# Seminal Plasma and Extracellular Vesicles as Molecular Gatekeepers: Oxidative Stress, Endocrine Crosstalk, and Biomarker Discovery in Male Infertility

## TL;DR

This review explores how seminal plasma and extracellular vesicles regulate sperm function and may serve as biomarkers for male infertility.

## Contribution

The paper introduces the concept of seminal plasma and extracellular vesicles as 'molecular gatekeepers' in male infertility.

## Key findings

- Seminal plasma and extracellular vesicles influence sperm motility, capacitation, and immune tolerance.
- Dysregulation of these systems in conditions like varicocele and obesity reduces assisted reproductive success.
- These components offer potential for biomarker-based diagnostics and therapies in infertility.

## Abstract

Conventional semen analysis fails to capture the molecular determinants underlying impaired reproductive function. Emerging evidence positions seminal plasma (SP) and extracellular vesicles (EVs) as dynamic regulators of sperm physiology, rather than passive transport components. SP, enriched with proteins, metabolites, hormones, and antioxidants, modulates sperm motility, capacitation, acrosome reaction, and immune tolerance. Complementarily, EVs, including prostasomes, epididymosomes, and testicular vesicles, deliver proteins, lipids, and small RNAs that remodel sperm membranes, protect against oxidative insults, and influence fertilization success. A critical dimension of the SP-EV axis is its role in balancing oxidative stress (OS) and endocrine signaling. Hormones and metabolic regulators within SP, together with EV-mediated transfer of receptors and regulatory RNAs, further integrate systemic metabolic health with local reproductive outcomes. Dysregulation of these networks, particularly in conditions such as varicocele, obesity, diabetes, and idiopathic infertility, compromises sperm function and reduces assisted reproductive technology (ART) success. This evidence-based review synthesizes current evidence on SP and EVs as ‘molecular gatekeepers’ in male infertility, emphasizing OS regulation, endocrine crosstalk, and their potential as biomarker reservoirs. By integrating proteomic, metabolomic, and transcriptomic insights, the translational opportunities for biomarker-informed diagnostics, prognostication, and therapeutic interventions are highlighted.