Oxidative Stress in Male Fertility
Ashok Agarwal, Ph.D.

More and more research is pointing to oxidative stress as an important underlying cause of male infertility.

Small quantities of the highly reactive oxygen ions known as reactive oxygen species (ROS) are necessary for normal sperm function, playing a physiological role in sperm hyperactivation, capacitation, and the acrosome reaction. However, excess ROS can be extremely damaging.

Spermatozoa have high concentrations of polyunsaturated fatty acids in their plasma membranes, making them susceptible to oxidative damage. Lipid peroxidation by ROS is associated with abnormalities of the spermatozoa midpiece, lowered motility, and loss of the spermatozoa's ability to undergo the acrosome reaction, which is necessary for fertilization. Oxidative stress has also been implicated in the disruption of spermatogenesis, resulting in low sperm counts.

Measuring ROS levels can shed light on male infertility. For example, spontaneous pregnancy rates are lower for oligospermic men with elevated seminal ROS than for other oligospermic men. Elevated ROS levels are also found more commonly in men with a diagnosis of infertility than in healthy sperm donors. In vitro studies show that sperm that produce large amounts of ROS are less likely to be able to fuse witll oocytes.

ROS levels alone, however, do not reveal the whole picture. Sperm cytoplasm and seminal plasma both possess antioxidant systems to scavenge ROS, although the antioxidant system in semen is relatively weak.

Oxidative damage and sperm dysfunction also can occur when there is a deficiency in total antioxidant capacity (TAC). Total antioxidant capacity is depressed in men with a variety of diagnoses related to infertility, including varicocele, prostatitis, and unsuccessful vasectomy reversal. To boost antioxidant activity, some researchers are beginning empirical trials with drugs such as oral vitamin E or intramuscular glutathione, with promising results.

To integrate the strengths of the ROS and TAC measures, we developed a composite ROS-TAC index that provides a quantitative predictor to validate the clinical diagnosis of infertility. The mean ROS-TAC score for healthy men was normalized at 50, with lower scores indicating oxidative stress. Our research has proven that the ROS-TAC index discriminates fertile men from infertile ones better than either ROS or TAC alone.

Another strength of the ROS-TAC index is it's ability to predict subsequent fertility better than clinical diagnoses. In our retrospective study of 127 men with varicocele, varicocele with prostatitis, unsuccessful vasectomy reversal, or idiopathic infertility, 13 of the men subsequently initiated pregnancies despite their diagnoses.

Our analysis showed that these men had ROS-TAC indices in the normal range, whereas those who remained infertile had depressed ROS-TAC indices. This shows that ROS-TAC index can identify patients with a clinical diagnosis of male infertility who may nevertheless be likely to initiate pregnancies in the long term.


Relationship of the ROS-TAC Score with ROS and TAC

Lipid Peroxidation in Human Spermatozoa


Estimated one-year pregnancy rate (and 95% confidence interval) over the range of ROS-TAC score for men with either varicocele or vasectomy reversal from logistic regression results

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Last Update : December 27, 2008
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