Treatment of the Underlying Cause of Sperm Oxidative Stress

No man is an island, entire of itself; every man is a piece of the continent, a part of the main.

John Donne (1572-1631)

The seventeenth century English poet and clergyman John Donne wrote this quote when reflecting upon the basic human need for interaction with others, not to act alone in isolation. Likewise, this quote is a useful poetic reminder to the clinician to not see sperm as an isolated testicular cell, but rather as part of a rich interlocking network of body systems, all capable of modifying sperm function. Therefore, when identifying and treating the underlying cause of sperm oxidative stress the physician must look beyond the sperm or testicle, and treat the patient in a holistic fashion.

Lifestyle and environmental factors should first be addressed when treating oxida-tive stress-related male infertility. Patients in the overweight category should be encouraged to lose weight, even though this has not yet been shown to improve sperm function by any properly conducted trial. A recent randomised control trial has shown that weight reduction created by a combination of exercise and calorie restriction does result in a significant reduction in levels of systemic oxidative stress [159], and there is no reason to believe that this improvement would not also be extended to the testicular micro-environment. Setting realistic goals for weight loss (1 kg/week for the first few weeks and then 0.5 kg/week thereafter) through a combination of dieting and exercise is important. Vigorous exercise regimes have been linked with the generation of oxidative stress [160], so it is probably best to limit exercise to a moderate amount three to four times per week to minimise any exercise pro-oxidant effect. Furthermore, exercise which significantly elevates scrotal temperature (e.g. prolonged bicycle training) is best avoided as this may also induce oxidative stress [161]. In the massively obese patient, pharmacological interventions (orlistat, sibutramine) and lap-band surgery probably have the highest chance of success.

The cessation or a reduction in smoking can best be achieved by a combination of pharmacological support (nicotine replacement therapy, bupropion) and supportive counselling. Similarly, a reduction in alcohol intake may be achieved by supportive psychotherapy.

The removal or reduction of environmental toxin exposure may require significant changes to the patient's work environment, including changing jobs where occupational exposure is unavoidable. However, simple measures such as adequate ventilation and the use of protective clothing may effectively reduce toxin exposure and improve sperm quality. Exposure to electromagnetic radiation from mobile phones can be minimised by preferably using landline phones when possible, avoiding long calls on the mobile phone and storing the mobile phone well away from the testicular area when not in use. Finally, a diet rich in antioxidant minerals (zinc, selenium) and antioxidant compounds such as vitamin C, vitamin E, carotenoids and flavonoids, all commonly present in fruit and vegetables, are likely to help augment sperm function.

While as yet untested by clinical trials, the effective treatment of systemic diseases linked with oxidative stress (diabetes, Hepatitis B/C, HIV, malaria, haemo-chromatosis, haemoglobinopathies, inflammatory bowel disease, psoriasis, rheumatoid arthritis, depression) is likely to reduce overall oxidative stress in the body and benefit sperm function. It is therefore ideal that patients delay conception until after these systemic diseases are under effective control, unless the medications used to achieve control have a detrimental effect on sperm function (e.g. meth-otrexate treatment of inflammatory conditions).

Several investigators have reported that surgical treatment of a varicocele can reduce seminal ROS levels and improve sperm DNA integrity [162-167]. While some of these studies suggest that this type of surgical treatment may result in increased rates of natural conception, this has not yet been conclusively proven by randomised controlled trials. However, as surgical ligation of a varicocele is a relatively simple low-risk procedure, it makes reasonable clinical sense to offer this therapy if lifestyle modification and simple oral antioxidants have not been successful in achieving conception.

Antibiotic therapy for men with MAGI may reduce the inflammatory stimulus causing neutrophils and macrophages to release ROS in close proximity of sperm. Two studies have now confirmed the ability of antibiotic treatment to reduce sperm oxidative stress and subsequently improve sperm quality [168, 169]. One relatively large and well-conducted study randomised men with Chlamydia or Ureaplasma infection to either 3 months of antibiotics or no treatment [169]. Compared to the controls, the antibiotic treated group exhibited a significant fall in seminal leukocytes and ROS production at 3 months, an improvement in sperm motility and a significant improvement in natural conception. A smaller study using only 10 days of antibiotic treatment did not produce any significant decline in seminal leukocyte count or improvement in motility [62]. While this study did not measure ROS production in semen, it is likely that prolonged courses of antibiotics (3 months) are required to completely irradiate difficult to treat MAGIs and reverse oxidative pathology. In addition to antibiotic treatment, non-steroidal anti-inflammatory (NSAID) drugs may also reduce seminal leukocytes production of free radicals. In one study men with antibiotic treated Chlamydia or Ureaplasma infection were randomised to either a NSAID or carnitine antioxidant and monitored for improvements in sperm quality over the next 4 months [170]. Those men treated with 2 months of NSAID followed by 2 months of carnitine had the most significant reduction in seminal ROS production and improvement in sperm motility/viability. A 1 month course of a COX-2 anti-inflammatory has been shown to significantly reduce sperm leukocyte count, while improving sperm motility, morphology and viability [171]. It would therefore appear that a combination of antibiotics followed by a course of anti-inflammatory medication is the preferred treatment path in infection-related oxidative stress.

If initial semen analysis suggests the presence of MAGI, formal semen culture and PCR analysis for Chlamydia and gonorrhoea should be performed to allow for tailored anti-microbial therapy. Of course, the presence of a confirmed sexually transmitted disease should trigger the screening and appropriate treatment of all sexual partners to prevent reinfection of the male patient.

Testicular sperm extraction is a new and controversial treatment for sperm oxidative stress damage. It is generally recognised that the primary site at which sperm oxidative attack occurs is while sperm are being stored in the epididymis. Here, the sperm sit for many days before ejaculation, unprotected from oxidative attack by supportive Sertoli cells or seminal plasma derived antioxidants. It has been proposed that by surgically collecting sperm direct from the testicle, it is possible to still obtain sperm that have yet to be damaged by ROS attack as they are "fresh off the sperm production line". Three studies have now shown that such a surgical approach can result in improved sperm DNA integrity and pregnancy outcomes [172-174]. However, surgical sperm aspiration can only be performed in conjunction with IVF-ICSI and does of course have some potential adverse effects (haemorrhage, infection, pain). Therefore, it is our practice to only offer this type of treatment when the use of ejaculate sperm has resulted in uniformly poor quality embryos despite our best conservative efforts to ameliorate sperm oxidative stress.

As previously outlined, sperm preparation using density gradient centrifugation (DGC) can exacerbate underlying sperm oxidative stress. Because of this we have moved away from routine use of DGC as a means of preparing sperm for IVF. Instead, we use a low g force centrifugation wash to remove seminal plasma, followed by a simple sperm "swim up" to isolate motile good quality sperm, as this creates less of an oxidative insult to sperm. Furthermore, sperm should be processed and stored in media containing antioxidant compounds [175] before being added to the oocytes for in vitro fertilisation. Finally, sperm should not be stored for long periods at atmospheric concentrations of oxygen as this has been shown to exacerbate oxidative stress-related DNA damage [176, 177]. A 5% oxygen environment is more than adequate to meet the sperm's metabolic needs, while minimising levels of oxidative stress.

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