Oxidative Stress and Varicoceles
Varicocele is one of the most common identifiable causes of male factor infertility.While this anatomic condition may be present in 8% to 23% of the general male population, there is a markedly increased incidence among infertile men. As many as 41% of infertile men have varicoceles. Although the association of varicocele and infertility has long been recognized, the underlying pathophysiology has yet to be clearly elucidated. Elevated temperature, local hormonal alterations and venous reflux have all been postulated as contributory factorls in the sperm dysfunction. There also is evidence of progressive testicular damage in some men with varicoceles manifested by the relative atrophy of affected testis as well as a progressive deterioration in semen quality. Some men with varicoceles are not affected and remain fertile.
Oxidative stress has been an area of active research for many physiologic processes. Elevated levels of oxygen free radicals, or reactive oxygen species (ROS), have been implicated in a variety of conditions, including myocardial reperfusion injury and central nervous system damage following stroke. Research over the past decade has implicated oxidative stress as a mediator of sperm dysfunction. ROS are highly unstable free oxygen radicals and include hydrogen peroxide, hydroxyl radical and superoxide anion. These are normally produced in low amounts by normal spermatozoa. The spermatozoal membrane is high in polyunsaturated fatty acids, which can be susceptible to peroxidation by abnormally elevated levels of seminal ROS. Sperm dysfunction may be a consequence of elevated seminal ROS. A variety of seminal antioxidants scavenge oxygen radicals attempting to protetct spermatozoa. Recent studies in our laboratory and others have investigated possible deficiencies in the antioxidant capacity of seminal plasma among infertile men and suggested that decreased antioxidant capacity is associated with infertility.
We recently studied seminal reactive oxygen production and antioxidative capacity among men with varicoceles. We hypothetized that infertility attributed to varicocele is, at least in part, associated with increased oxidative stress, in terms of both ROS generation and diminished antioxidative capacity.
Over the past year, we studied men with normal testicular anatomy and normal semen quality, men with incidentally noted varicoceles but no history of fertility problems, and infertile men with varicoceles. We found significantly better semen quality in the normal subjects than in the infertile varicocele subjects. Men with incidental varicoceles were intermediate with respect to their semen quality. Using a chemiluminescence-based assay, we measured both the levels of ROS production from spermatozoa and the amount of antioxidants present in the seminal plasma. We found that men with varicoceles had increased production of ROS, regardless of their fertility status. Further, we found decreased levels of antioxidants in their semen. Interestingly, there were no significant differences in the degree of oxidative stress between the infertile and incidental varicocele subjects.
Based on these observations, it appears that men with varicoceles have increased oxidative stress in their semen. This oxidative stress manifests as elevated levels of oxygen free radical production, as well as decreased levels of protective antioxidants in the seminal fluid. Whether these abnormalities are the cause or the result of abnormal sperm has yet to be determined. Our findings support a possible rationale for antioxidant supplementation in infertile men with varicocele.
Center for Reproductive Medicine
The Cleveland Clinic
9500 Euclid Avenue, Desk A19
Cleveland OH 44195