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

Spermatogenesis is an extremely active replicative process capable of generating approxi mately 1,000 sperm a second. The high rates of cell division inherent in this process imply correspondingly high rates of mitochondrial oxygen consumption by the germinal epithelium. However, the poor vascularization of the testes means that oxygen tensions in this tissue are low1 and that competition for this vital element within the testes is extremely intense. Since both spermatogenesis2 and Leydig cell steroidogenesis3,4 are vulnerable to oxidative stress, the low oxygen tension that characterizes this tissue may be an important component of the mechanisms by which the testes protects itself from free radical-mediated damage. In addition, the testes contain an elaborate array of antioxidant enzymes and free radical scavengers to ensure that the twin spermatogenic and steroidogenic functions of this organ are not impacted by oxidative stress. These antioxidant defence systems are of major importance because peroxidative damage is currently regarded as the single most important cause of impaired testicular function underpinning the pathological consequences of a wide range of conditions from testicular torsion to diabetes and xenobiotic exposure. This chapter sets out the specific nature of these antioxidant defence systems and also reviews the factors that have been found to impair their activity, precipitating a state of oxidative stress in the testes and impairing the latter’s ability to produce viable spermatozoa capable of initiating and supporting embryonic development.

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Antioxidant systems and oxidative stress in the testes.

Origins of lifetime health around the time of conception: causes and consequences.

DNA damage is a common feature of human spermatozoa with purported links to poor rates of conception, impaired embryonic development, an increased incidence of miscarriage and the appearance of various kinds of morbidity in the offspring including childhood cancer. However, difficulties in interpretation arise, because these associations are not consistently observed across all data sets. Such inconsistency reflects the inherent complexity of the reproductive process, large variations in sample size, differences in patient selection, inadequate study design as well as inter-individual differences in the type of DNA damage being detected and the effectiveness of repair mechanisms in the oocyte. This review considers the type, source and measurement of DNA damage in human spermatozoa. It also addresses the clinical utility of the information generated in such studies, and highlights areas where further research is needed to bridge the gap between an intriguing biological phenomenon and the evidence-based clinical management of male patients characterized by high levels of DNA damage in their spermatozoa.

Biological and clinical significance of DNA damage in the male germ line.

The results of several studies point to an increased likelihood of abnormal semen parameters among overweight men, and an elevated risk for subfertility among couples in which the male partner is obese. Obesity is, therefore, associated with a higher incidence of male factor infertility. Several mechanisms might account for the effect of obesity on male infertility, both directly and indirectly, by inducing sleep apnea, alterations in hormonal profiles (reduced inhibin B and androgen levels accompanied by elevated estrogen levels) and increased scrotal temperatures, ultimately manifesting as impaired semen parameters (decreased total sperm count, concentration and motility; increased DNA fragmentation index). Neither the reversibility of obesity-associated male infertility with weight loss nor effective therapeutic interventions have been studied in-depth. The increasing prevalence of obesity calls for greater clinical awareness of its effects on fertility, better understanding of underlying mechanisms, and exploration into avenues of treatment.

https://www.clevelandclinic.org/reproductiveresearchcenter/docs/scipubs2009_01.pdf

The effect of obesity on sperm disorders and male infertility.

BACKGROUND: Diabetes mellitus (DM) is increasing in men of reproductive age. Despite this, the prevalence of diabetes in men attending fertility clinics is largely unknown. Furthermore, studies examining the effects of DM on sperm fertility potential have been limited to conventional semen analysis. METHODS: Conventional semen analysis (semen volume, sperm count, motility and morphology) was performed for 27 diabetic (mean age 34 ± 2 years) and 29 non-diabetic subjects (control group, men undergoing routine infertility investigations, mean age 33 ± 1 years). Nuclear DNA (nDNA) fragmentation was assessed using the alkaline Comet assay and mitochondrial DNA (mtDNA) deletions by Long-PCR. RESULTS: Other than a small, but significant, reduction in semen volume in diabetic men (2.6 versus 3.3 ml; P < 0.05), conventional semen parameters did not differ significantly from control subjects. Diabetic subjects had significantly higher mean nDNA fragmentation (53 versus 32%; P < 0.0001) and median number of mtDNA deletions (4 versus 3; P < 0.05) compared with control subjects. CONCLUSIONS: Diabetes is associated with increased sperm nuclear and mtDNA damage that may impair the reproductive capability of these men.

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Insulin dependant diabetes mellitus: implications for male reproductive function

Light microscopic studies comparing sperm parameters show little association between diabetes and male fertility. However, with the introduction of new analytical techniques, evidence is now emerging of previously undetectable effects of diabetes on sperm function. Specifically, a recent study has found a significantly higher sperm nuclear DNA fragmentation in diabetic men. As advanced glycation end products (AGEs) are important instigators of oxidative stress and cell dysfunction in numerous diabetic complications, we hypothesized that these compounds could also be present in the male reproductive tract. The presence and localization of the most prominent AGE, carboxymethyl-lysine (CML), in the human testis, epididymis and sperm was determined by immunohistochemistry. Parallel ELISA and Western blot analyses were performed to ascertain the amount of CML in seminal plasma and sperm from 13 diabetic and nine non-diabetic subjects. CML immunoreactivity was found throughout the seminiferous epithelium, the nuclei of spermatogonia and spermatocytes, in the basal and principle cells cytoplasm and nuclei of the caput epididymis and on most sperm tails, mid pieces and all cytoplasmic droplets. The acrosomal cap, especially the equatorial band, was prominently stained in diabetic samples only. The amount of CML was significantly higher (p = 0.004) in sperm from non-diabetic men. Considering the known detrimental actions of AGEs in other organs, the presence, location and quantity of CML, particularly the increased expression found in diabetic men, suggest that these compounds may play a hitherto unrecognized role in male infertility.

Advanced glycation end products accumulate in the reproductive tract of men with diabetes

The effects of diabetes mellitus on male reproductive health have not been clearly defined. A previous publication from this group reported significantly higher levels of nuclear DNA fragmentation and mitochondrial DNA deletions in spermatozoa from men with type 1 diabetes. This study compared semen profiles, sperm DNA fragmentation and levels of oxidative DNA modification in spermatozoa of diabetic and non-diabetic men. Semen samples from 12 non-diabetic, fertile men and 11 type 1 diabetics were obtained and subjected to conventional light microscopic semen analysis. Nuclear DNA fragmentation was assessed using an alkaline Comet assay and concentrations of 7,8-dihydro-8-oxo-2-deoxyguanosine (8-OHdG), an oxidative adduct of the purine guanosine, were assessed by high-performance liquid chromatography. Conventional semen profiles were similar in both groups, whilst spermatozoa from type 1 diabetics showed significantly higher levels of DNA fragmentation (44% versus 27%; P < 0.05) and concentrations of 8-OHdG (3.6 versus 2.0 molecules of 8-OHdG per 10(5) molecules of deoxyguanosine; P < 0.05). Furthermore, a positive correlation was observed between DNA fragmentation and concentrations of 8-OHdG per 10(5) molecules of deoxyguanosine (rs = 0.7, P < 0.05). The genomic damage evident in spermatozoa of type 1 diabetics may have important implications for their fertility and the outcome of pregnancies fathered by these individuals.

https://www.rbmojournal.com/article/S1472-6483(10)60602-5/pdf

A.B. Atkinson

Papers

Insulin dependant diabetes mellitus: implications for male reproductive function

Advanced glycation end products accumulate in the reproductive tract of men with diabetes

Increased concentrations of the oxidative DNA adduct 7,8-dihydro-8-oxo-2-deoxyguanosine in the germ-line of men with type 1 diabetes.

Advanced Glycation End Products (AGEs) accumulate in the Reproductive Tract of Men with Diabetes.