Hannah E. Lyons

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.

BACKGROUND: Obesity is a prevalent modifiable cause of male factor infertility. Preconception guidelines recommend men maintain a healthy weight; however, they provide limited guidance regarding methods or volume of weight loss for men with obesity. First-line interventions for weight loss involve lifestyle optimization (healthy diet and exercise), followed by pharmacotherapy or bariatric surgery in severe cases. Each modality has differing weight loss potential and complications for which the reproductive implications are currently unclear. OBJECTIVE AND RATIONALE: To synthesize the available evidence regarding the reproductive effects of obesity interventions in men with obesity. Where possible, to evaluate whether the observed effects depend on the magnitude of weight loss. SEARCH METHODS: Searches for articles published in English was performed using PubMed, Web of Science, Embase, Cochrane Central Register of Controlled Trials and Scopus from inception until December 2024, using prespecified keywords pertaining to four categories: male, overweight/obesity, weight loss (bariatric surgery, nutrition, diet, lifestyle, exercise, pharmacotherapy) and fertility (conception, assisted reproduction, sperm, semen). Studies of reproductive-aged men (18–50 years) who underwent an obesity intervention with established weight loss benefits and undertook repeated assessment of reproduction capacity (semen analysis, conception rates, assisted reproduction outcomes) before and after the intervention were included. Meta-analysis was performed when two or more studies of the same modality assessed an outcome measure in a manner suitable for meta-analysis. A meta-regression considering weight loss achieved was performed when five or more suitable studies were available. Narrative review of studies not suitable for meta-analysis occurred. OUTCOMES: 32 studies were included in the analysis, with one study assessing both lifestyle interventions and pharmacotherapy. Assessment of conception rates and assisted reproduction was limited across all modalities. In almost all cases, the effect of obesity interventions on semen quality was examined as a surrogate for reproductive capacity and the certainty of evidence was low. Bariatric surgery was assessed in 18 studies, including 12 quasi-experimental studies, one randomized controlled trial, one case series and four case reports. Fixed- and random-effects meta-analysis of randomized controlled trials identified no differences in sperm parameters between control and intervention arms across any intervention, although small sample size limits interpretability. Random-effects meta-analyses of pre-post outcomes identified no clinically significant semen parameters or DNA damage changes following bariatric surgery. Pharmacotherapy (metformin and liraglutide) was assessed in five studies, including four quasi-experimental studies and one case report. There were insufficient data to draw clear conclusions regarding the impact of these agents on fertility outcomes. Lifestyle interventions were assessed in 10 studies, including five quasi-experimental studies and five randomized controlled trials. Fixed-effect meta-analysis identified improvements in sperm normal morphology (Mean difference = 0.59%, 95% Confidence interval = [0.23, 0.94]), and progressive motility (10.56% [8.97, 12.15]) following a lifestyle intervention. WIDER IMPLICATIONS: Data regarding weight loss interventions and male fertility is limited primarily to observational studies examining semen quality. Improvements in semen quality following lifestyle interventions suggest a potential benefit of optimizing nutrition and physical activity, whereas a limited change with bariatric surgery indicates obesity-associated sperm dysfunction does not resolve in a dose-dependent manner with weight loss and/or negative effects of rapid weight loss exist. Substantial knowledge gaps were identified, including limited randomized trials, inadequate examination of conception outcomes and limited assessment of GLP-1 agonist effects. REGISTRATION NUMBER: CRD 42022349665.

Declining fertility, overlooked mental health, and reduced life expectancy underscore the urgent need for renewed attention to men’s health. A semen analysis, traditionally used to assess fertility, holds untapped potential as a tool for promoting lifestyle changes and preventing chronic diseases in men. Spermatogenesis is highly sensitive to environmental and lifestyle factors and can be an early indicator of overall health. Disruptions in this process can signal underlying systemic issues and predict long-term health risks, including cardiovascular disease and metabolic disorders. An increasing number of men seek to engage in preconception care, as fertility is closely tied to a man’s sense of masculinity, identity and aspirations for fatherhood. In this context, a semen analysis can be a powerful motivator to encourage healthy behaviours and proactive health management. By incorporating semen analysis into primary care, health care providers can leverage men’s desire for fatherhood as an entry point to discuss broader health concerns, such as mental well-being, nutrition and physical activity. This approach would address immediate reproductive health, and also promote long-term wellness, helping to reduce the burden of chronic disease in men.

Objective: Seminal plasma cytokines are associated with fertility and reproductive health, but progressing their clinical utility is hampered by absence of reference data on concentration ranges of relevant cytokines in healthy men. We employed a systematic approach to assemble current evidence on the concentrations of immune regulatory cytokines present in seminal plasma (SP) of normozoospermic and/or fertile men and evaluated the impact of different platform methodologies for cytokine quantification.Evidence review: A systematic literature search was performed utilising PubMed, Web of Science and Scopus. Databases were searched from inception until 30th June 2022 inclusive, using combinations of keywords pertaining to seminal fluid and cytokines, and was restricted to human participants. Original data with values reported as concentration of specific cytokines in SP of men clearly defined as fertile or normozoospermic were extracted from studies written in English.Results: A total of 3769 publications were initially identified, of which 118 fulfilled the eligibility criteria for inclusion. A total of 51 individual cytokines are detectable in SP of healthy men. The number of studies reporting on each cytokine range from 1 to >20. The reported concentrations for many cytokines linked with fertility status, including IL6, CXCL8/IL8, and TNFA, are highly variable between published studies. This is associated with the different immunoassay methodologies utilised and may be exacerbated by a lack of validation of assays to ensure suitability for SP assessment. Due to the large variation between studies, accurate reference ranges for healthy men cannot be determined from the published data.Conclusions: The concentrations of cytokines and chemokines detected in SP is inconsistent and highly variable between studies and cohorts, limiting current capacity to define reference ranges for cytokine concentrations in fertile men. The lack of standardisation in methods used to process and store SP, and variation in platforms used to evaluate cytokine abundance, are factors contributing to the observed heterogeneity. To progress the clinical utility of SP cytokine analysis will require standardisation and validation of methodologies so that reference ranges for healthy fertile men can be defined.