References

The effect of obesity on sperm disorders and male infertility. Nat Rev Urol. 2010 7(3) 153-61. 2. World Health Organization. WHO technical report diet, nutrition and the prevention of chronic disease. World Health Organization, Geneva. 2003. http www.who int en. Accessed 6 Feb 2011. 3. Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP. The continuing epidemics of obesity and diabetes in the United States. JAMA. 2001 286 1195-200. 4. Hedley AA, Ogden CL, Johnson...

Targeting eNOS Uncoupling

BH4, an essential NOS cofactor, and its precursor sepiapterin, are commonly used to prevent eNOS uncoupling and oxidative stress and to prevent the development or progression of cardiovascular diseases in animal models 24 . Several large clinical trials are testing the efficacy of the oral formulation of BH in the treatment of systemic hypertension, peripheral arterial disease, coronary artery disease, pulmonary arterial hypertension, and SCD 23 . In addition, several agents are being tested...

Physical Manifestations

Obese males also encounter physical mechanisms that may enhance and, thus, further attribute to decreased fecundity and fertility. These problems include hypogo-nadotropic hypogonadism (HH), erectile dysfunction (ED) and sleeping disorders, such as sleep apnea. 26.3.3.1 Hypogonadotropic Hypogonadism HH is a form of secondary hypogonadism in which a problem with the pituitary or hypothalamus gland causes the absence or a decreased function of the male testes. This condition is elicited from a...

Nonenzymatic Epididymal Scavengers

Many molecules with intrinsic radical-scavenging activity exist in the epididymis compartment. I do not intend here to present them in an exhaustive fashion. I only focus on those that are quite classical and those that have been highlighted because they are present in unusual concentrations in this tissue. 5.3.1.1 Glutathione and Thiol-Containing Compounds The tripeptide glutathione (GSH) is generally the most important abundant nonenzymatic scavenger in and outside cells. Its cysteine residue...

Laboratory Application of Chemiluminescent Assays

From the above descriptions, it will be evident that while chemiluminescent probes such as luminol and lucigenin cannot yield specific data on ROS generation by human spermatozoa, they are nevertheless sensitive, semiquantitative indicators of redox activity in these cells and many publications have shown that the chemilumi-nescent activity detected in their presence is inversely related to sperm function and significantly elevated in the cases of male infertility 23, 46-54 . A unique...

Varicocele and Oxidative Stress

Seminal oxidative stress (OS) results from an imbalance between ROS production (superoxide anions, hydrogen peroxide, hydroxyl radical, hydroperoxyl radical, and nitric oxide) and ROS scavenging by seminal antioxidants (superoxide dismutase, glutathione peroxidase, catalase, uric acid, vitamins C and E, and albumin). Seminal OS is believed to be one of the main factors in the pathogenesis of sperm dysfunction and sperm DNA damage in male infertility 40-43 . Spermatozoa are particularly...

Endogenous Antioxidants in the Penis in ED

Endothelial and smooth muscle cells of the rat penis contain antioxidants such as SOD3 37,46,113,114 , catalase 115 , reduced glutathione 38, 65 , and glutathione peroxidase 116 . Cavernosal tissue and blood from men contain vitamin C, albumin, bilirubin, uric acid, and glutathione 42, 117 . Controversial data were, however, obtained regarding the status of endogenous antioxidants in the diseased penis. Penis from aged animals exhibit decreased levels of reduced glutathione but increased...

Measurements

The assessment of very low levels of ROS needs special caution because the probes themselves and any of the products under study may influence cells or cause interference in the measurement techniques. First of all, most of the probes can affect capacitation, even to the point of inhibition, simply because they react with ROS to produce a signal and, at the same time, they remove too much of these same ROS that are essential to trigger capacitation. An example is that of luminol and lucigenin,...

Xanthine Oxidase

Xanthine oxidase catalyzes the oxidation of hypoxanthine to xanthine and uric acid in a reaction that involves a one-electron transfer to oxygen to yield superoxide. The source of xanthine oxidase is not completely clear, but increased cholesterol levels, liver damage, inflammation, and hypoxia may stimulate the release of the enzyme from the liver and other organs into the circulation. This circulating xanthine oxidase binds to endothelial cells to produce superoxide 20 . Endothelial cells...

Oxidative Stress in Diabetes Mellitus Associated ED

Diabetes mellitus is one of the major risk factors for ED. It has been estimated that 50-75 of diabetic men have ED 41 . Compelling data from molecular, cellular, and in vivo animal studies implicate a crucial role for oxidative stress in the development and progression of ED associated with diabetes. Both hyperglycemia and free fatty acids augment ROS production. Penile tissue and blood from diabetic men with ED 42-45 and type 1 diabetic animals 46-53 contain high levels of superoxide....

Oxidative Stress and the Endometriosis

Researches did not report a definitive conclusion about the association between OS and endometriosis. Endometriosis may result in infertility due to mechanical blockage of the sperm-egg union by endometriomata, or adhesions, or pelvic anatomy malformations. Peritoneal fluid of women with endometriosis has been found to be increased in size and contains high concentration of activated macrophages, cytokines, and pros-taglandins. Activated macrophage may be responsible for increased production of...

Detrimental Effects of ROS in Patients with Prostatitis

In patients suffering from prostatitis, a negative association with sperm motility and morphology has repeatedly been shown because this condition is also associated with increased leukocyte infiltration in semen. 109, 110 . Accordingly, significantly increased seminal oxidative stress has been observed in patients with prostatitis categories NIH I, NIH II, NIH IIIA and NIH IV 111, 112 . However, even in prostatitis categories NIH III (chronic abacterial prostatitis) and NIH IIIB...

Oxidative Stress and Female Fertility

ROS play crucial roles in the female reproduction they may act as mediators in hormone signaling, oocyte maturation, ovarian steroidogenesis, ovulation, luteoly-sis, luteal maintenance in pregnancy, implantation, compaction, blastocyst development, germ cell function, and corpus luteum formation 135 . Oocytes and spermatozoa can also experience direct damage, which can lead to impaired fertilization due to an environment of OS in the peritoneal cavity. Many events related to infertility may...

Oxidative Stress in Female Reproductive System and ART Outcomes

Of the patients attending an infertility clinic, 40 have detectable levels of ROS formation in their semen and 25 have levels higher than the normal limits 165 . Men with high levels of ROS may have a lower fertility potential compared to those with low ROS 39, 110 . A reduction in ROS production could significantly improve ART outcome 166 . Oxidative stress can originate from the early steps of ART involving the oocyte, sperm, and embryo, as well as later on in the endometrial environment...

Strategies to Overcome OS in Assisted Reproduction

ROS may originate from the male or female gamete or the embryo or indirectly from the surroundings, which includes the cumulus cells, leucocytes, and culture media. In human IVF ICSI procedures, the clinical pregnancy rates have remained unchanged at 30-40 218 . It is hypothesized that the altered redox state in in vitro conditions may play a role in poor ART outcomes, and controlling OS may improve ART outcomes. Fertilization and embryo development in vivo occur in an environment of low oxygen...

Oxidative Stress and Chronic Bacterial Prostatitis

Bacteria responsible for prostate infection may originate from the urinary tract or can be sexually transmitted 28, 29 . The OS observed during chronic bacterial prostatitis is the result of elevated ROS production and or reduced total antioxidant capacity 20, 30 . Indeed, infecting microorganisms trigger an inflammatory defense reaction in the prostate with a resulting OS due to ROS overproduction 18, 25, 31, 32 . Current or past C. trachomatis infection has also been linked with an increased...

Aging and DNA Damage and Repair Relationship to Oxidative Stress

Several studies have been done on the effects of oxidative stress and antioxidants on male germ cells during aging however, there are relatively few studies designed to understand whether how oxidative stress is related to DNA damage in male germ cells in the testes. Under normal conditions, sperm maturing in the epididymis generate low levels of ROS, a process that is thought to be related to capacitation 94 . One of the main sources of ROS is electron leakage from the mitochondria of...

Carnitine

Carnitine is a water-soluble antioxidant derived mostly from the human diet. Some sources include fish, meat, poultry, and dairy products. It is formed from the biosynthesis of lysine and methionine. Carnitine is found in nearly all cells of the body and is essential in sperm energy production by transporting long-chain fatty acids from the cytosol into the mitochondria. In addition, carnitine is involved in the removal of cytotoxic compounds from the cell. Normally, the body produces a...

Cocaine

Cocaine promotes oxidation via involvement of the enzymes inducible nitric oxide synthase (iNOS) and xanthine oxidase 39 . Daily intraperitoneal injection of 20 mg kg cocaine in rats shows a significant oxidative stress in basal conditions that may be related to their impaired learning ability 39 , It may probably mean that changes in intensity of LPO processes observed during prenatal cocaine exposure are not directly linked to NO pathway activation. Use of cocaine within 2 years of their...

Conclusion

The effect of heat stress on spermatogenesis has been investigated for several decades. As described in this chapter, the mode of heat stress is very different in in vitro experiments, animal experiments, and human studies. Therefore, close attention must be paid to recognize the cells exposed and the type of heat stress. Conventionally, in vitro and animal experiments do not fit the pathophysiology of human beings. Further investigation in this area will reveal more insights regarding the...

Conclusions

Conditions such as varicocele, genitourinary tract infection, leukocytospermia, and idiopathic infertility are associated with OS and have the potential of causing male factor infertility. Environmental factors such as smoking and pollution can also lead to elevated levels of ROS and subfertility in males. OS results in in vitro and in vivo clinical complications that may affect male fecundity. High ROS levels impair male fertility through lipid peroxidation, decreased motility, DNA damage, and...

Contents

1 Electromagnetic Radiation and Oxidative Stress Geoffry N. De Iuliis, Bruce V. King, and R. John Aitken 2 Mitochondria as a Source of ROS 3 Cryostorage and Oxidative Stress 4 Sperm Capacitation as an Oxidative 57 Eve de Lamirande and Cristian O'Flaherty 5 Protection of Epididymal Spermatozoa 6 Lipid Peroxidation in Human 119 7 Age and Oxidative Stress in the Germ 131 Bernard Robaire, Catriona Paul, and Johanna Selvaratnam 8 Heat and Oxidative Stress in the Germ 149 9 Cytokines and Oxidative...

Critical Commentary

Although there is a paucity of information in the literature, preliminary reports suggest a promising role for NSAIDs in improving sperm quality. They are thought to stabilize lysosomal membranes, thereby partially preventing apoptosis 94, 97, 98 . Some evidence has shown that an increase in prostaglandin concentration in seminal plasma can inhibit spermatic function 98 . One study found success in treating men with iOAT and prostaglandin-F2 in seminal plasma by treating them with a NSAID...

Cytokines and Spermatogenesis

Testes are considered to be an immunoprivileged organ due to their tolerance of autoantigens secreted during sexual maturity by reproductive cells. This phenomenon supports spermatogenesis 6 . The mechanisms which protect testes against autoimmune diseases are immunological anatomical blood-testis barrier (BTB) which protects against the antigenic leakage out of germ cells to immunological, intraparenchymal cells and against the transition of antibodies from endothelium to the lumen of...

Dihydroethidium

The first probe to be assessed in detail in this context was dihydroethidium or hydro-ethidine (DHE) 69 . This probe is nonfluorescent in its own right, but on oxidation will produce DNA-sensitive fluorochromes that will stain the mitochondrial and nuclear DNA (Fig. 14.6). The application of this probe is not straightforward, however, and its interpretation has to be considered with care. One of the major issues with DHE is that it is generated by the chemical reduction of ethidium bromide...

Discussion

With the advances in technology that revolutionize everyday lifestyles and industrialization all around the world, obesity has become a modern-day global pandemic. Moreover, as obesity is predicted to reach record numbers in the near future and fertility rates continue to plummet, scientists have began to link the two together. They have revealed that as much as half of all fertility problems come from male-factor defects. Many researchers have pointed to the increased adipocyte accumulation to...

DNA Damage

DNA is usually protected from oxidative damage by its condensed form and the antioxidants present in the cytoplasm. After lipid peroxidation, DNA in both the mitochondria and nucleus becomes more susceptible to react with ROS. Sperm DNA damage has been associated with poor sperm parameters, infertility, and poor in vitro fertilization (IVF) outcomes 14 . DNA damage may present as fragmentation, deletions, frameshifts, point mutation, and DNA cross-links, as well as other genetic modifications...

Effects of Heat Stress on the Cell Kinetics of the Germ Cells

Transitions during spermatogenesis from mitotic divisions are accompanied by dynamic transitions in the expression of different networks of cell cycle genes, and they suggest that at least some of this differential gene expression may play key roles in regulating the progression of spermatogenic cells through the process of spermatogenesis 89 . Decreased expression of proliferating nuclear cell antigen (PCNA), which is a marker of DNA synthesis, especially in spermatogonia, has been reported in...

Enzymatic Scavengers

Primary antioxidant enzymes work in a tightly associated manner constituting the commonly called antioxidant catalytic triad (Fig. 5.2). SOD (EC 1.15.1.1) recycles the spontaneous formation of superoxide anion and doing so generates H2O2. To adapt H2O2 concentrations precisely, cells rely on three enzymes, GPx (EC 1.11.1.9), catalase (CAT EC 1.11.1.6), and peroxiredoxins (PRDX EC 1.11.1.5). GPx and PRDX activities cover both the intracellular and the extracellular compartments while CAT located...

Fatty Acids and the Induction of Lipid Peroxidation

So far in this review, the emphasis has been placed on the susceptibility of unsaturated fatty acids to oxidative attack. However, free PUFA may also be a significant cause of oxidative stress in these cells. This suggestion hinges on the ability of free, unesterified PUFA to stimulate ROS generation by sperm mitochondria 42 . In this study, a wide range of free PUFA (arachidonic, linoleic, and docosahexaenoic acids DHAs ) were found to trigger mitochondrial ROS generation by human spermatozoa,...

Introduction

The pathophysiology of erectile dysfunction (ED) refers to the derangement of the normal erectile response, which involves neurological and vascular processes resulting in relaxation of the smooth muscles in the penis and penile erection. It is increasingly evident that oxidative stress, an imbalance between the production and B. Musicki, PhD (*) A.L. Burnett, MD Department of Urology, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, A. Agarwal et al. (eds.), Studies on Men's Health...

Mammalian GPx Epididymal Coverage

It has been shown that the mammalian epididymis expresses several GPx and, to date, it is the organ in which, although at different levels and in different subterritories, most of the known GPx are expressed, from GPxl to GPx8 6, 8 . Within the GPx multigenic family, four members (GPxl, GPx3, GPx4, and GPx5) are particularly well represented and characterized and are located in the epididymal epithelium, luminal compartment, and spermatozoa. Figure 5.3 presents a diagram of the localization of...

Management 2041 Diagnosis

The diagnosis of OS, DNA damage, and apoptosis in the context of male infertility can be made by focusing on the clinical and laboratory presentations that were proven to be associated with these conditions. Additionally, there are specific tests that can be used to identify whether OS, DNA damage, and apoptosis do actually play a role in a specific case of male infertility 113 . There has been no recommendation to implement these tests in routine clinical practice to date. However, there are...

Oxidative Stress and MAGI

MAGI are a consequence of microorganism canalicular spreading via urethra, prostate gland, seminal vesicles, deferent duct, epididymis, and testis. Hematogenous infections are rare. In the diagnostic workup of MAGI, sperm analysis is viewed as a fundamental step. Indeed, MAGI is diagnosed in the presence of one or more sperm parameter abnormalities (OAT) associated with a combination of two or more of the following factors (Fig. 25.1) Factor A history positive for urinary tract infections and...

Oxidative Stress and Ovarian Function

Different levels of ROS were detected in the follicular fluid environment that may interfere with folliculogenesis and steroidogenesis 139, 140 . Folliculogenesis refers to the maturation of the ovarian follicle, a densely packed shell of somatic cells that contains an immature oocyte. The production of cytokines, kinins, prosta-glandins, proteolytic enzymes, nitric oxide, and steroids before last stage of oocyte production enhances the flow of blood to the ovary 141 . Low intrafollicular...

Oxidative Stress DNA Damage and Protamines

The molecular structure of the human protamine-DNA complex is still poorly understood 48-51 . Most of the models proposed to date are a mere approximation of the actual structure. There is general consensus that the sperm chromatin responds differentially to stressing factors. The reason for this differential response still belongs to the field of speculation. One of the explanations for this differential sensitivity could be related to the fact that the protamines facilitate an efficient...

Oxidative Stress in the Seminiferous Tubules and Epididymis

As previously indicated, oxygen radical-induced DNA damage may take place in germ cells during the process of spermatogenesis leading to sperm DNA fragmentation and telomere damage. This may be the result of either an increase in oxygen radical production, a decrease in the expression of antioxidant enzymes or both. Although in most mammalian species the process of spermatogenesis results in the release of mature sperm into the seminiferous tubules, in some species, including the human, a...

Oxidative Stress Theory of Aging

The free radical theory of aging was first proposed by Harman 12 . This theory essentially implies that biological aging is a result of the production of increased levels of ROS. The theory maintains that the normal respiratory chain function of the mitochondria results in sustained ROS production throughout an organism's life span, resulting in an accumulation of ROS-induced damage 12 . It has been proposed that ROS of mitochondrial origin, when produced consistently over time, can cause...

Role of Oxidative Stress and Inflammation in the Pathogenesis of BPH

Inflammation is a complex phenomenon consisting of humoral (cytokines) and cellular (leukocytes) components. Inflammation can influence the tissue microenvironment through the production of free radicals, COX activity, and NO synthesis, all linked to the deleterious oxidative effect of inflammation on prostatic tissue. These factors can alter protein structure and function, induce gene changes, cause post-translational modifications, including those involved in DNA repair and apoptotic...

ROSGenerating Enzymes in Human Sperm Capacitation NOS and Oxidase One or Two Enzymes

The three isoforms of NOS (epithelial, neuronal, and inducible) are found in spermatozoa both in the head and flagellum (immunoblotting and immunocytochemis-try data) 30, 31, 66 . The oxidase responsible for sperm O.'- generation during capacitation is, however, still elusive. It should be at the membrane level because O2'- is released in the extracellular milieu and SOD (cell impermeant) prevents capacitation 55 . The first consideration given to the possibility that the sperm enzyme is of the...

Signal Transduction Cascades and Phosphorylation Events

Protein Tyr phosphorylation increases during sperm capacitation, from about 2 h of incubation, and is often considered as a marker for this process 2, 17, 39, 44, 103, 104 . However, over the years, we described several transduction cascades forming a tightly regulated network of phosphorylation events, all regulated by ROS, that occur as earlier steps and are prerequisites for capacitation. Soon after the onset of capacitation, there is a rise in cAMP levels 1, 2, 39, 43, 105, 106 both...

The Positive Impact of Lipid Peroxidation The Induction of Sperm Capacitation

We have known since the excellent studies published by Claude Gagnon and Eve de Lamirande in the early 1990s that sperm capacitation is an oxidative process that is heavily dependent on the active generation of ROS 9 . While several independent laboratories have confirmed the oxidative drive to capacitation 10-12 , the way in which changes in the redox status of human spermatozoa allows these cells to attain a capacitated state has remained largely unresolved. To date, there is evidence that...

Electromagnetic Radiation and Oxidative Stress in the Male Germ Line

King, and R. John Aitken Abstract The beneficial impacts of mobile-based communications on society are considerable. Health concerns over the broadcast of radio frequency electromagnetic waves, which carry the information for this medium, are now gaining momentum but are not without its controversies. Studies in the past that aim to determine whether concerns are warranted are sometimes lacking in impact because of poor understanding of radiation science....

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 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....

The Influence ofROS and Total Antioxidant Capacity in IVF and ICSI Cycles

Women who have undergone IVF have a tendency toward higher levels of ROS in their follicular fluid than those who conceive naturally 170 . Bedaiwy et al. 173 assessed day 1 culture media ROS effects on fertilization rates, cleavage rates, fragmentation, and blastocyst formation after prolonged culture. The authors compared conventional IVF with ICSI in order to determine which technique produced higher ROS levels. The results showed that slow development, high fragmentation, and reduced...

EMR Defined

EMR is a form of radiation that ranges from extremely high-energy cosmic and gamma rays at frequencies above 1018 Hz down through the visible spectrum (frequencies near 1015 Hz) to the relatively low-energy microwave (1010 Hz or 10 GHz) and radio frequencies (108 Hz or 100 MHz) (Fig. 1.1). The part of the spectrum used for mobile phone communications is in the frequency range from 800 MHz to 2.5 GHz, labelled Global System for Mobile Communications (GSM) in Fig. 1.1. EMR may be considered to...

Marijuana

MJ is the most commonly used recreational drug worldwide 13-15 . It is one of the most commonly abused substances in the USA, where 3.3 of young adults 19-28 years of age use MJ on a daily basis and 54 of people between 26 and 34 have used MJ at least once 16 . Medicinal uses of cannabis date back thousands of years, and both crude smoke and the psychoactive component, delta-9-tetrahydocannabinol (D9-THC), have been used for treating migraine headache, glaucoma, nausea, and anorexia 17 . MJ...

OS and In Vitro Infertility

Reactive oxygen and nitrogen species that lead to OS have a negative impact not only on male fertility in natural conception but also on assisted reproductive technologies (ART) in an in vitro setting. In any ART procedure, there is a risk of oxidative damage from sources such as exposure to ambient air 70 . Other sources of OS in an ART setting include the oocyte, embryo, cumulus cells, and immature sperm cells 6 . In addition, spermatozoa used in any ART procedure originate from an...

Clinical Implications

2.2.5.1 Mitochondrial ROS and DNA Damage A strong marker for oxidative DNA damage is the major oxidized base adduct formed when DNA is subjected to attack by ROS, 8OHdG. Clinically, this marker has been shown to be higher in spermatozoa of subfertile patients 132 . The importance and clinical implications of oxidative DNA damage will be covered in Chap. 11, although it is important to further emphasize the ability of mitochondrial ROS to contribute to nuclear DNA damage. Admittedly mtDNA damage...

The Role of Cytokines in Semen Inflammation

Fertilization Oxidative Stress

The activation of leukocytes at a site of the inflammatory process is strictly connected with both the oxidative burst and the initiation of an immune response directed against an infectious agent. The secretion of cytokines is one of the first signals from the innate host defense to combat inflammation. Proinflammatory cytokines are one of the mediators of the host response to inflammatory reaction. Generated by both the cells of the immune system as well as those of surrounding tissues in...

Studies on EMR and Male Infertility

Within the last decade, there have been several well-designed and executed studies on the effects of mobile phone radiation on spermatozoa, covering three main areas, clinical epidemiological, human (in vitro) and in vivo animal models. The association between RF-EMR and male infertility was initially suggested by an epidemio-logical study in 2001 where it was speculated that differences in fertility parameters from Chinese males in various professions may be due to EMR exposures 52 . More...

Obesity and Male Infertility

Infertility Obesity Mechanism

BMI has been found to be associated with altered sperm parameters in numerous reports. In a recent study investigating factors related to semen quality, the prevalence of infertility in obese men was found to be three times greater than in male partners of couples with idiopathic or female-factor infertility 12 . Moreover, sperm density and total count was shown to have a statistically significant negative correlation to increasing BMI 12 . Another study looked at normozoospermic partners in an...

Mechanism of Penile Erection

Shear Stress Erection

The main mediator of penile erection is nitric oxide (NO). NO is synthesized by two enzymes endothelial NO synthase (eNOS NOS3) and neuronal NO synthase (nNOS NOS1). nNOS-containing (nitrergic) nerve fibers course from the major pelvic ganglia (MPG) and terminate in the penis. eNOS localizes to the vascular and sinusoidal endothelium in the penis 4 . Sensory reflexogenic and psychogenic sexual stimulation activates nNOS, which initiates the erectile response. Sexual stimulation also neuronally...

Physiology of Penile Erection

The penis contains two chambers (the corpora cavernosa), which run the length of the organ, and are surrounded by a membrane (the tunica albuginea). Erection or flaccidity of the penis results from relaxation or contraction, respectively, of smooth muscle cells in the corpora cavernosa. Penile erection is a complex neurovascular process involving relaxation of the corpus cavernosal smooth muscles and vasodila-tion of blood vessels supplying the corpora cavernosa. This is due to both increased...

Potential Therapeutic Role of PARP in Male Infertility

As PARPs play an important role in cell death and apoptosis, they could be good candidates in therapeutic regimens. It was hypothesized that PARP inhibitor causes prevention of DNA repair of malignant cells following exposure to chemotherapy 89 , In cancer patients, the antitumor properties of PARP can preserve fertility even after chemotherapy or radiotherapy 2 . Jha et al. proposed that PARP inhibition can protect sperm against chemically induced injury in vitro 10 . In a recent study by...

Relationship Between Cytokines and Seminal Parameters

Human semen contains a variety of different cytokines and other immunological factors and their effects on semen quality and sperm function are still the subject of debate. There is increasing evidence that many of the cytokines adversely affect spermatogenesis and steroidogenesis 28 . However, there is an ongoing controversy concerning the biological role of particular cytokines in the fertilization process. A lot of studies have indicated the lack of any connection between the cytokine levels...

Cytokines Influence on Steroidogenesis

Testicular Steroidogenesis

Cytokines take part in gonadal steroidogenesis (Fig. 9.2). In testis, they are physiologically produced by Sertoli cells and Leydig cells and they regulate cell proliferation as well as steroidogenesis. However, increased concentrations of cytokines may adversely influence cell function. For example, IL-1a may negatively influence expression of regulatory protein steroidogenic acute regulator (StAR) as well as its phosphorylation, thus inhibiting cholesterol translocation to inner mitochondrial...

Clinical Consequences of Oxidative Stress in Male Infertility

Gokul, and Ashok Agarwal Abstract Male infertility affects 40 of infertile couples in the USA and may be attributed to conditions such as varicocele, leukocytospermia, infection, and idiopathic infertility. Such conditions may be associated with elevated levels of reactive oxygen species (ROS), decreased antioxidants, and oxidative stress (OS). OS can lead to male infertility in both an in vitro and in vivo setting. The negative effects of ROS on male fertility present...

Oxidative Stress DNA Damage and Apoptosis in Male Infertility

Said, Constanze Fischer-Hammadeh, Mohammed Hamad, Khaled Refaat, and Mohamad Eid Hammadeh Abstract Oxidative stress, sperm DNA damage, and apoptosis are associated with male infertility as a cause and as a manifestation. Several clinical conditions and laboratory findings may be indicative of the presence of oxidative stress, sperm DNA damage, and apoptosis. The use of standardized assays for the diagnosis of oxidative stress, sperm DNA damage, and apoptosis should be limited to cases...

Apoptosis Oxidative Stress and BPH

An alternative mechanism for BPH may be related to metabolic disturbances. Obesity and elevated fasting glucose are components of the metabolic syndrome 61 Both the obesity and the metabolic syndrome are associated with systemic inflammation and oxidative stress 62 . Inflammation has been previously implicated as a primary stimulus for prostate carcinogenesis 63 , and in the same way, it is possible that BPH represents an alternate, nonmalignant pathway of unregulated prostate growth promoted...

Nox Family of Nadph Oxidases

The NADPH oxidases are a family of enzymes that catalyze electron transfer from cytosolic NADPH to molecular oxygen to generate superoxide as its primary product. To date, seven NADPH oxidase isoforms have been identified in different mammalian cells and tissues 18 . The prototype gp91phox-containing NADPH oxidase possesses cytosolic subunits (p47phox, p67phox, or homologues) and membrane-bound subunits (gp91phox and p22phox) , which form a functional enzyme complex upon activation 16 . NADPH...

Inflammatory Conditions in the Gonad Oxidative Stress

Oxidative Stress And Female Infertility

The oxidative stress and lipid peroxidation, which occur in the gonad, are significant factors responsible for male infertility arising from the imbalance between production of reactive forms of oxygen and the efficiency of systems which eliminate Exogenous antioxidants polyphenols, vitamin C, vitamin E and carotenoids Fig. 9.3 Oxidative stress as a link between inflammation and apoptosis. The inflammatory state induces activation of macrophages and release of cytokines leading to free radicals...

Antioxidants A Practical Approach for Treating iOAT

As a multifactor disorder, iOAT presents a clinical challenge in the diagnosis and medical treatment of infertile men. ICSI has enabled iOAT to be circumvented mechanically however, it fails to address the fundamental factors contributing to male factor infertility. Oral supplementation of hormones and antioxidants has been the primary area of focus for pharmacotherapy treatment of iOAT. Significant improvements in sperm concentration, motility, and morphology have been reported 45 . Therefore,...

Cigarette Smoking

Tobacco plants, like many other plants, will invariably contain certain amounts of lead absorbed from the soil however, lead may also be deposited on the surface of the leaves. The widespread use of lead arsenate as a pesticide on tobacco crops has, in the past, resulted in lead contamination of tobacco products. The effect of tobacco constituents on classical sperm parameters and fertility has been under investigation for decades 47 . Kunzle et al. 48 , when evaluating many men attending a...

Biomarkers for Inflammation in BPH

Inflammation has important association with the pathogenesis, symptoms, and progression of BPH. Then, discovery of a biomarker would be invaluable for monitoring the progress of the disease. There are a number of early candidates and many others are currently being assessed by international research groups. A small study 115 suggested that measurement of serum malondialdehyde (MDA), an index of inflammation and oxidative stress, may be a useful marker in BPH. Serum MDA levels were analyzed in...

Commercial Antioxidants

Several beverages, such as pomegranate juice, red wine, blueberry juice, cranberry juice, orange juice, and green tea, have been touted to have roles in improving erectile function in disease states via their ROS scavenging capacities. In animal models of arteriogenic ED, pomegranate juice decreased oxidative stress and improved, although it did not normalize, erectile function 171, 172 . This beneficial effect of pomegranate juice may be due to its main active ingredients such as polyphenol...

Cytokines as Potential Diagnostic Markers of Male Infertility

The clinical role of evaluation of cytokines participating in urogenital infections inflammations has been recently found to be the important area of interest. The present routine diagnostics of inflammation in the male reproductive tract is mainly based on the determination of leukocyte concentration and microbiological evaluation of the semen. Because the harmful effect of cytokines on spermatozoa is closely connected with the accompanying leukocytospermia, the evaluation of the leukocyte...

Mitochondrial Antioxidants and Fertility

The deleterious effects resulting from the formation of ROS in the mitochondrion are, to a large extent, prevented by various antioxidant systems, and as such, mammalian mitochondria possess a relative abundance of enzymatic and nonenzymatic antioxidants designed to manage and counteract the ROS generated. An in-depth presentation of the literature is well beyond the scope of this chapter however, a brief description is provided to represent the well-characterized ROS scavenging systems that...

Oxidative Stress in Male Reproductive System and ART Outcomes

The quality of the spermatozoa used for ART is crucial to get successful fertilization and pregnancy 126 . Spermatozoa are vulnerable to oxidative stress because their membranes are rich in unsaturated fatty acids 126 and they have no mechanisms for repairing their damaged DNA 127 . This will result in decrease in membrane fluidity and reduce the activity of membrane and ion channels which will end with impaired spermatozoa fertilization capacity. Hammadeh et al. demonstrated that using...

Cryptorhidism Means

Testicular torsion or spermatic cord torsion is the most common genitourinary tract emergency of childhood and probably the second most common surgical emergency in the adolescent age group after acute appendicitis 1-3 . This clinical entity is commonly referred to as the acute scrotum. Of the diseases that cause an acute scrotum, spermatic cord torsion is undoubtedly the most important. Misdiagnosis and inappropriate treatment lead to male factor infertility. Thus, a child presenting with an...

Influence of Cytokines on Sperm DNA and Apoptosis

The poor quality of sperm DNA appears to be one of the important factors affecting male reproductive ability 141 . This has been confirmed by numerous reports in which a high percentage of spermatozoa with fragmented DNA have been found in infertile men when compared to the fertile individuals 142, 143 . In case of inflammation of the genitourinary tract, the redox imbalance is probably the main etiological factor responsible for destructive effects of the inflammatory process on male gametes,...

Mitochondrial ROS and Spermatozoa 2211 Mitochondrial ROS Production

The first reports of mitochondrial ROS generation in mammalian spermatozoa were established in the rabbit using cytochrome c peroxidase assays 26 and an in-depth study in the rat via chemiluminescence 9 . The first analysis of human spermatozoa using the novel MitoSOX Red superoxide fluorescent probe by Koppers et al. 27 indicated that the mitochondria was indeed a major source of ROS and oxidative stress observed in defective human spermatozoa. The level of mitochondrial ROS generation within...

The Role of Obesity in ROS Generation and Male Infertility

Kashou, Stefan S. du Plessis, and Ashok Agarwal Aim To discuss the relationship between obesity and male infertility, specifically exploring the role of reactive oxygen species (ROS) production in obesity and the subsequent generation of oxidative stress, as well as abnormal hypothalamus-pituitary-gonadal regulation associated with obese males. Results Both enhanced ROS generation and abnormal hormonal regulation due to obesity are strongly correlated to suboptimal semen quality and,...

Effect of Oxidative Stress on ART Outcome

Mohamad Eid Hammadeh, Mohammed Hamad, Khaled Refaat, Tamer M. Said, and Constanze Fischer-Hammadeh Abstract Oxidative stress is a condition that causes cellular damage including destruction of all cellular components including lipids, proteins, nucleic acids, and sugars. It affects negatively the quality of oocytes, sperm oocyte interaction, implantation, and early embryo development which influence the success of pregnancy. Many events related to infertility may occur due to OS in the female...

Effect of Varicocelectomy on Oxidative Stress

Varicocelectomy is the most common urological procedure for male factor infertility. In most of the published studies, varicocele repair has been associated with an improvement in semen parameters and spontaneous pregnancy rates, although the data remain controversial 81, 82 . Varicocele repair may improve pregnancy outcomes after assisted reproduction technologies (ARTs) 83, 84 . There is now evidence to show that varicocelectomy may reduce seminal oxidative stress and this provides another...

Role of Caspase PARP and Oxidative Stress in Male Infertility

Abstract The etiology and pathogenesis of male infertility remain not well defined. Oxidative stress has been identified as one of the major causes of male infertility. Integrity of the sperm DNA, which could be caused by oxidative stress, also plays an important role in vivo and in vitro male fertility. Poly (ADP-ribose) polymerase (PARP) is a DNA repair enzyme that has been demonstrated in mature spermatozoa and fertile men. PARP becomes activated in an attempt to repair oxidative DNA strand...

Targeting Nadph Oxidase 281011 PDE5 Inhibitors

PDE5 inhibitors, e.g., sildenafil citrate, tadalafil, vardenafil hydrochloride, promote penile erection in response to sexual stimulation by inhibiting PDE5-catalyzed degradation of cGMP. They are widely accepted as an efficacious option for the treatment of ED in most, but not all, cases 6 . Recently, interest has been generated in the additional effects of PDE5 inhibitors on preventing formation of ROS and inhibition of ROS-mediated PDE5 upregulation in the penis. Several animal studies have...

Identification of Sperm Oxidative Stress from Clinical History

Male Infertility Causes Mnemonics

The various causes of male infertility are outlined in Fig. 16.1, with the majority of these sources of sperm dysfunction being relatively easy to identify through history alone. The mnemonic Testicular is a helpful aide-memoire for recalling the underlying causes of male infertility, with sperm oxidative stress playing a pivotal role in the majority of these male infertility pathologies. Exposure to oxins such as heavy metals through the manufacture of lead acid batteries or soldering fumes is...

Pathophysiology of Varicocele

The true effect of varicocele on testicular function and male fertility remains unknown. Although numerous studies have clearly demonstrated an association between varicocele and reduced male reproductive function (e.g., poor semen parameters, infertility), most varicocele studies involve highly selected populations (e.g., infertile men), making it difficult to ascertain the role of varicoceles in male infertility. Moreover, the lack of reliable end-points for measuring fertility represents...

Diagnosis of OS and ROS Levels

The chemiluminescence assay is a direct method of quantifying extracellular ROS levels. This assay uses lucigenin and luminol to assess the generation of the superoxide anion and hydrogen peroxide 76 . Lucigenin detects superoxide anion, while luminol detects hydrogen peroxide. These agents are oxidizable substrates that react with certain oxygen species in order to measure levels of ROS. The chemilumines-cence assay or calorimetric assay can also be used to measure the total antioxidant Fig....

Clinical Conditions of Exacerbated Oxidative Stress That Lead to Sperm DNA Damage

Clinical varicocele has been associated with an increase in free radical production including both oxygen and nitrogen-derived radical species 34, 35 . Nitric oxide production is proportional to the severity of varicocele 36 and patients with varicocele have increased levels of 8-oxo-guanosine (8-OHdG) in leukocyte DNA indicating oxidative damage 37 . Saleh et al., using the Sperm Chromatin Structure Assay (SCSA) test, reported a significant increase in the extent of sperm DNA damage in...

Sperm Oxidative Stress and DNA Damage

From what is currently known about sperm cell damage and dysfunction, there is certainly scope for RF-EMR to contribute to this affliction. The three main types of cellular damage which can account for the adverse observations made are membrane, protein and DNA damage. The factors responsible for contributing to this damage in the male germ line can be grouped into several categories. Quality of spermatogenesis defines the susceptibility of cells to damage 23 . Biological factors including diet...

Abnormal HPG Regulation

Although several mechanisms that parallel obesity to infertility have been proposed, many remain ambiguous and relatively undefined. Studies indicate that the central factor linking the mechanisms associated with obesity and infertility is an abnormal regulation of the HPG axis, as well as the previously discussed OS. The HPG axis responds to fluctuations in hormones causing a range of widespread and local effects on the body and aspects of reproduction. Excess fat accumulation can impair the...

Idiopathic Oligoasthenoteratozoospermia

IOAT is a complex medical condition that affects approximately 30 of all infertile men and is the most common cause of male infertility 16, 17 . As a three-part disorder, low sperm concentration and motility and morphologically abnormal sperm characterize iOAT. Three classifications have been put into place to evaluate the severity of the disease (1) isolated astheno teratozoospermia (no alteration in sperm concentration) (2) moderate (sperm concentrations between < 20 x 106 mL and > 5 x...

Contributors

Ashok Agarwal, PhD Center for Reproductive Medicine, Cleveland Clinic, Lerner College of Medicine, Cleveland, OH, USA R. John Aitken, PhD, ScD Department of Biological Sciences, University of Newcastle, Callaghan, NSW, Australia Naif Al-hathal, MD Department of Surgery, St. Mary's Hospital, Montr al, QC, Canada Juan G. Alvarez, MD, PhD Department of Male Infertility, Centro Androgen, La Coruna, La Coruna, Spain Mark A. Baker, PhD Department of Environmental and Life Science, University of...

Experimental Testicular Torsion and Antioxidant Therapy

Under normal condition, free radicals are produced and their effects are counterbalanced by the endogenous antioxidant system. When ROS generation exceeds the defense mechanisms' capacity to control, oxidative stress is occurred and contributes to reversible or irreversible cell damage 7, 140 . All living aerobic cells are normally exposed to some ROS, but if ROS levels rise, oxidative stress may occur, which results in oxygen and oxygen-derived oxidants, and in turn increases the rates of...

Testicular Torsion IR Injury in Testis and Oxidative Stress

The mechanism of tissue damage due to I R is common to other organs such as the brain, heart, kidneys, and testis. The primary pathophysiologic event in testicular torsion is ischemia followed by reperfusion thus, testicular torsion detorsion is I R injury to the testis 7 . I R also induce morphological and biochemical changes by both ischemia and reperfusion of the tissues and induce germ cell-specific apoptosis through cell membrane lipid peroxidation, protein denaturation, and DNA damage....

Lessons from the Mouse GPx Knockout Models

n 2009, the group of Marcus Conrad (Germany) generated a transgenic mouse model in which the mGPx4 was disrupted 52 by introducing an in-frame transla-tional stop into the mitochondrial leader sequence of mGPx4. Analysis of this model revealed that mGPx4- mice are viable, in contrast to early embryonic lethality recorded in the GPx4 ' mice in which the somatic isoform (cGPx4) as well as the two sperm-specific variants, mGPx4 and snGPx4, were absent 72, 73 . Interestingly, the mouse mGPx4-...

Oral Antioxidant Therapy

As outlined in Chap. 23, many studies have been conducted examining the effect of a wide variety of different antioxidant combinations on sperm function and pregnancy outcome. Table 16.2 summarises the outcomes of the various antioxidant treatment regimes tested in a placebo controlled setting. In January 2011, the Cochrane collaboration, widely perceived as the definitive authority on evidence-based medicine, published a review on the effect of oral antioxidant therapy on sperm quality and...