Research Appraisals
Evidence-based critical appraisals of the latest medical research, systematically evaluated using Oxford CEBM methodology.
Showing 5 appraisals
PloS one
Distinct endometrial protein profiles in spontaneous and stimulated cycles in women with poor ovarian response: A prospective case-crossover clinical trial
The window of implantation is a critical period for embryo implantation. Ovarian stimulation can disrupt endometrial receptivity, potentially through altered gene expression and downstream protein profiles. However, the impact on the endometrial proteome remains underexplored. Identifying biomarkers of endometrial receptivity may provide an opportunity to develop targeted interventions aimed at improving implantation outcomes. This prospective, case-crossover, open-label study was conducted at the Department of Human Reproduction, Division of Obstetrics and Gynecology, University Medical Centre Ljubljana, Slovenia, from September 2023 to June 2024. The study included 15 women aged <43 years with primary infertility and poor ovarian response. Endometrial samples were collected using a pipelle biopsy during the window of implantation in spontaneous and stimulated cycles and analyzed using protein microarrays targeting 1,466 proteins. Differential protein abundance was assessed using a multi-factorial linear model, including patient-specific effects as an additional factor to account for the paired case-crossover design. Effect sizes are reported as log2-fold changes with corresponding 95% confidence intervals. Differential abundance was defined a priori as |log2FC| > 0.5 with FDR-adjusted p-value < 0.05. Comparison of endometrial samples from spontaneous and stimulated cycles revealed 114 antibodies with differential abundance. Key proteins were associated with immune response (IL-8, proteins S100-A8 and S100-A9, CAMP) and extracellular matrix remodeling (MMP-9). Exploratory KEGG pathway mapping suggested involvement of immune and inflammatory pathways, including cytokine-cytokine receptor interaction and IL-17 signaling. Cluster analysis demonstrated distinct proteomic patterns, with all stimulated-cycle samples showing alterations and a subset of stimulated-cycle samples (40%) exhibiting more pronounced changes. The findings indicate that ovarian stimulation is associated with measurable alterations in the endometrial proteomic profile during the window of implantation. These changes may be relevant to biological pathways involved in endometrial receptivity and implantation. Further studies in larger cohorts are needed to validate the identified candidate markers and determine their clinical relevance for implantation outcomes. Trial registration: ClinicalTrials.gov NCT06804174.
22 May 2026
Read appraisal →Reproductive biomedicine online
AI-driven paradigm shift in follicle ultrasound monitoring: from automated segmentation to clinical decision support
This commentary delineates the developmental pathway of artificial intelligence (AI) in ultrasound follicular monitoring, highlighting a paradigm shift from automated segmentation to clinical decision support. The deep learning-based CR-Unet and C-Rend models have enabled accurate follicle segmentation and measurement from two-dimensional to three-dimensional imaging, substantially improving boundary segmentation accuracy and measurement consistency. Building on this foundation, the study further establishes two-dimensional follicle area and three-dimensional follicle volume as novel biomarkers, providing quantitative criteria for predicting oocyte maturity and optimizing the timing of human chorionic gonadotrophin triggering. Through seamless integration of algorithms into the Acclarix LXK9 ultrasonography equipment, an intelligent monitoring platform with real-time analytical capabilities has been developed, demonstrating significantly superior measurement accuracy and consistency compared with manual operations. These advancements represent a transformative leap from image segmentation to AI-driven clinical decision making, offering robust technical support for standardized and precise management in assisted reproduction.
9 May 2026
Read appraisal →JMIR research protocols
Integrating Sperm Microscopy, Environmental Exposures, and Lifestyle Factors for Male Fertility Analysis: Protocol for the Nippon Semen and Environmental Exposure Database (N-SEED) Cross-Sectional Study
BACKGROUND: Conventional semen analysis does not fully capture male reproductive potential. The sperm DNA fragmentation index (DFI) may detect latent infertility, although the sperm chromatin structure assay (SCSA) is costly and technically demanding. Image-based analysis of semen microscopy, including artificial intelligence (AI), may enable lower-cost noninvasive assessment. However, progress is limited by a lack of standardized multimodal datasets linking sperm images with the DFI and relevant covariates. OBJECTIVE: This protocol describes the initial phase of the Nippon Semen and Environmental Exposure Database (N-SEED) initiative. The study aims to (1) establish standardized acquisition and quality control procedures for sperm microscopy/video and DFI measurement; (2) evaluate the feasibility and magnitude of associations between predefined image-/video-derived variables and the DFI; and (3) characterize clinical, environmental, physical, and lifestyle factors that may act as candidate correlates or confounders for subsequent image-based fertility research. METHODS: This multi-institutional cross-sectional study centralized clinical assessment and specimen collection at a single site in Japan. The prespecified group-specific enrollment targets were 25 for group 1 (a relatively homogeneous low-risk cohort for DFI quality control) and 100 for group 2 (apparently healthy community-based adult volunteers for exploratory association analyses). Microscopic sperm videos, automated semen parameters, and sperm oxidative stress data were obtained at collection. SCSA-based DFI assays are currently being performed sequentially. Group 2 participants additionally provided fasting blood and early-morning urine samples for endocrine, metabolic, environmental chemical, and elemental assays. They also underwent physical measurements and completed structured questionnaires/interviews on lifestyle, nutrition, sleep, psychological status, sexual function, and collection conditions. The primary outcome measure is the continuous DFI assessed with SCSA. Group 1 data will be used to evaluate intraday, interday, and interfacility variability and to fix flow cytometry gating settings. In groups 1 and 2, predefined image-/video-derived summary variables after standardized preprocessing will be analyzed against the continuous DFI using correlation analyses and simple linear regression to assess whether sperm microscopy data contain information relevant to sperm DNA integrity. Exploratory categorical DFI analyses will use simple logistic regression. Secondary exploratory analyses will examine candidate covariates and data completeness, including sensitivity analyses. RESULTS: The study was registered in the University Hospital Medical Information Network Clinical Trials Registry on January 18, 2026. Between January 18 and February 21, 2026, 124 unique participants were recruited (group 1: n=25; group 2: n=103; both groups: n=4). Sample and data collection were completed on February 21, 2026. Biospecimen assays and primary association analyses are expected to be completed by March 2028. CONCLUSIONS: This initial N-SEED phase will deliver a standardized, quality-controlled multimodal resource linking sperm microscopy/video data with the DFI and broader physiological and environmental measures. Its immediate contribution is not to provide an immediately deployable clinical AI tool but rather to support feasibility assessment, confounder identification, and planning for subsequent database expansion and external validation of image-based male fertility assessment methods. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000060395; https://tinyurl.com/mryfymw5. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/93803.
19 Apr 2026
Read appraisal →Biology of reproduction
The relationship between seminal microbiome and male reproductive wellness: a systematic review
The seminal microbiome, which is composed of different types of bacteria in semen and seminal plasma, has a significant impact on male reproductive health by changing the quality of semen and fertility. Previously regarded as sterile, the male reproductive tract contains microbes originating from the gastrointestinal tract, reproductive organs, and external sources such as sexual partners. Dysbiosis alters sperm parameters, triggers inflammation and oxidative stress, and is associated with conditions such as infertility, HPV infection, prostatitis, prostate cancer, and azoospermia. This systematic review adhered to the PRISMA 2020 guidelines (with 2025 extensions for reproducibility) and examined studies from PubMed, Scopus, and Science Direct (2015-2025, with prior context), concentrating on human, in vitro, and rodent models. Firmicutes, Proteobacteria, Actinobacteria, and Bacteroidetes are among the most important phyla. Beneficial genera, such as Lactobacillus, improve sperm motility, concentration, and DNA integrity, whereas dysbiotic taxa, such as Prevotella, Pseudomonas, and Ureaplasma, are associated with declines. Sexual activity facilitates bidirectional microbial transfer, modifying diversity and fostering the dysbiosis. Inflammatory cytokines, reactive oxygen species, and metabolic disruptions are all involved in this process. Changes that are specific to a disease, such as higher levels of Fusobacterium in HPV-positive samples, worsen the situation. This review highlights how the microbiome alters sperm function and causes infertility. Standardized methods and long-term studies are needed to prove causality. Probiotics and other therapeutic interventions show promise in restoring balance and boosting fertility.
16 Apr 2026
Read appraisal →African journal of reproductive health
The therapeutic potential of exosomes derived from mesenchymal stem cells for premature ovarian failure: A systematic review
This review evaluates mesenchymal stem cell-derived exosomes (MSC-Exos) for treating premature ovarian failure (POF). A comprehensive search was conducted across five databases, including PubMed, Embase, and Web of Science (WoS), yielding 17 English-language studies published between 2016 and 2025. Studies primarily using animal and in vitro models assessed the therapeutic effects and mechanisms of MSC-Exos from diverse sources. MSC-Exos significantly elevated estrogen levels, reduced follicle-stimulating hormone (FSH), increased antral follicle counts, and restored estrous cyclicity. Specifically, BMSC-Exos activated the PI3K/AKT pathway via miRNAs to suppress granulosa cell apoptosis; hUCMSC-Exos mitigated cellular senescence and autophagy; ADSC-Exos promoted follicular development through SMAD and SIRT1/FOXO1; PMSC-Exos attenuated ROS damage by improving mitochondrial function; AFSC-Exos together with MenSC-Exos enhanced oocyte maturation via the P53 pathway. Notably, perinatal exosomes showed 18-32% greater efficacy in functional recovery than adult-tissue counterparts with fewer doses. MSC-Exos present a promising therapeutic strategy for POF by targeting apoptosis, autophagy, angiogenesis, and oxidative stress. Perinatal-derived exosomes offer superior potential due to their non-invasive collection and minimal ethical concerns. Nonetheless, challenges pertaining to heterogeneity, long-term safety, and standardized manufacturing necessitate resolution through multicenter clinical trials to advance clinical applicability.. Cette revue évalue l’utilisation d’exosomes dérivés de cellules souches mésenchymateuses (MSC-Exos) pour le traitement de l’insuffisance ovarienne prématurée (IOP). Une recherche exhaustive a été menée dans cinq bases de données, notamment PubMed, Embase et Web of Science (WoS), et a permis d’identifier 17 études publiées en anglais entre 2016 et 2025. Les études, reposant principalement sur des modèles animaux et in vitro, ont examiné les effets thérapeutiques et les mécanismes d’action des MSC-Exos issus de différentes sources. Les MSC-Exos ont significativement augmenté les taux d’œstrogènes, réduit l’hormone folliculostimulante (FSH), accru le nombre de follicules antraux et rétabli la cyclicité œstrale. Plus précisément, les exosomes dérivés de cellules souches mésenchymateuses de la moelle osseuse (BMSC-Exos) ont activé la voie PI3K/AKT via des miARN afin de supprimer l’apoptose des cellules de la granulosa ; les exosomes dérivés de cellules souches mésenchymateuses du cordon ombilical humain (hUCMSC-Exos) ont atténué la sénescence cellulaire et modulé l’autophagie ; les exosomes dérivés de cellules souches mésenchymateuses du tissu adipeux (ADSC-Exos) ont favorisé le développement folliculaire via les voies SMAD et SIRT1/FOXO1 ; les exosomes dérivés de cellules souches mésenchymateuses placentaires (PMSC-Exos) ont réduit les dommages liés aux espèces réactives de l’oxygène (ROS) en améliorant la fonction mitochondriale ; les exosomes dérivés de cellules souches du liquide amniotique (AFSC-Exos), associés aux exosomes dérivés de cellules souches mésenchymateuses menstruelles (MenSC-Exos), ont amélioré la maturation ovocytaire via la voie P53. Il est à noter que les exosomes d’origine périnatale ont montré une efficacité de récupération fonctionnelle supérieure de 18 à 32 % à celle des exosomes issus de tissus adultes, et ce avec un nombre de doses plus faible. Les MSC-Exos constituent une stratégie thérapeutique prometteuse pour l’IOP en ciblant l’apoptose, l’autophagie, l’angiogenèse et le stress oxydatif. Les exosomes d’origine périnatale offrent un potentiel supérieur grâce à un prélèvement non invasif et à des préoccupations éthiques limitées. Néanmoins, des défis liés à l’hétérogénéité, à la sécurité à long terme et à la standardisation de la fabrication doivent être résolus au moyen d’essais cliniques multicentriques afin de favoriser une application clinique. Cette revue évalue l’utilisation d’exosomes dérivés de cellules souches mésenchymateuses (MSC-Exos) pour le traitement de l’insuffisance ovarienne prématurée (IOP). Une recherche exhaustive a été menée dans cinq bases de données, notamment PubMed, Embase et Web of Science (WoS), et a permis d’identifier 17 études publiées en anglais entre 2016 et 2025. Les études, reposant principalement sur des modèles animaux et in vitro, ont examiné les effets thérapeutiques et les mécanismes d’action des MSC-Exos issus de différentes sources. Les MSC-Exos ont significativement augmenté les taux d’œstrogènes, réduit l’hormone folliculostimulante (FSH), accru le nombre de follicules antraux et rétabli la cyclicité œstrale. Plus précisément, les exosomes dérivés de cellules souches mésenchymateuses de la moelle osseuse (BMSC-Exos) ont activé la voie PI3K/AKT via des miARN afin de supprimer l’apoptose des cellules de la granulosa ; les exosomes dérivés de cellules souches mésenchymateuses du cordon ombilical humain (hUCMSC-Exos) ont atténué la sénescence cellulaire et modulé l’autophagie ; les exosomes dérivés de cellules souches mésenchymateuses du tissu adipeux (ADSC-Exos) ont favorisé le développement folliculaire via les voies SMAD et SIRT1/FOXO1 ; les exosomes dérivés de cellules souches mésenchymateuses placentaires (PMSC-Exos) ont réduit les dommages liés aux espèces réactives de l’oxygène (ROS) en améliorant la fonction mitochondriale ; les exosomes dérivés de cellules souches du liquide amniotique (AFSC-Exos), associés aux exosomes dérivés de cellules souches mésenchymateuses menstruelles (MenSC-Exos), ont amélioré la maturation ovocytaire via la voie P53. Il est à noter que les exosomes d’origine périnatale ont montré une efficacité de récupération fonctionnelle supérieure de 18 à 32 % à celle des exosomes issus de tissus adultes, et ce avec un nombre de doses plus faible. Les MSC-Exos constituent une stratégie thérapeutique prometteuse pour l’IOP en ciblant l’apoptose, l’autophagie, l’angiogenèse et le stress oxydatif. Les exosomes d’origine périnatale offrent un potentiel supérieur grâce à un prélèvement non invasif et à des préoccupations éthiques limitées. Néanmoins, des défis liés à l’hétérogénéité, à la sécurité à long terme et à la standardisation de la fabrication doivent être résolus au moyen d’essais cliniques multicentriques afin de favoriser une application clinique.
15 Apr 2026
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