Leukocytospermia and Oxidative Stress

Chapter 23 Leukocytospermia and Oxidative Stress Margot Flint , Ashok Agarwal , and Stefan S. du Plessis Abstract The invasion of microorganisms and infective bacteria in the genito- urinary tract leads to the rapid increase in white blood cells, a condition referred to as leukocytospermia. This infl ammatory response, aimed at killing the microorganisms via the production and release of reactive oxygen species (ROS), can result in pathologically high concentrations of ROS. When these concentrations greatly exceed the level required for normal physiological function, the natural defense system of scavenging antioxidants can be overwhelmed, resulting in oxidative stress (OS) thereby compromising the integrity of spermatozoa and functional parameters vital for successful fertilization. The complexity of OS is furthered when additional factors (e.g., smoking, varicocele) increase ROS levels in the male genito-urinary system. At present, the association between semen parameters and leukocyte concentrations is a focal point in the fi eld of male reproductive science. This chapter aims at exploring the relationship between leukocytospermia, OS, the harmful effects on male reproductive potential, as well as possible treatment regimes. Keywords Leukocytospermia • Oxidative stress • Male genitalia tract infections • Reactive oxygen species • Leukocytes • Antioxidants M. Flint, MSc • S. S. du Plessis, PhD, MBA (*) Division of Medical Physiology , Stellenbosch University , Francie van Zijl Avenue , PO Box 19063 , Tygerberg 7505 , South Africa e-mail: [email protected] A. Agarwal, PhD Center for Reproductive Medicine , Cleveland Clinic , Lerner College of Medicine, 9500 Euclid Avenue , Cleveland , OH 44195 , USA A. Agarwal et al. (eds.), Studies on Men’s Health and Fertility, Oxidative Stress 517 in Applied Basic Research and Clinical Practice, DOI 10.1007/978-1-61779-776-7_23, © Springer Science+Business Media, LLC 2012 518 M. Flint et al. 23.1 Introduction Various infective pathological conditions can result in the defensive reaction of tissues to the attack of microorganisms. An infection leads to the activation of specifi c immune cells, in particular a form of white blood cells (WBC’s) known as leukocytes. The result which arises from such defensive action is the generation of reactive oxygen species (ROS). These are chemically reactive molecules containing oxygen and are produced by the invading leukocytes. The defensive oxidative path- way that the ROS take in killing microbes can have a biopositive effect when ROS concentrations are maintained at a low level or are counterbalanced by the protec- tive antioxidant scavenging system which maintains homeostasis [ 1 ] In certain conditions whereby homeostasis is disrupted, an imbalance arises between oxidants and antioxidants, in favor of the former, resulting in a condition known as oxidative stress (OS) [ 1, 2 ] . The harmful effect of this imbalance is OS-induced damage, which is a threat to all cellular elements, including: amino acids, carbohydrates, lipids, and nucleic acids [ 3 ] . OS is considered as the circumstance which underlies the etiology of various human conditions [ 4 ] . In context of this, a wide variety of diseases exist in which the pathophysiological role of ROS and OS has been implicated in the patho- genesis of the condition. Examples of these include: cancer, diabetes, and infl ammatory bowel disease [ 3 ] . In the male reproductive system, the harmful effect that ROS can have on sperm and their parameters has been known for a relatively long period of time. In the mid- 1980s, Professor John Aitken and his group pioneered studies into the activities of ROS in male reproductive biology [ 3 ] , which has continued comprehensively over the following years, in particular the Cleveland Clinic Foundation in America which has extensively researched the effects of OS in male infertility. Research into the negative infl uence that leukocytospermia can have on semen parameters introduced investigations into the role of leukocyte-produced ROS. ROS are spontaneously generated and required at a basal level for certain spermatozoal physiological functions [5 ] . It has been proven that samples considered being per- oxidase-positive have higher concentrations of ROS [ 6 ] and these polymorphonu- cleated leukocytes (PMNL) release oxygen radicals, such as hydrogen peroxide and superoxide which are known toxic factors towards spermatozoa. Irrelevant of the concentration of leukocytes in semen, the presence of these WBC’s have been shown to be associated with OS which can negatively effect semen parameters such as sperm concentration and morphology [ 7 ] . 23.2 Male Genital Tract Infections Specifi c seminal parameters and chemical components which contribute towards the ejaculate can serve as diagnostic tools in assessing if the accessory sex glands are normally functioning [8 ] . Diverse irregularities or deviations from the standard 23 Leukocytospermia and Oxidative Stress 519 reference values of these physical characteristics indicate a possible underlying pathophysiological condition [ 9 ] . The response of the genito-urinary tract to the invasion of microorganisms and infl ammation is an important component of the immune defense system [ 10 ] . The reaction is considered to be extremely similar to the reaction in other body sites [11 ] . Therefore, a semen analysis can serve as a valuable diagnostic tool in assessing possible disorders of the male genital tract and the secretory pattern of the male accessory sex glands [ 9 ] . The most common infective bacteria in mixed accessory gland infection (MAGI) are Chlamydia trachomatis (41.4%), a common sexually transmissible pathogens in sexually active young men, followed by Ureaplasma urealyticum (15.5%) and Mycoplasma hominis (10.3%) [ 12, 13 ] as well as Neisseria gonorrhoeae , an additional marker of seminal tract infection [ 8, 14 ] . In men experiencing infertility issues, the presence or colonization of U. urealyticum and M. hominis in semen is a common fi nding [14 ] and semen cultures of bacterial pathogens remain the most common diagnostic method for seminal tract infections [ 8 ] . This passive or active invasion of these bacterial strains induces a generalized or local reaction in the urogenital tract [ 1 ] . This infl ammatory response which can continue for extended periods of time leads to a pathological condition resulting in the activation of seminal WBC’s [ 15 ] . Inadequate treatment of an infection and eradication of bacterial pathogens can lead to a chronic bacterial infection of the male accessory sex glands [ 4 ] . 23.3 Leukocytospermia Human semen is a heterogeneous fl uid which contains a variety of cellular elements beyond spermatozoa. Several immunologic factors are present in human semen, such as chemokines, immunoglobulins, and growth factors [ 16 ] , as well as a subset of WBC’s. The microscopic evaluation of almost all semen samples will display nonspermatozoal cells, in particular WBC’s [ 17 ] , which encompass various forms such as granulocytes, lymphocytes, and macrophages [13 ] . An abnormally high concentration of WBC’s in the semen is a condition called leukocytospermia, also referred to as leukospermia, pyospermia, or pyosaemia [ 18 ] . An increased concentration of leukocytes is the basic molecular defense mechanism against the detection of foreign organisms. The World Health Organization (WHO) criteria defi nes leukocytospermia as the presence of >1 × 10 6 WBC’s/mL of semen [ 18 ] . This thresh- old is regarded as a possible indicator of an ongoing male genital tract infection [ 18 ] . Specifi cally, the detection of pathological concentrations of leukocytospermia with the exclusion of a bladder infection or urethritis has been suggested as a basic diagnostic tool in recognizing genital tract infection [ 19, 20 ] . The activation of PMNL, which constitute 50–80% of the total seminal WBC count [ 8, 21 ] , results in releasing a protease by degranulation known as elastase [ 22 ] . The presence of this particular protease is considered a highly reliable and sensitive marker of an asymptomatic infection [ 23 ] and can be used in diagnosing 520 M. Flint et al. a clinically silent illness [ 24 ] . At present, due to the fact that the condition is asymptomatic and various sites in the reproductive system can be affected, the exact location of the origin of excess leukocytes is unknown [ 25, 26 ] . Due to the lack of understanding as to where exactly leukocytes are produced from, their release may be initially prompted by an infl ammatory response of the genital tract to a bacterial invasion and then continually produced in their absence by immuno- logical activity [ 7 ] . 23.4 Effects of Leukocytospermia Among the increasing number of partners experiencing fertility challenges, it has been estimated that the male factor is solely responsible for 30% of the failed fertilization rates [ 26 ] . Symptomatic and asymptomatic urinary tract infections which produce leukocytes is a condition frequently observed in infertility clinics [ 27, 28 ] . This negative effect on the male’s fertilizing potential can be a result of the direct correlation which is found between increased concentrations of leukocytes and chromatin alterations and morphological abnormalities [6 ] . Despite the controversy which has been created from studies, the general biological and clinical conclusion is that the presence of leukocytes in semen, regardless of the concentration [ 7 ] , is associated with OS and can be of

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