Research Appraisals
Evidence-based critical appraisals of the latest medical research, systematically evaluated using Oxford CEBM methodology.
Showing 6 appraisals
European journal of clinical pharmacology
Clomiphene citrate versus testosterone replacement therapy in male hypogonadism: a systematic review of literature and meta-analysis
INTRODUCTION: Male hypogonadism, including age-related and functional forms, is characterized by insufficient testosterone production often associated with obesity and metabolic comorbidities. Testosterone replacement therapy (TRT) increases serum testosterone but suppresses spermatogenesis and may cause adverse effects. Selective estrogen receptor modulators (SERMs), such as clomiphene citrate, have emerged as an alternative approach to restore endogenous testosterone while preserving fertility. This study aimed to compare the efficacy of clomiphene citrate versus testosterone replacement therapy (TRT) in increasing serum testosterone levels in men with hypogonadism. METHODS: We conducted a systematic review of the literature in PubMed, Embase, Scopus, The Cochrane Library, and Google Scholar to identify studies comparing clomiphene citrate and testosterone replacement therapy (TRT) in men with male hypogonadism'. The primary outcome was the change in serum testosterone levels before and after treatment. Secondary outcomes included variations in other hormonal parameters, and clinical symptom improvement assessed through standardized instruments. RESULTS: A total of 11 studies with 1512 patients were included (764 on clomiphene citrate; 748 on testosterone replacement therapy, TRT). For serum testosterone, the overall pooled effect showed no significant difference between clomiphene and TRT (MD = 6.64 ng/dL; 95% CI -35.35 to 48.63; I² = 80.6%). Subgroup analyses indicated injectable testosterone achieved higher levels than clomiphene (1 study, 62 patients; MD = -290.50; 95% CI -518.78 to -62.22), whereas gel-based TRT showed no difference (8 studies, 1012 patients; MD = 24.29; 95% CI -18.91 to 67.48; I² = 76.1%). For sexual function, three studies (199 patients; 85 on clomiphene; 114 on TRT) assessing post-treatment libido (ADAM 1-5) showed lower libido scores with clomiphene than TRT (MD = - 0.54; 95% CI - 0.87 to - 0.21; P = 0.009; I² = 18.8%). CONCLUSIONS: No statistically significant difference in serum testosterone levels was observed between clomiphene citrate and testosterone gel, although the evidence is limited by high heterogeneity and some concerns to high risk of bias. TRT was associated with greater improvements in libido. These findings should be interpreted as preliminary, and large-scale randomized trials incorporating clinical and fertility endpoints are needed.
13 July 2026
Read appraisal →World journal of urology
Comparative study on the efficacy of large language models (LLMs) in health management for patients with urological and andrological diseases: a multidimensional quality evaluation and applicability analysis
PURPOSE: This study aims to evaluate the efficacy of large language models (LLMs) in health management for urological and andrological conditions by comparing two Chinese LLMs: DeepSeek and Kimi. METHODS: The responses of DeepSeek and Kimi to 30 questions on six urological and andrological diseases were quantitatively assessed using quality assessment tools, expert assessments, and readability metrics. RESULTS: In quality assessments, DeepSeek outperformed Kimi in only two instances: responses to "What are the surgical options for kidney stones?" (PEMAT-AI: P = 0.012; DISCERN-AI: P = 0.024) and "What are the treatment modalities for bladder cancer?" (PEMAT-AI and DISCERN-AI: P < 0.001). Expert assessments revealed that DeepSeek demonstrated superior accuracy and safety compared to Kimi only in addressing "Dietary considerations for kidney stone patients" (accuracy: P < 0.001; safety: P = 0.02). No statistically significant differences were found in quality assessments or expert assessments between the models for disease-specific categories. However, Kimi outperformed DeepSeek in readability evaluations. CONCLUSION: Both DeepSeek and Kimi exhibit substantial efficacy and clinical applicability in managing urological and andrological diseases. To enhance their practical use, Kimi requires improvements in accuracy and safety, while DeepSeek should focus on improving readability.
18 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 →Human fertility (Cambridge, England)
The global evaluation of the effects of antioxidants on seminal outcomes in infertile men: a systematic review and meta-analysis
The aim of the current review is to summarise information from publications on the impact of antioxidants on seminal outcomes in infertile men. A systematic search was performed in the five valid databases (Scopus, PubMed, Medline, Embase, and Web of Science) utilizing two sets of keywords up to September 2025, according to the PRISMA approach. Of the 11749 papers identified, 101 papers were included in this review, for a total of 11889 infertile men. Sperm concentration, normal sperm morphology, progressive sperm motility, and total sperm motility, were considerably higher in experimental groups compared with control groups. Both sperm concentration (106 mL-1) and total motility (%) were higher in experimental groups compared to control groups with an overall pooled standardised mean difference (SMD) of 2.33 (95% CI: 1.73, 2.94) for sperm concentration and SMD of 1.62 (95% CI: 1.20, 2.04) for total motility (%). Subgroup analysis demonstrated that duration of treatments of more than 6 months were more effective than those of less than 3 months. Based on the findings of this review, no definitive recommendation can be made regarding the use of antioxidants as a therapy for male infertility, and further research is necessary.
16 Apr 2026
Read appraisal →Genetics
Mapping whole-organism genetic comorbidities across model Species using unified ontologies
Understanding how genetic variation contributes to organism-wide phenotypes is critical for identifying mechanisms of disease. Here, we present a computational approach to analyze whole-organism comorbidities associated with genes underlying non-obstructive azoospermia (NOA), the most severe form of male infertility. We curated 204 mouse genes with experimentally validated spermatogenic failure and mapped their orthologs and phenotype annotations across humans, M. musculus, D. rerio, D. melanogaster, and C. elegans using a unified cross-species phenotype structure. This framework integrates a newly developed reproductive phenotype ontology with standardized whole-body phenotype categories to enable direct cross-species comparisons, using thousands of genotype-phenotype associations stored in model organism databases. Our analysis shows that most NOA genes have conserved orthologs across models, and that perturbation of these genes is frequently associated with non-reproductive phenotypes. In particular, integumentary defects and neoplastic phenotypes recur across species, supporting a shared genetic basis for epidemiological links between male infertility and systemic disease. Gene-level comorbidity patterns are partially predictable from single-cell RNA-seq, whole-body gene expression, and Gene Ontology annotations, suggesting that fundamental biological constraints shape the systemic consequences of reproductive gene dysfunction. Clustering genes by comorbidity profiles further distinguished genes with isolated reproductive effects from those with broad organismal consequences. This work demonstrates the power of ontology-based cross-species analysis for identifying pleiotropic effects of Mendelian disease mutations, and provides a resource, CoMorbidity DataBase Mapper (CoMo DBM), for joint analysis of genotype-phenotype associations in model organism databases.
6 Apr 2026
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