The potential role of inducible nitric oxide synthase (iNOS) activity in the testicular dysfunction associated with varicocele: An experimental study

Abstract

Nitric oxide (NO) has been reported to be increased in the spermatic veins of men affected by varicocele. The aim of the present study was to determine whether iNOS (inducible nitric oxide synthase) has a role in testicular dysfunction associated with varicocele, immunohistochemistry analyze was used to study iNOS activity in testis of adolescent rats with experimental left varicoceles. Rats were randomly divided into three groups. The first group consisted of rats undergoing partial ligation of left renal vein (n:12). The second group consisted of rats undergoing a sham operation (n:6) and, the third group referred to as control rats (n:7). Immunohistochemistry slides were evaluated by counting the number of positive cells and expressed as percents (% iNOS activity). We found that iNOS was predominantly expressed in the cytoplasm of Leydig cells in each group and only a small amount of iNOS was expressed in Sertoli cells. There were significant differences in % iNOS activity between both testes of varicocele group and both of testes control group (p < 0.01), but no significant differences were noted between other groups (p > 0.05). Because of iNOS activity was markedly increased in the Leydig cells of varicocele bearing rats, we suggest that iNOS activity may play a role in the testicular dysfunction associated with varicocele during adolescence.

The Hypoxic Testicle: Physiology and Pathophysiology

“…In this regard, the damage caused by varicocele becomes worse as the time between its first appearance and varicocelectomy increases [149], indicating that the testes have intrinsic mechanisms for avoiding permanent damage under certain conditions, but that damage is inevitable when the hypoxia (or elevated temperature) is sustained over time. Changes in testicular tissue have been described in both humans and animal models of varicocele, particularly in rats, producing smaller testicles with a decrease in Leydig cell functioning and a low total sperm count but with no abnormalities in the motility or morphology of the spermatozoa [150–152]. …”

Role of reactive nitrogen species in male infertility

“…Each isoform has a reductase domain that contains a compound known as tetrahydrobiopterin (BH4), which is essential for efficient production of NO [24,25]. Interestingly, a testis-specific subclass of nNOS, known as TnNOS, has been recently identified as a major contributor to the formation of NO [31-34]. TnNOS is found to localize solely in the Leydig cells of the testis, thereby suggesting its involvement in steroidogenesis.…”

“…However, it has been shown that this form of NOS can be induced by factors released from round spermatids, implicating a regulatory role of germ cells on Sertoli and Leydig cell NOS function [20,34]. Overall, these three isoforms are found in various cells of the testis, including Sertoli cells, germ cells in the seminiferous epithelium, Leydig cells, myofibroblasts, myoid cells, endothelial cells, and spermatozoa.…”

“…NO, specifically formed from iNOS has been implicated in the many symptoms associated in varicocele, including testicular hypoxia, Leydig and germ cell dysfunction due to small vessel occlusion, elevation in scrotal temperature, diminished gonadotropin secretion, and testicular dysfunction. Despite these proposed disruptions in varicocele, the exact mechanistic pathway by which NO functions in this pathophysiology is unclear [33,34,58-61]. …”

Role of TNF-related apoptosis-inducing ligand (TRAIL) in the pathogenesis of varicocele-induced testicular dysfunction

“…These theories include increased apoptosis, increased DNA damage in sperm, oxidative stress, tissue hypoxia, degenerative changes in the seminiferous tubule and immunological infertility caused by the increased apoptosis of germ cells. [4][5][6][7][8][9] However, the presence of a varicocele does not necessarily cause infertility or worsen semen viability. Therefore, further studies are still necessary to understand the relationship between varicoceles and male infertility.…”