Calcineurin Inhibitors and Male Fertility in Renal Transplant Recipients: A Comprehensive Review of Molecular Pathomechanisms and Reproductive Toxicity of Cyclosporine A and Tacrolimus.

This comprehensive review provides a detailed organ-resolved and translational synthesis of the effects of calcineurin inhibitors, such as cyclosporine A (CsA) and tacrolimus (FK506), on male reproductive function following kidney transplantation. This review summarises experimental and clinical evidence relating to the testes, epididymis, accessory glands, the hypothalamic-pituitary-gonadal axis and semen parameters. It also considers molecular mechanisms, clinical outcomes and transplant-related confounding factors. Experimental evidence indicates that calcineurin inhibitors can cause testicular injury in a dose- and duration-dependent manner, resulting in seminiferous epithelium disorganisation, impaired Sertoli-germ cell interactions, Leydig cell atrophy, reduced testosterone synthesis, and reduced sperm count and motility. In animal models, CsA appears to induce more pronounced histological and steroidogenic disruption. In contrast, murine studies suggest that FK506 primarily exerts molecular alterations on post-testicular sperm maturation. Proposed preclinical mechanisms include oxidative stress, mitochondrial dysfunction, apoptosis and microvascular remodelling. However, their direct role in human recipients remains to be fully verified. Clinical findings demonstrated that successful transplantation often improves pre-existing uremic hypogonadism, and semen quality usually recovers within one to two years, particularly with stable graft function and lower calcineurin inhibitor exposure. However, persistent abnormalities can occur, and outcomes are confounded by, among others, renal function or combination therapy. It is important to distinguish direct calcineurin inhibitor-induced reproductive toxicity from the confounding effects of chronic kidney disease, prior dialysis exposure, and glucocorticoid use, as these transplant-related factors significantly modulate gonadal function independently of calcineurin inhibition.