REVIEW article
Front. Endocrinol.
Sec. Reproduction
Idiopathic Male Infertility Revisited: Can Redox Endophenotypes Resolve Reframe the 'Idiopathic' Label?
Pallav Sengupta, PhD 1
Sulagna Dutta 2
Ralf Henkel 3
Israel Maldonado Rosas 4
Shubhadeep Roychoudhury 5
1. Gulf Medical University, Ajman, United Arab Emirates
2. Ajman University, Ajman, United Arab Emirates
3. University of the Western Cape, Cape Town, South Africa
4. Citmer Reproductive Medicine, Mexico City, Mexico
5. Life Science & Bioinformatics, Assam University, Silchar, India, Assam, 788011
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Abstract
Male infertility accounts for nearly half of all infertility cases worldwide, yet up to 30-40% of affected men remain categorized as 'idiopathic', reflecting limitations of conventional diagnostics such as semen analysis, hormonal profiling, karyotyping, and Y-chromosome microdeletion testing. These methods describe sperm quantity and morphology but fail to uncover underlying molecular dysfunctions. Increasing evidence suggests that oxidative stress plays a central role in driving sperm damage, encompassing lipid peroxidation, protein oxidation, mitochondrial dysfunction, DNA fragmentation, and epigenetic instability. Such diverse pathways highlight the inadequacy of a single idiopathic category and necessitate mechanistic stratification. This evidence-based study proposes redox endophenotypes, including hyper-and hypo-oxidative, DNA damage-dominant, mitochondrial dysfunction, epigenetic-redox, and inflammatory-redox phenotypes, as a framework for reclassifying idiopathic male infertility. Each phenotype integrates specific biomarkers, such as oxidation-reduction potential (ORP), isoprostanes, 8-hydroxy-2′-deoxyguanosine, or advanced oxidation protein products, with distinct functional impairments and clinical outcomes. Redox endophenotyping offers diagnostic refinement, guides personalized antioxidant or adjunctive therapy, and informs clinicians and embryologists for appropriate assisted reproductive technology (ART) protocols by counselling and treating the patient, and tailoring sperm selection and preparation strategies. Future directions include multi-center validation of redox assays, integration with omics and exposome data, and application of artificial intelligence for biomarker-driven algorithms. Recognizing redox endophenotypes not only reduces the reliance on exclusionary 'idiopathic' diagnoses but also advances precision andrology, improving patient diagnostics and care, reproductive outcomes and mitigating intergenerational health risks.
Summary
Keywords
Assisted Reproductive Technology, male fertility, Oxidative Stress, redox biomarkers, Reductive stress, sperm DNAdamage
Received
16 November 2025
Accepted
16 February 2026
Copyright
© 2026 Sengupta, PhD, Dutta, Henkel, Maldonado Rosas and Roychoudhury. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Shubhadeep Roychoudhury
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.