Up to 40% of male infertility is labeled "idiopathic" — this review argues that's a diagnostic failure, not a biological reality
Journal: Frontiers in Endocrinology | Published: 2026-03-03 | Type: Narrative Review | PMID: 41852475 Authors: Sengupta P (Gulf Medical University, UAE), Dutta S (Ajman University, UAE), Henkel R (University of the Western Cape, South Africa), Maldonado Rosas I (Citmer Reproductive Medicine, Mexico), Roychoudhury S (Assam University, India) Funding/COI: Funding not disclosed. Authors declared no commercial conflicts. Reviewer AN disclosed a past co-authorship with lead author PS — a non-trivial peer review concern for a Frontiers journal.
Conventional male infertility workups — semen analysis, hormone panels, karyotyping, Y-chromosome microdeletion testing — leave 30–40% of cases unexplained, a cohort dumped into the "idiopathic" bin. This review argues that oxidative stress is the missing mechanistic link, and proposes five redox endophenotypes (hyper-oxidative, DNA damage-dominant, mitochondrial dysfunction, epigenetic-redox, inflammatory-redox) as a structured reclassification framework. No original data is presented; this is a conceptual architecture paper, not a clinical trial.
This is a narrative review, not a systematic review or meta-analysis. There is no PRISMA flow, no defined inclusion/exclusion criteria, no synthesis of effect sizes. The authors call it an "evidence-based study," which is a stretch — it is a conceptual framework paper that selectively draws on existing literature to build a theoretical argument. That doesn't make it worthless, but it means every claim here is the authors' interpretive synthesis, not an independent pooled analysis.
The five proposed redox endophenotypes are a classification system without a validation dataset. The paper itself admits that no standardized assay protocols exist, no universal diagnostic thresholds have been established, and the proposed biomarkers remain predominantly research tools. The framework is internally coherent, but it is currently unfalsifiable in clinical practice.
This paper makes a sound diagnostic critique and dresses it in a framework that could, if validated, meaningfully reduce the "idiopathic" catch-all. But the redox endophenotype taxonomy is hypothesis, not evidence — there is no cohort study, no prospective trial, no validation set anywhere in the paper. The peer review was compromised by a prior co-authorship relationship, and the journal's standards are inconsistent. Read this as a roadmap for future research, not a clinical reference. The argument that conventional semen analysis misses molecular-level sperm dysfunction is well-established and credible; the proposed solution is a reasonable next question, not an answer.