they represent a significant step forward in bridging the gap between basic research and clinical understanding of endometrial disorders.","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"117 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147583986","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: Disentangling ovarian reserve and embryo quality in vaginal progesterone effectiveness studies.","authors":"Rima Dhillon-Smith,Arri Coomarasamy","doi":"10.1093/humrep/deag055","DOIUrl":"https://doi.org/10.1093/humrep/deag055","url":null,"abstract":"","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"6 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147578139","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":"Disentangling ovarian reserve and embryo quality in vaginal progesterone effectiveness studies.","authors":"Sara Peralta,Baris Ata,Barbara Lawrenz,Anastasia Salame,Human M Fatemi","doi":"10.1093/humrep/deag054","DOIUrl":"https://doi.org/10.1093/humrep/deag054","url":null,"abstract":"","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"6 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147578140","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":"Decoding serotonin in endometriosis: unveiling its role in disease pathogenesis via the gut-reproductive microbiota axis.","authors":"Xinlei Wang,Yan Jia,Chao Wang,Danyang Li,Xiaoping Guo,Shengyu Jiang,Zhengjie Zhou,Chencheng Gao,Fang Wang","doi":"10.1093/humrep/deag047","DOIUrl":"https://doi.org/10.1093/humrep/deag047","url":null,"abstract":"STUDY QUESTIONHow can the potential mechanisms and targets of endometriosis be explored through multi-omics and multi-location approaches?SUMMARY ANSWERThis exploration of the gut-reproductive axis in patients with endometriosis found that serotonin is elevated in endometriosis and promotes disease progression through enhanced cell proliferation and inflammation.WHAT IS KNOWN ALREADYEndometriosis is a common inflammatory disease. Recent studies indicate that peripheral serotonin, which is regulated by the gut microbiota, can promote the progression of irritable bowel syndrome and various cancers.STUDY DESIGN, SIZE, DURATIONThis cross-sectional study enrolled 22 endometriosis patients and 22 control patients with uterine fibroids (surgical cases, October 2022-June 2023). Samples of vaginal secretions, endometrial tissue, peritoneal lavage fluid, feces, and ectopic lesions were collected from both groups. For validation, serum samples were added from 20 additional endometriosis patients and 20 healthy reproductive-age volunteers.PARTICIPANTS/MATERIALS, SETTING, METHODSThis study employed 16S rRNA gene sequencing to analyze the microbiota in the vagina, endometrial tissue, peritoneal fluid, and feces of patients with endometriosis and control groups, complemented by untargeted metabolomic analysis of peritoneal fluid. The results identified serotonin as a key metabolite and revealed specific bacterial species, shared between the reproductive and gastrointestinal tracts of endometriosis patients, which were significantly correlated with serotonin levels. Mendelian randomization analysis was conducted to explore the relationship between serotonin, these bacterial species, and endometriosis. Serum serotonin levels in endometriosis patients, BALB/C mouse models, and their respective controls were measured using ELISA. Immunohistochemistry and fluorescence staining were used to detect the expression of serotonin and its receptors in both ectopic and normal endometrium. The effects of serotonin on the biological behavior of various endometriosis cell models, including proliferation, migration, invasion, and apoptosis, were investigated using CCK8 assay, wound healing test, Transwell assay, apoptosis detection, ELISA, transcriptomics, and qPCR. The impact of serotonin on BALB/C mouse models was evaluated using H&E staining, flow cytometry, and ELISA.MAIN RESULTS AND THE ROLE OF CHANCEWe identified a significant enrichment of Akkermansia muciniphila (a bacterium shared by the gut and reproductive tract) in endometriosis patients, which positively correlated with peritoneal serotonin levels; Mendelian randomization analysis linked both to elevated endometriosis risk. Serotonin levels were elevated in patients' serum (using mouse models) and in ectopic endometrium, in comparison to those of controls. In vitro, serotonin boosted endometriosis cell proliferation, migration, invasion, and inflammation, with upregulated IL-17/NF-κB pathways. In mice, serotonin tr","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"32 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147535747","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":"Double-stranded sperm DNA fragmentation measured with neutral comet assay as a predictor of IVF outcomes: evidence from three European clinics in a multi-centred prospective study.","authors":"Peter Humaidan,Betina B Povlsen,Andrew J Drakeley,Mette B Jensen,Anette V Gabrielsen,Sara H McDowell,Luca Moore,Craig J Ledgerwood,Lewis Rae,Alastair Sloan,Martin Lawlor,Lynsey Poots,Elizabeth Bailie,Rebecca L Lunt,Emily Newton,Rachel C Gregoire,Tara C B Moore,Sandro C Esteves","doi":"10.1093/humrep/deag046","DOIUrl":"https://doi.org/10.1093/humrep/deag046","url":null,"abstract":"STUDY QUESTIONCan measurement of double-stranded sperm DNA fragmentation (dsSDF) via a neutral comet assay predict the probability of live birth following IVF?SUMMARY ANSWERIn a multicentre IVF cohort, dsSDF measured by a neutral comet assay was a strong, independent predictor of live birth.WHAT IS KNOWN ALREADYWhile much of the focus has traditionally been on female factors, emerging research highlights sperm DNA fragmentation as a significant contributor to reproductive outcomes. Over the past decade, studies have shown that different types of sperm DNA damage can affect reproduction differently, with single-stranded breaks being closely linked to reduced spontaneous conception rates, while double-stranded breaks are linked to higher miscarriage rates.STUDY DESIGN, SIZE, DURATIONProspective cohort study including a total of 302 males from three European IVF clinics, over a 3-year study period (March 2021-October 2024), with 126 healthy sperm donors with confirmed live birth serving as controls.PARTICIPANTS/MATERIALS, SETTING, METHODSdsSDF was quantified with a neutral comet assay, expressed as Average Comet Score (ACS) and Incidence of Damage (IOD). The primary outcome was live birth per initiated cycle. Associations were evaluated using multivariable logistic regression, adjusting for female and male age (and centre in sensitivity analyses).MAIN RESULTS AND THE ROLE OF CHANCEAcross the cohort, 30% of couples achieved a live birth. Higher dsSDF was associated with reduced odds of live birth, and this association remained statistically significant after adjustment for female age, male age, and recruitment site. Both ACS and IOD were independently predictive of live birth in adjusted models. For ACS, each 1-point increase was associated with 16% lower odds of live birth (OR = 0.84, 95% CI 0.72-0.97; P = 0.026). For IOD, each 1-point increase corresponded to 5% lower odds of live birth (OR = 0.95, 95% CI 0.90-0.99; P = 0.025). As expected, female age remained a strong inverse predictor of live birth across models (OR = 0.86, 95% CI 0.78-0.94; P &lt; 0.001). Using a pragmatic threshold of IOD ≥ 6%, couples were identified with approximately half the odds of achieving a live birth compared to those with IOD &lt; 6% at similar female ages (OR = 0.51, 95% CI 0.28-0.94; P = 0.029). The adverse association between dsSDF and live birth was stronger at higher female ages.LIMITATIONS, REASONS FOR CAUTIONThis study examined couples undergoing their first or only IVF cycle and did not include couples with repeat IVF failures. Limitations include potential centre-level confounding, which may benefit from mixed-effects modelling. We did not collect or adjust for several cycle-level covariates that influence live birth (e.g. IVF vs ICSI, number of oocytes retrieved, embryo transfer strategy, use of preimplantation genetic testing for aneuploidy, stimulation protocol), so residual confounding is possible.WIDER IMPLICATIONS OF THE FINDINGSThese results support dsSDF as","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"30 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147535748","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":"Spatial transcriptomics in the human adult ovary: insights into key signalling pathways during follicular atresia.","authors":"Hanne Vlieghe,Fu Wei,Hui Cheng,Tessa H R Stolk,Judith A Huirne,Norah M van Mello,Christiani A Amorim,Susana M Chuva de Sousa Lopes","doi":"10.1093/humrep/deag051","DOIUrl":"https://doi.org/10.1093/humrep/deag051","url":null,"abstract":"STUDY QUESTIONAre key signalling pathways WNT, TGFβ/BMP, NOTCH, and HH involved in follicular atresia in the human adult ovary?SUMMARY ANSWERIn this study, we used spatial transcriptomics to investigate the progression of follicular atresia, focusing on genes of interest associated with steroidogenesis and key signalling pathways WNT, TGFβ/BMP, NOTCH, and HH.WHAT IS KNOWN ALREADYWhile extensive research has focused on the mechanisms driving follicular growth, much less is known about the process of follicular atresia, despite its relevance for ovarian aging and reproductive longevity. Follicular atresia is characterized by complex molecular and cellular changes, that lead to the degeneration of granulosa and theca cells.STUDY DESIGN, SIZE, DURATIONSpatial transcriptomics was conducted on 16 regions of human ovarian tissue from different donors (N = 6) containing 21 small antral follicles (diameter 0.5-4 mm) healthy and at different stages of atresia.PARTICIPANTS/MATERIALS, SETTING, METHODSWe selected 80 genes to facilitate cell type identification in the ovary and to investigate the key signalling pathways WNT, TGFβ/BMP, NOTCH, and HH. Haematoxylin and eosin staining was used to manually select different follicle types for spatial transcriptomics. The Molecular Cartography platform (Resolve BioSciences) multiplexing single-molecule fluorescence in situ hybridization on cryo-sections was used for spatial transcriptomics. The cell segmentation masks were obtained from Resolve BioSciences and transcripts for each gene were assigned to individual cells based on the segmentation mask. Downstream visualization and quantification were performed using AnnData and Python.MAIN RESULTS AND THE ROLE OF CHANCEBy comparing the molecular signature of cell types present in healthy small antral follicles to those observed during the progression of atresia, we revealed a profound cellular and molecular shift. Key signalling pathways exhibited a general downregulation in granulosa cells, whereas expression in internal theca cells increased transiently at the onset of atresia, in line with ongoing cellular degeneration and follicular remodelling.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONThis study was conducted on ovarian tissue from transmasculine donors. We cannot exclude that testosterone therapy impacts follicular dynamics.WIDER IMPLICATIONS OF THE FINDINGSOur study provides novel insights into the spatial and molecular mechanisms of follicular atresia, contributing to a deeper understanding of the ovarian biology in humans.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by the Fonds National de la Recherche Scientifique de Belgique (T.0004.20 to H.V. and C.A.A.), the Novo Nordisk Foundation (NNF21CC0073729, reNEW to F.W., H.C., and S.M.C.S.L.), the Dutch Organization for Health Research and Development (ZonMW PSIDER-2021-10250022120001 to S.M.C.S.L.), and the China Scholarship Council (CSC 202008450034 to F.W., CSC 202008320362 to H.C.). T","PeriodicalId":13003,"journal":{"name":"Human reproduction","volume":"25 1","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147518650","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":"Early pregnancy concentrations of pregnancy-associated plasma protein-A (PAPP-A) and insulin-like growth factor-1 (IGF-1) following frozen embryo transfer: secondary analyses from a randomized controlled trial.","authors":"Nina Freiesleben Mørch, Bugge Nøhr, Mille Kirk, Line Rode, Pernille Fog Svendsen","doi":"10.1093/humrep/deag044","DOIUrl":"https://doi.org/10.1093/humrep/deag044","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Study question: &lt;/strong&gt;Are maternal concentrations of pregnancy-associated plasma protein-A (PAPP-A) and insulin-like growth factor-1 (IGF-1) influenced by the frozen embryo transfer (FET) protocol in early pregnancy?&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Summary answer: &lt;/strong&gt;Maternal concentrations of PAPP-A and IGF-1 were significantly lower in programmed cycle (PC) FET compared to modified natural cycle (mNC) FET among ovulatory women and compared to gonadotrophin-stimulated cycle (gSC) FET in anovulatory women.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;What is known already: &lt;/strong&gt;PC-FET has been associated with increased risks of preeclampsia and other placenta-related complications, pointing to altered placental development. PAPP-A and IGF-1 are biochemical markers of early placental function, and reduced levels have been linked to preeclampsia and other adverse outcomes. These markers may therefore provide insight into the pathways underlying the distinct risk profile of PC-FET.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Study design, size, duration: &lt;/strong&gt;This is a secondary analysis from a randomized controlled trial investigating estradiol and progesterone concentrations in FET treatments. The trial was conducted at Copenhagen University Hospital-Herlev, Denmark, from April 2021 to December 2024. Biochemical analyses for PAPP-A and IGF-1 were performed on stored biobank samples from the trial. The main analyses included women with ongoing pregnancies (n = 116), while additional analyses of IGF-1 were conducted in all ovulatory women with available biobank samples (n = 193).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Participants/materials, setting, methods: &lt;/strong&gt;Eligible participants were women aged 18-40 years with BMI ≤35 kg/m2 undergoing frozen-thawed autologous blastocyst transfer. Ovulatory women were randomized to mNC or PC, and anovulatory women to gSC or PC. Samples were collected at the following 7 timepoints throughout treatment: on the 2nd or 3rd day of menstrual bleeding, on the day of trigger/endometrial thickness ≥7 mm, on the day of embryo transfer and by gestational ages (GA) 4 + 2, 6 + 0, 8 + 0, and 9 + 6. Data on placental weight were collected at delivery.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main results and the role of chance: &lt;/strong&gt;The present analyses included women with ongoing pregnancies from the parent trial: 43 in the ovulatory mNC group, 42 in the ovulatory PC group, 16 in the anovulatory gSC group, and 15 in the anovulatory PC group. PC had substantially lower IGF-1 concentrations from treatment initiation through GA 8 + 0 compared to both mNC and gSC. Ovulatory women treated with PC showed significantly lower PAPP-A concentrations during endometrial preparation (7.4 vs 8.7 mU/l; adjusted P = 0.02), at embryo transfer (6.7 vs 8.8 mU/l; adjusted P &lt; 0.001), and GA 4 + 2 (7.2 vs 8.5 mU/l; adjusted P = 0.03) than women treated with mNC. Among anovulatory women, PAPP-A concentrations were also reduced during endometrial preparation (5.8 vs 9.1 mU/l; adjusted P = 0.008) in PC compared to gSC.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Limita","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":"147511785","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}