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Phosphodiesterases, particularly the type 5 isoform (PDE5), have gained recognition as pivotal regulators of male reproductive physiology, exerting significant influence on testicular function, sperm maturation, and overall fertility potential. Over the past several decades, investigations have expanded beyond the original therapeutic intent of PDE5 inhibitors for erectile dysfunction, exploring their broader reproductive implications. This narrative review integrates current evidence from in vitro studies, animal models, and clinical research to clarify the roles of PDEs in effecting the male reproductive tract, with an emphasis on the mechanistic pathways underlying cyclic nucleotide signaling, the cellular specificity of PDE isoform expression, and the effects of PDE5 inhibitors on Leydig and Sertoli cell functions.

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The microbiome-gut-testis axis has emerged as a significant area of interest in understanding testicular cancer, particularly testicular germ cell tumors (TGCTs), which represent the most common malignancy in young men. The interplay between the gut and testicular microbiomes is hypothesized to influence tumorigenesis and reproductive health, underscoring the complex role of microbial ecosystems in disease pathology. The microbiome-gut-testis axis encompasses complex interactions between the gut microbiome, systemic immune modulation, and the local microenvironment of the testis.

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