Male Infertility and Neurodegenerative Diseases: A Systematic Review of Associations and Molecular Mechanisms

13-study systematic review finds preliminary mechanistic overlap between male infertility and neurodegeneration — no prospective evidence yet

Journal: International Journal of Molecular Sciences | Published: 2026-04-02 | Type: Systematic Review | PMID: 41977402 Authors: Noora et al. — all authors from Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Dubai Funding/COI: Not disclosed

Summary

This systematic review asked whether male infertility and neurodegenerative diseases (NDDs) share underlying molecular pathways — and whether infertility might one day serve as a biomarker for future neurological risk. Of 1,566 studies screened, only 13 met inclusion criteria, spanning case-control, in vitro, bioinformatic, and pedigree designs. The proposed overlapping mechanisms are mitochondrial dysfunction, oxidative stress, and disrupted proteostasis — but the authors are candid: the evidence is preliminary and heterogeneous, and no prospective clinical data exists.

Claims

• 13 of 1,566 identified studies were included (0.8% inclusion rate)
• Proposed shared mechanisms between male infertility and NDDs: mitochondrial dysfunction, oxidative stress, and proteostasis dysregulation
• Included study designs: case-control, experimental, in vitro, bioinformatic, and pedigree — no prospective cohort or longitudinal follow-up studies
• Infertility was defined inconsistently across studies: clinical diagnosis, semen parameters, and reproductive outcomes were all used
• Authors conclude large prospective studies are required before infertility assessment could function as a neurodegenerative risk marker

Study Quality

The review follows PRISMA 2020 and was pre-registered on PROSPERO (CRD420261301509), with dual independent reviewers and a third to adjudicate conflicts. Quality appraisal used ROBINS-E for observational studies and OHAT for experimental/toxicological evidence — appropriate tool selection given the heterogeneous study types. No meta-analysis was attempted, which is correct given the incompatibility of designs.

The core methodological problem is unfixable at the review level: the 13 included studies are too diverse in design, population, and infertility definition to synthesize meaningfully. In vitro and bioinformatic studies can propose mechanisms but cannot establish clinical associations. Without a single prospective cohort linking a baseline infertility diagnosis to later NDD incidence, the central hypothesis remains untestable.

Red Flags

• No prospective data anywhere in the included studies — the causal direction cannot be established
• Extreme funnel: 1,566 → 13 studies raises questions about what was excluded and why
• Heterogeneous infertility definitions make cross-study comparison unreliable
• In vitro and bioinformatic studies are mechanism-generating, not association-proving — pooling them with case-control data conflates evidence tiers
• Funding and conflicts of interest are not disclosed for either the review or the included studies
• All authors are from a single institution with no noted external collaboration

Strengths

• PROSPERO registration and PRISMA 2020 compliance — protocol was transparent and pre-specified
• Used validated, appropriate quality tools (ROBINS-E, OHAT) rather than generic checklists
• Multi-database search (PubMed, Embase, Scopus, Cochrane CENTRAL)
• Authors do not overclaim — the abstract explicitly calls the evidence "heterogeneous and preliminary" and calls for prospective studies
• The biological hypothesis (shared mitochondrial and oxidative stress pathways) is mechanistically coherent and points toward a testable research agenda

Verdict

This is a responsible hypothesis-generating review that knows what it is. It doesn't pretend 13 mechanistically diverse studies constitute clinical evidence, and the authors say so plainly. The molecular overlap between male infertility and neurodegeneration is a plausible and underexplored research question — spermatogenesis and neuronal maintenance both depend heavily on mitochondrial function and proteostasis, so the conceptual link isn't invented. But a collection of in vitro experiments and bioinformatic analyses cannot tell us whether infertile men are actually at elevated NDD risk. File this under "interesting question, no answer yet."