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Apoptosis Is Highly Correlated With Reactive Oxygen Species In Spermatozoa From Infertile Men: New Findings

Ashok Agarwal, Ph.D., HCLD

Apoptosis, also described as programmed cell death, is a physiological phenomenon characterized by cellular morphological and biochemical alterations that cause a cell to commit suicide. Apoptosis helps discard cells that have an altered function or no function at all. In the context of male reproductive function, apoptosis may be responsible for controlling the overproduction of male gametes. Apoptosis is genetically determined and appears to be induced by a wide variety of stimuli such as irradiation, chemotherapy, toxin exposure, and viral infection. Results from animal studies have suggested that apoptosis is a key regulator of spermatogenesis in normal and pathological states. Spontaneous germ cell apoptosis has been identified in spermatogonia, spermatocytes, and spermatids in the testis of healthy men and in patients with non-obstructive azoospermia.

Ejaculated spermatozoa have also been shown to demonstrate changes consistent with apoptosis. However, the pathophysiology of apoptosis in spermatozoa from infertile men is unclear. A reactive oxygen species (ROS)-dependent pathway for apoptosis has been suggested based on the finding that hydrogen peroxide induces apoptosis in cell cultures. The role of ROS in inducing apoptosis in human spermatozoa has never been investigated.

In a recent study, our laboratory used the annexin-V staining assay to study the expression of phosphatidylserine, a marker of early apoptosis, in mature and immature spermatozoa from infertility patients (n = 23) and healthy donors (n = 17). Mature and immature spermatozoa were separated by density gradient centrifugation. The percentage of apoptosis was determined by epifluorescent microscopy, and the results were analyzed in relation to levels of seminal ROS.

We found that levels of apoptosis in the mature spermatozoa from the infertile men wre significantly higher compared to the healthy donors (Table 1). This is an important finding that may indicate the presence of a defect in these patients that prevents the clearance of mature spermatozoa earmarked for elimination by apoptosis.

We also found that levels of seminal ROS were significantly correlated with apoptosis both in the mature (r = 0.5, P = 0.006) and immature spermatozoa (r = 0.4, P = 0.03). Such a correlation suggests a ROS-mediated pathway of apoptosis in the infertile men. High levels of ROS may disrupt the inner and outer mitochondrial membranes, which may cause mitochondria to release cytochrome-C protein. This may activate a cascade of caspases, which in turn induce apoptosis.

These findings suggest that apoptosis has a prominent role in male infertility. Future research should look toward defining the mechanisms of regulation of apoptosis as a key mediator of abnormal sperm production. Understanding the underlying regulatory mechanisms of apoptosis is a crucial step towards the development of new therapeutic strategies for male infertility.



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Last Update : December 29, 2008
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