As a subject matter expert, while I commend the authors for assembling a comprehensive review on a clinically significant topic, I must raise serious concerns regarding the uncritical and often overstated interpretation of the evidence presented. The most egregious example is the unqualified endorsement of antioxidant therapy, where the citation of a Cochrane review is deployed to claim efficacy in improving pregnancy and birth rates without the crucial caveat that the same review emphasizes the low quality of the underlying evidence due to high risk of bias, significant heterogeneity, and imprecision in the studies. This omission risks misleading clinicians into adopting a one-size-fits-all antioxidant regimen despite a lack of robust evidence for its safety and efficacy, particularly concerning the very real threat of reductive stress from excessive supplementation, a risk the paper mentions but fails to weigh appropriately against its optimistic conclusions. Furthermore, the promotion of nanoantioxidants is predicated almost entirely on pre-clinical animal data, with a single, small human trial cited, rendering the transition to clinical recommendations premature and potentially irresponsible without a thorough discussion of their unknown pharmacokinetic and long-term safety profiles in humans. Similarly, the diagnostic cut-off values presented for assays like chemiluminescence and ORP are treated as established standards, yet they originate from limited, single-center studies without validation in large, multi-center cohorts, ignoring the profound impact of inter-laboratory variability. This review, in its effort to be exhaustive, often conflates preliminary findings with established clinical fact, thereby lacking the critical skepticism necessary to advance the field beyond empirical treatment and toward truly evidence-based, precision medicine for male infertility.
