For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phag...

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The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

Oxidative stress occurs when the production of potentially destructive reactive oxygen species (ROS) exceeds the bodies own natural antioxidant defenses, resulting in cellular damage. Oxidative stress is a common pathology seen in approximately half of all infertile men. ROS, defined as including oxygen ions, free radicals and peroxides are generated by sperm and seminal leukocytes within semen and produce infertility by two key mechanisms. First, they damage the sperm membrane, decreasing sperm motility and its ability to fuse with the oocyte. Second, ROS can alter the sperm DNA, resulting in the passage of defective paternal DNA on to the conceptus. This review will provide an overview of oxidative biochemistry related to sperm health and will identify which men are most at risk of oxidative infertility. Finally, the review will outline methods available for diagnosing oxidative stress and the various treatments available.

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Oxidative stress and male infertility—a clinical perspective

Role of reactive oxygen species in male infertility.

The purpose of this evidence summary is to provide the best available information on the effect of anti-oxidants on mortality in patients with various diseases.

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Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases

Extensive research in our center at the Cleveland Clinic indicates that the seminal oxidative stress test has diagnostic and prognostic capabilities beyond those of conventional tests of sperm quality or functions. An oxidative stress test can accurately discriminate between fertile and infertile men and identify patients with a clinical diagnosis of male-factor infertility who are likely to initiate a pregnancy if they are followed over a period of time. In addition, the test can help select subgroups of patients with infertility in which oxidative stress is a significant factor, and who may benefit from antioxidant supplementation. Incorporation of such a test into routine andrology laboratory practice may be of particular importance to the future management of male infertility. In recent years, the generation of reactive oxygen species (ROS) in the male reproductive tract has become a real concern because of their potential toxic effects at high levels on sperm quality and function. ROS are highly reactive oxidizing agents belonging to the class of free radicals (Aitken, 1994). A free radical is defined as ‘‘any atom or molecule that possesses one or more unpaired electrons’’ (Warren et al, 1987). Recent reports have indicated that high levels of ROS are detected in semen samples of 25% to 40% of infertile men (de Lamirande et al, 1995; Padron et al, 1997). However, a strong body of evidence suggests that small amounts of ROS are necessary for spermatozoa to acquire fertilizing capabilities (Aitken, 1999). Spermatozoa, like all cells living in aerobic conditions, constantly face the oxygen (O2) paradox: O2 is required to support life, but its metabolites such as ROS can modify cell functions, endanger cell survival, or both (de Lamirande and Gagnon, 1995). Hence, ROS must be continuously inactivated to keep only a small

https://onlinelibrary.wiley.com/doi/pdf/10.1002/j.1939-4640.2002.tb02324.x

Oxidative stress and male infertility: from research bench to clinical practice.

A double-blind randomized placebo cross-over controlled trial using the antioxidant vitamin E to treat reactive oxygen species associated male infertility*†

Summary. Peroxidative damage induced by reactive oxygen species (ROS) has been proposed as one of the major causes of defective sperm function. In previous studies of the production of ROS in semen, the contribution of contaminating leucocytes was not assessed. We determined the levels of ROS in 60 semen samples from men attending our infertility clinic and demonstrated by performing extraction experiments with antibody-coated magnetic beads that, within this unselected population of patients, leucocytes were the major source of ROS in the low-density Percoll fraction. Of the sperm motion parameters examined using computerized semen analysis, beat-cross frequency was the only one significantly affected by the ROS in semen.

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Origin of reactive oxygen species in human semen: spermatozoa or leucocytes?

This review addresses critical issues in the selection of semen donors who are very fertile. Traditional semen parameters have been employed and are still used to assess pre- and post-freeze samples in order to discriminate between donors of high and low fecundity. The most predictive factor is the number of motile spermatozoa per straw and the number of motile spermatozoa inseminated. Nevertheless, no absolute standards for fertile samples can be derived from the basic semen examination. The employment of sperm function testing such as the hamster penetration test or computerized motility analysis has been shown to enhance moderately the prediction of fertility of semen samples however, further studies are necessary to determine if these improvements are clinically useful. The need to determine with a high degree of confidence the fecundity of donor semen is enhanced by limitations in the number of pregnancies allowed per donor. The recent publication of league tables in the UK has put extra pressure in clinics to use highly fertile donors. Spermatozoa are also cryostored for patients prior to cancer treatment. With the development of intracytoplasmic sperm injection every sample produced by cancer patients can be stored irrespective of the quality. However, several factors need to be elucidated to maximize the fertility of those patients. The establishment of regional centres in Europe will be a good starting point to deal with many of the issues raised in this review.

Semen characteristics and fertility tests required for storage of spermatozoa. Discussion

A high-quality basic semen analysis represents one cornerstone in the investigation of the infertile couple. However, the clinical value of traditional semen parameters in the diagnosis of male fertility is the subject of considerable debate. Some authorities clearly hold the view that apart from a diagnosis of azoospermia (or very severe oligozoospermia), a basic semen assessment is of little clinical value. A recent example of this is reflected by the opinion of McDonough (1997, p. 587), who wrote: “traditional sperm analysis as a clinical test may become nothing more than an ancestral heirloom. It may be performed spasmodically by those who know how to do it, like a 1940 airshow or laparotomy, to remind us of the good old days. We have come to the end of something. Surely someone will want to carve a headstone for traditional sperm analysis or perhaps a mausoleum would be more fitting.” Is this a correct view? Well, it does have some merit. For example, the diagnosis of an abnormal or normal semen sample according to the World Health Organization (WHO) guidelines (1992) is somewhat artificial, and this dichotomy is of limited diagnostic value. It is well documented that a significant proportion of fertile men are diagnosed as abnormal if such criteria, i.e., WHO (1992), are used (Ombelet et al, 1997). The question that needs to be asked is the following: what is the clinical value of

The diagnostic and prognostic value of traditional semen parameters.

Human gamete interaction is of fundamental biological importance, yet the molecular interactions between spermatozoa and the zona pellucida are poorly understood. Surprisingly, the role of the polypeptide backbone of zona pellucida glycoprotein 3 (ZP3), the putative ligand for spermatozoa activation, has been largely overlooked. Purified recombinant human ZP3 was expressed in Escherichia coli as a C-terminal fusion to the dimeric glutathione S-transferase (GST) from Schistosoma japonicum and was shown to induce acrosomal exocytosis in live, capacitated human spermatozoa. The level of exocytosis is comparable with that obtained using purified, glycosylated, recombinant human ZP3 [van Duin, M., Polman, J.E.M., DeBreet, I.T.M., Van Ginneken, K., Bunschoten, H., Grootenhuis, A., Brindle, J. and Aitken, R.J. (1994). Biol Reprod. 51, 607-617]. These data imply that the polypeptide chain of human ZP3 contributes to recognition of spermatozoa during acrosomal exocytosis in vitro.

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E. Kessopoulou

Papers

A double-blind randomized placebo cross-over controlled trial using the antioxidant vitamin E to treat reactive oxygen species associated male infertility*†

Origin of reactive oxygen species in human semen: spermatozoa or leucocytes?

Semen characteristics and fertility tests required for storage of spermatozoa. Discussion

The diagnostic and prognostic value of traditional semen parameters.

The polypeptide backbone of recombinant human zona pellucida glycoprotein-3 initiates acrosomal exocytosis in human spermatozoa in vitro