A global view of the pathophysiology of varicocele.

Varicocele is the most common abnormality identified in men being evaluated for subfertility. In this comprehensive review of the pathophysiology of varicocele, we will shed light on novel pathophysiological findings and their clinical implications that may direct future researches; we will shed light on the impact of transient scrotal hyperthermia and the roles of inflammation and differential protein expression and androgen expression in spermatozoa on inducing pathophysiological findings. Furthermore, we will clarify the linked processes contributing to the pathophysiology of varicocele and the impact of genetics on the induction of these processes. Spermatogenesis is a temperature-sensitive process, and heat stress of varicocele is considered the most plausible cause of impaired spermatogenesis. The three processes associated with the presence of varicocele - heat stress, excess reactive oxygen species, and increased apoptosis - appear to be linked; heat stress is associated with increased levels of reactive oxygen species and oxidative stress, which can induce apoptosis. The genetic role should not be overlooked as a contributing factor in the induction of heat stress, excess reactive oxygen species/oxidative stress, and apoptosis; this is evidenced by the association of varicocele with decreased expression of heat-shock proteins, higher polymorphism of glutathione S transferase and nitric oxide synthase genes, and increased BAX and decreased BCL2 genes and proteins. In this article, we will highlight the need of application of novel diagnostic techniques that can provide a precise pathophysiological diagnosis to guide potential specific innovative therapies. Innovative therapies can counteract the varicocele-induced stasis, suppress the degenerative effects of testicular hyperthermia, reduce the varicocele-induced apoptosis, and target the elevated-neutrophil products aiming at abrogating the testicular damage caused by the induced varicocele in rats/mice. In conclusion, on the basis of the novel scientific research, it may be possible to formulate new treatments and achieve the appropriate selection of patients who can benefit from these treatments.