Seminal plasma cytokines in fertile versus infertile men: a systematic review and meta-analysis.

Abstract

Background: Male fertility investigation is currently limited to semen analysis. However, the origins of abnormal sperm parameters are not well-understood, and normal sperm do not assure fertility in men. Improved pathophysiological and prognostic insight might be achieved utilising additional measures of male reproductive tract function. Cytokine and chemokine levels in seminal plasma (SP) may be relevant, but evidence on their clinical significance is unclear. The utility of measuring SP cytokines remains uncertain, and no consensus exists on which cytokines are most informative.

Objective and rationale: To perform a systematic review and meta-analysis on the association between fertility status and concentration of seminal plasma cytokines in men. The sixth edition of the WHO laboratory manual for the examination and processing of human semen raises the prospect of evaluating cytokines in SP as part of an extended examination. We performed a systematic search and meta-analysis to assess whether the current literature is sufficient to identify cytokines present in human SP that exhibit a relationship with fertility status in men.

Search methods: We searched PubMed, Web of Science, Scopus, and Embase from inception until April 2025, using keywords pertaining to seminal fluid and cytokines, restricted to humans and the English language. Original data with values reported as concentration of cytokines in SP of men clearly defined as infertile, compared to a discernible population of fertile/normozoospermic healthy control men, were included. A total of 5737 studies were identified, with 2737 duplicates removed. Title and abstract screening were performed for 3000 studies, then 291 studies underwent full-text screening, and 68 studies progressed to quality assessment using the NHLBI-NIH quality assessment tool and 52 studies underwent data extraction.

Outcomes: We identified 52 research articles published from 1993 to 2025 that quantified at least one cytokine in the seminal plasma of 8153 men, after 19 studies of poor quality and/or containing serious flaws were excluded. Data on 30 cytokines in the SP of healthy control and infertile men were extracted and included in narrative synthesis. Compared to fertile controls, infertile men had elevated concentrations of IL6 (SMD 0.39, 95% CI; 0.14-0.64, I2 = 80.7%), TNFA (SMD 0.13, 95% CI; 0.00-0.25, I2 = 4.3%), and CXCL8 (SMD 0.24, 95% CI; 0.06-0.43, I2 = 0.0%) in seminal plasma. IL6 reported a high degree of heterogeneity between studies, whilst CXCL8 and TNFA reported low heterogeneity. No significant moderator effects due to study quality or composition of the control cohort were identified.

Wider implications: With one in six couples experiencing infertility worldwide and a male factor identified as a primary or contributing cause in up to 50% of cases, there is a strong imperative to develop a better understanding of the pathophysiology of male infertility. This analysis identifies an association between infertility and elevated SP IL6, CXCL8, and TNFA, but whether these pro-inflammatory cytokines reflect events affecting fertility or are simply markers of transient inflammation and/or cofactors of fertility status remains to be determined. Greater precision in quantifying seminal plasma cytokines will be attained, and additional informative cytokines may be identified, by utilising standardised technical approaches in future studies.

Registration number: CRD42023398438.