Protective effects and mechanisms of polyphenols in animal models of testicular dysfunction: a preclinical systematic review and meta-analysis

Background Testicular dysfunction is a significant contributor to male infertility, characterized by impaired spermatogenesis, reduced testosterone production, and structural damage to testicular tissue. Polyphenols, a class of naturally occurring plant metabolites abundant in fruits, vegetables, and plant-derived beverages, show considerable promise in ameliorating testicular dysfunction in animal models. Their protective effects are primarily mediated through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, along with the modulation of steroidogenic pathways. This study examines the effects of polyphenols on testicular dysfunction in experimental animal models. Methods A systematic search of six electronic databases (PubMed, Embase, the Cochrane Library, the Web of Science Core Collection, China National Knowledge Infrastructure and Wanfang Data) was performed using keywords related to polyphenols and testicular dysfunction. The analysis incorporated preclinical animal studies evaluating polyphenol interventions for testicular injury. The methodological quality of the included studies was assessed using the CAMARADES checklist. This review was registered in PROSPERO (CRD420251171737). Results A total of 46 studies involving 1,252 animals were included. The meta-analysis demonstrated that polyphenols: 1) Improved sperm parameters, significantly increasing sperm count [SMD = 3.36, 95% CI (1.62, 5.09), P < 0.0001] and progressive sperm motility [SMD = 6.95, 95% CI (4.54, 8.96), P < 0.0001], while reducing sperm abnormality rate [SMD = −5.70, 95% CI (−8.42, −2.97), P < 0.0001]; 2) Enhanced testicular structure, significantly increasing seminiferous tubule diameter [SMD = 3.91, 95% CI (1.46, 6.36), P < 0.01], germinal epithelium height [SMD = 4.70, 95% CI (2.34, 7.06), P < 0.0001], and epididymal weight [SMD = 1.98, 95% CI (0.08, 3.89), P < 0.05]; 3) Elevated serum testosterone concentration [SMD = 2.72, 95% CI (1.93, 3.50), P < 0.0001]; 4) Attenuated oxidative stress, decreasing ROS [SMD = −4.91, 95% CI (−7.10, −2.72), P < 0.0001] and MDA levels [SMD = −4.63, 95% CI (−6.18, −3.09), P < 0.0001], while increasing SOD [SMD = 4.41, 95% CI (2.46, 6.35), P < 0.0001] and GSH [SMD = 4.72, 95% CI (3.02, 6.43), P < 0.0001] activities; 5) Suppressed inflammatory responses, reducing TNF-α [SMD = −4.06, 95% CI (−5.70, −2.42), P < 0.0001], IL-6 [SMD = −8.46, 95% CI (−13.44, −3.48), P < 0.01], and COX-2 [SMD = −8.50, 95% CI (−15.85, −1.16), P < 0.05] levels; 6) Inhibited apoptosis, decreasing Caspase-3 [SMD = −8.52, 95% CI (−10.72, −6.32), P < 0.0001] and Caspase-9 [SMD = −4.29, 95% CI (−7.58, −1.00), P < 0.05] expression; 7) Enhanced steroidogenesis, increasing 3β-HSD activity [SMD = 4.24, 95% CI (1.96, 6.53), P < 0.001]. Conclusion Polyphenols significantly ameliorate testicular dysfunction in animal models by activating the Nrf2/ARE antioxidant pathway, inhibiting NF-κB-mediated inflammatory signaling, suppressing mitochondrial apoptotic cascades, and preserving steroidogenic enzyme function. Future research should focus on translating these promising preclinical findings into clinically effective interventions for male reproductive disorders. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420251171737 , identifier CRD420251171737.