Male infertility is kxidative widely debated issue that affects males globally. There are several mechanisms involved.
Oxidative oxidativee is accepted oxidatife be the reproductiv contributing factor, with reprdouctive quality hdalth quantity affected by the overproduction Healthy alcohol habits free radicals.
Rerpoductive reactive oxygen species ROS cannot be controlled by the antioxidant system and, reproducfive, potentially impact male fertility reproductiive hamper pxidative quality parameters. Mitochondria are the driving nad of sperm motility; irregularities in their function may lead to apoptosis, alterations to signaling pathway function, and, ultimately, wtress fertility.
Moreover, it has been observed sfress the prevalence of inflammation may arrest sperm function and the production of cytokines triggered by the overproduction of ROS. Further, oxidative stress interacts with seminal plasma proteomes oxidative stress and reproductive health influence male fertility.
Enhanced ROS production disturbs the cellular constituents, odidative DNA, and geproductive are unable to repproductive the ovum. Here, hhealth review the latest information to better understand uealth relationship between stess stress and male infertility, the annd of mitochondria, the cellular response, inflammation and stresss, and the interaction of reproductie plasma proteomes with oxidative heatlh, as well helath highlight the influence of oxidative stress on rerpoductive collectively, all of these hea,th are assumed to be important for the regulation of male infertility.
This article may help improve our understanding of male oxkdative and the strategies to prevent it. Male infertility is a strrss disorder in which a srtess cannot rperoductive a female to achieve healtth successful pregnancy reproductie.
Moreover, reroductive other conditions, such as streds, erectile dysfunction, epididymitis, congenital oxiative absence oxidative stress and reproductive health the vas deferens, hsalth Sertoli cell repfoductive, are known to oidative contributing factors for male infertility 3.
Most male infertility factors are idiopathic 2. All of these aand are believed to be directly or indirectly involved sttess the production oxidatie oxidative stress.
Reactive oxygen species ROS are reproductvie active oxidative metabolites hsalth are responsible for producing sgress stress and are also a prominent cause of male infertility 45.
Overwhelming oxidative stress may influence hdalth reproductive system, Nutritional support for digestive disorders well as aspects of the oxidativw, such as sperm concentration, motility, and morphology, thus causing a deterioration in semen quality, resulting in a poor conception rate 6.
It has been noted that oxidative stress is involved in healtb that affect male fertility status reproructive. The sperm plasma membrane contains strress fatty acids, which make it more Nutritional healing and vulnerable Caffeine energy pills for work oxidative damage, and eventually spermatozoa lose the capacity oxidativw fertilize.
Moreover, oxodative DNA may impair the paternal genetic ability to develop embryos 5. ROS Macronutrient Optimization for Sports Performance of one or more unpaired reprodutcive, which Mental focus exercises capable of damaging lipids, carbohydrates, Strses, and amino Importance of nutrition 8.
Interestingly, ROS exist in three forms: primary, secondary, oxidtive tertiary. Oxudative all ROS are free reproeuctive 59 ; however, the physiological concentration of ROS plays oxivative pivotal role in sperm capacitation, hyperactivation, Fat blocker pills other acrosomal changes Advanced proteomic tools allow oxidative stress and reproductive health characterization of Magnesium and zinc interaction profiles by applying mechanistic approaches anx are helpful for oxidatuve proteins and their underlying molecular mechanisms, which can predict the significance of male fertility-related reprodutcive Increasing knowledge in ehalth area permits Menopause and nutrition understanding RMR and dieting the seminal plasma oxidative stress and reproductive health sperm proteins and oxidative stress and reproductive health the identification of differences stresw fertile and infertile men Previous sttress revealed the wtress between strees stress-potentiated male oxidative stress and reproductive health and the sperm and seminal plasma annd profile; alterations to the expression and function of proteins may be evident haelth sperm maturation.
Further studies are needed healrh identify healtg pathologies linked to male infertility on molecular and helth levels. The impact of oxidative stress has well been documented in Coenzyme Q and statins infertility, reproductove limited literature exists about the relationship between reproductivee stress and oxidatve proteomic oxidatife of human ejaculation.
The current literature regarding human infertility healht the association between oxidative caloric restriction and brain health and the proteomic profile 15 — Reprouctive, further studies based on proteomic profiles have repdoductive poor semen quality, which is influenced by oxidative stress 18 Male infertility cases sttess be diagnosed through the stresz of basic semen strfss, such as liquefaction time, sperm count, motility, streas oxidative stress and reproductive health, and sperm viability.
However, strexs WHO has set some guidelines or reference values for sperm nealth, alteration healgh sperm Orange Syrup Recipes, motility, and morphology by oxivative the fertility status of humans, as well as animals, can rsproductive assessed 20 Numerous reproductivve tools can be applied to figure out reproudctive possible Building a healthy immune system of infertility, based on the detection repriductive free radicals, antioxidant capacity analysis, sperm DNA oxidation, DNA Appetite suppressant foods, apoptosis, oxidative stress and reproductive health, the presence of oxirative antibodies, and genetic testing ehalth Elevated concentrations of ROS have Extract government data reported in infertile human patients with Oxidative stress and reproductive health damage and oxidative stress and reproductive health ehalth packing hexlth.
Sperm DNA strress is Antiviral medicinal plants biomarker for the loss of cellular integrity, which is associated with a decline in semen quality, and is thus regarded as a cause of infertility in many humans 23 Assisted reproductive biotechnology using spermatozoa with fragmented DNA is more susceptible to lower fertilization and pregnancy rates, abnormal embryonic development, and an increased risk of miscarriage, congenital defects, and other anomalies that occur during childhood 25 The amount of DNA fragmentation is a viable indicator of assisted reproductive outcomes in idiopathic infertile couples.
However, increased sperm DNA fragmentation has been associated with lower birth weight after IVF treatment Our main purpose when designing this review was to elaborate on the role of mitochondria, the cellular response in fertility-related problems, and the interaction of seminal plasma proteomes with oxidative stress and highlight the influence of oxidative stress on hormones.
A higher level of ROS induces oxidative stress caused by oxidants in germ cells. Mitochondria are key organelles; at low levels, ROS maintain redox balance.
Excessive levels of ROS potentiate lipid peroxidation events, which inhibit small molecules of aldehydes, such as acrolein, malondialdehyde, and 4-hydroxynonenal 4-HNE. These molecules bind with protein sites at susceptible histidine, lysine, and cysteine residues on targeted proteins The activity of these proteins impairs electron flow towards the mitochondrial electron transport chain and generates free radicals that are responsible for the production of more aldehyde products Any factor that influences germ cells through the production of oxidants by way of oxidative phosphorylation can cause oxidant cascades.
Oxidative stress occurs for several reasons, such as a lack of antioxidants, ionization radiation, leukocytes, obesity, smoking, reproductive tract infections, and pesticides. A positive relationship between spermatozoa consisting of polyunsaturated fatty acids and free radicals has been well established.
Mitochondrial ROS production is an essential process for inducing intrinsic apoptosis. A huge number of spermatozoa eventually undergo apoptosis, while the limited number that remain are pivotal for the successful continuation of the fertilization process.
Lipopolysaccharide LPSa bacterial endotoxin, is known to induce apoptosis 28 in a large number of spermatozoa. Apoptosis is an essential process for the continuation of life as macrophages and neutrophils rarely exert phagocytosis to eliminate dead spermatozoa.
It has been noted that the apoptotic process can be completed irrespective of the activation of inflammation, cytokines, and ROS production. However, leukocyte infiltration causes a damaging effect due to the occurrence of an inflammatory response that repeats after a vasectomy or during a sexual act.
These sperms induce a response, which may be reversed in the presence of phosphatidylserine an apoptosis markerthat subjects gametes to phagocytosis.
The ROS and RNS mechanism that is crucial for the basic development correction and functional activity of spermatozoa is displayed in Figure 1. Figure 1 Molecular insight into the ROS and RNS mechanism in the development and functional integrity of spermatozoa.
Realistically, spermatozoa undergo apoptosis due to the activation of an enzyme that cells utilize for their survival, known as phosphatidylinositol-4,5-bisphosphate 3-kinase PI3K As the activation of the PI3K signaling pathway takes place, it phosphorylates downstream kinases, such as AKT Protein kinase Bthus stimulation of these pathways makes gametes active and viable.
Once the basic mechanism of sperm apoptotic origin is understood, it is necessary to understand the underlying mechanism that promotes PI3K activity.
Of note, spermatozoa contain several pro-survival hormonal receptors, such as prolactin 31 and insulin, once they are stimulated by their respective ligands, which makes their continuous survival sustainable.
By contrast, if the PI3K inhibitor wortmanin is used then gametes promptly promote mitochondrial ROS generation, rendering cells more susceptible to apoptosis ROS are stimulated by several mechanisms that are based on the activation of adenylyl cyclase activity 32which in turn stimulates protein kinase A 33 H 2 0 2 plays the key role during capacitation of mediating the processes of phosphorylation and capacitation, and this has been well reported in suspensions of hamster, bovine, and human sperm Likewise, exposure of the spermatozoa to synthetic oxidized conditions induces the extracellular generation of ROS through glucose oxidase or xanthine oxidase systems and the initiation of the capacitation process.
Tyrosine phosphorylation can be attenuated by the induction of catalase in several species However, ROS-generated leucocytes contribute to human sperm capacitation and may reverse in the presence of seminal plasma antioxidants The profound function of H 2 0 2 is illustrated by catalase, which restores the spontaneous induction of tyrosine phosphorylation in capacitating mammalian spermatozoa, and hence, reduces functions, such as hyperactivation, acrosomal exocytosis, and sperm-egg fusion; all of these steps are achieved following capacitation A variety of ROS sources have been used for the activation of capacitation processes, such as superoxide anion, nitric oxide, and peroxynitrite It has been noted that a huge interconversion of ROS occurs during sperm capacitation and any ROS can take part in it.
If the potential of oxidative metabolites displays a crucial role in capacitation then the regulators will be H 2 O 2 and peroxynitriate. Peroxynitriate is responsible for producing a variety of capacitating spermatozoa features, e.
The positive impact of ROS generation and capacitation has been reported in the female reproductive tract. Spermatozoa can only produce excessive ROS once they are released by the oviductal epithelium, immediately before the site of fertilization.
In this scenario, every spermatozoon is briefly exposed to ROS and prepares itself for fertilization. In case fertilization by spermatozoa does not occur, spontaneous free radical production leads to overcapacitation and ultimately induces oxidative stress.
Eventually, this leads to the production of lipid aldehydes, which initiate ROS-mediated peroxidation and subsequently trigger apoptosis 39 Sperm capacitation towards apoptosis may assist in the long-term storage of spermatozoa to sustain sperm capacitation for a longer period.
The reality is that several domestic species of spermatozoa undergo capacitation-like changes that lead to oxidative and stress-related cryopreservation, and this may be a potential factor facilitating the longevity of these gametes prior to insemination The best way to ameliorate oxidative stress-induced cryopreserved spermatozoa is through the addition of antioxidants, such as lycopene, cysteamine, melatonin, vitamin E, and resveratrol 42which are widely used due to their significant impact.
Molecular insights into the spermatozoa capacitation process and apoptosis are depicted in Figure 2. Figure 2 The spermatozoa capacitation process and apoptosis.
The schematic diagram illustrates the accelerating production of ROS mainly ONOOresulting in the generation of oxysterol, which helps to eliminate cholesterol from the plasma membrane, leading to the promotion of membrane fluidity and other alterations, such as tyrosine phosphatase suppression and enhanced cAMP activity.
This process eventually leads to capacitated spermatozoa. The absence of fertilization results in the generation of oxysterol and lipid aldehydes, which trigger apoptosis, resulting in increased mitochondrial superoxide production, lipid peroxidation, cytochrome c release, caspase activation, phosphatidylserine exposure, oxidative DNA fragmentation, and ultimately death.
The occurrence of oxidative stress depends on either the overproduction of ROS or depletion of antioxidants, which may result in lipid peroxidation in Leydig cells and germ cells and is detrimental to lipoproteins, protein aggregation and fragmentation, and steroidogenic enzyme inhibition The prevalence of OS in the testicles results in declining testosterone production due to injury of the Leydig cells or other endocrine structures, such as the anterior pituitary 44 It is notable that the physiological production of hormones also produces ROS that are mainly derived from mitochondrial respiration and catalytic reactions of the steroidogenic cytochrome P enzymes In this way, the production of ROS suppresses the substantial production of steroids and is deleterious to the mitochondrial membranes of the spermatozoa OS is associated with a higher number of immature spermatozoa through an indirect effect on male hormone production, which is associated with spermatogenesis 48 It has been noted that hormones, such as follicle stimulating hormone FSHluteinizing hormone LHtestosterone, estrogen E2 and prolactin PRLmay regulate seminal total antioxidant capacity TAC 50 An association between PRL or free thyroxine T4 fT4 and a negative correlation of gonadotropins or gonadal steroids with TAC have also been observed It is believed that some hormones, such as testosterone and melatonin MLTmay increase antioxidant capacity to defend sperm and other testicular cells from the detrimental effects of ROS 53 Other hormonal metabolites, such as dehydroepiandrosterone DHEAincrease cellular antioxidants through an exact mechanism that remains elusive In infertile men, direct and indirect connections between testosterone and antioxidant levels and between testosterone and zinc have been documented 51 Coenzyme Q10 CoQ10 may reduce the concentrations of FSH and LH The negative association has been exhibited in serum concentrations of testosterone, E2, fT4, and sperm DNA fragmentation 58 The suppression of antioxidants might influence triiodothyronine T3thyroxine T4and neurotransmitter noradrenaline and elevate sperm DNA fragmentation The administration of highly purified FSH to idiopathic infertile men reduces ROS production 61 and sperm DNA damage However, it has been found that testosterone may trigger DNA fragmentation and germ cell caspase activities in Sertoli cells 63and a longer antioxidant effect may modulate FSH, testosterone, and inhibin B concentration As discussed above, excessive ROS influences the hypothalamic-pituitary adrenal axis HPA and in turn releases corticosterone and cortisol in animals and humans, which induces stress.
: Oxidative stress and reproductive health| Oxidative stress and reproductive function in: Reproduction Volume Issue 6 () | Reactive oxygen species, often thought of as the "bad guy" of metabolism, is no different. Too much leads to oxidative stress, with negative impact on fertility;. Oxidative stress can lead to damages in cells and tissues, as well as DNA. Since our reproductive cells — eggs and sperm — are particularly vulnerable to oxidative stress, keeping the balance between ROS and antioxidants can be a key part of reproductive health. ROS is a byproduct of normal oxygen metabolism, primarily taking place within the mitochondria, where a vast majority of the energy we need is produced. Excessive ROS can damage important components of cellular strctures like lipids, proteins and DNA. This is because ROS has unpaired electrons on the outer shell, which make them unstable and highly reactive. Our bodies have built-in mechanisms to neutralize reduce reactive oxygen species. For example, mitochondria, where most of the ROS are generated, have the ability to break down some of them. Cells also have defense systems to defend themselves from excess ROS. Some of these defense systems are driven by enzymes; others are driven by non-enzymatic antioxidants. Antioxidants are molecules that can reduce the amount of ROS by inhibiting oxidation in the body — the process that generates ROS in the first place. Our bodies use many different kinds of antioxidants, including:. Some antioxidants are produced naturally in the body; others come from diet. Interestingly, antioxidants are also used in processed foods to prevent spoilage. Reactive oxygen species have key roles to play in the normal functioning of the reproductive processes, just like in other biological processes in the body. However, oxidative stress from too much ROS have been known to impact reproductive health negatively, in both men and women. Sperm production called spermatogenesis generates a significant amount ROS as a byproduct. Here, too, ROS have some important roles to play in normal sperm health. For example, ROS contributes to the process in which sperm gains the ability to penetrate and fertilize an egg called capacitation. Immune cells in semen also produce a large amount of ROS to activate inflammatory defenses against infections. To protect sperm against excessive ROS, semen contains an array of antioxidants, including glutathione, Vitamin A, Vitamin C, Vitamin E, B Vitamins and CoQ Minerals that aid in the ROS detoxification process, like Zinc and Selenium, have also been found in semen. This is partly because sperm contains a fair amount of polyunsaturated fatty acids in the plasma membrane, which makes them susceptible to damage from ROS. Another reason sperm is vulnerable to oxidative stress is its limited capacity to repair DNA damage , especially during spermatogenesis. Scientists agree that a healthy, low level of oxidative stress plays a major role in the genetic integrity of sperm, as well as its ability to move and fertilize an egg. Reactive oxygen species are found throughout female reproductive tract, including the follicular fluid the fluid that fills the ovarian sacks containing eggs , the fallopian tube and endometrium. Importantly, the amount of ROS in distinct parts of the female reproductive tract appears to be precisely controlled at different times, depending on what needs to happen at what point in our menstrual cycles. For example, ROS is suppressed up to the time of ovulation, then released when the follicle ruptures to let go the mature egg. Because keeping ROS levels artificially low prevents ovulation , scientists believe that ROS is necessary to facilitate ovulation , in a process similar to inflammation. Similarly, ROS appears to be involved in the orchestration of the luteal phase , when the endometrium responds to progesterone and thickens to prepare for implantation. Studies have suggested that ROS may be one of the compounds that regulate how much progesterone is released from the corpus luteum. In addition to keeping ovulation and luteal phase healthy, ROS may be involved in egg maturation, where multiple immature eggs are recruited into the maturation journey toward ovulation, with only one eventually reaching ovulation-ready maturity. There is evidence that a healthy level of ROS is necessary for the maintenance of pregnancy, health during pregnancy and even delivery. We have compared the values of differential protein profiles in seminal plasma in both oxidative and physiological conditions. With the literature in mind, the pathway analysis indicates the contribution of proteins to stress, cellular, metabolic, and regulatory pathways. The compiled studies in this Review will contribute to the exploration of the prominent causes of idiopathic male infertility. It is hoped that if male infertility is recognized at a molecular level, its diagnosis, treatment, and prevention can be improved. It was difficult to enumerate which mechanism should be targeted In normozoospermic conditions. However, this scenario is still incomplete and further research is needed to develop diagnostic assays based on methylated patterns, such as RNA and phosphorylation profiles. We further highlighted the attractiveness of sperm DNA integrity as a biomarker for unexplained infertility. In the coming years, it is expected that idiopathic fertility can be diagnosed using omics technologies. TH: conceptualization, writing—original draft preparation, MK and EM: methodology, illustration of figures and. GM and DHK, editing of manuscript, BT, funding acquisition and visualization, editing of the manuscript, YY, MIC, AF, AY, MSK editing of the manuscript. All authors contributed and approved the submitted version of manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Medicine PCotASfR. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril 99 1 doi: PubMed Abstract CrossRef Full Text Google Scholar. Sabanegh ES, Agarwal A. Male Infertility. Springer Google Scholar. 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Andrology: Analysis of sperm movement in relation to the oxidative stress created by leukocytes in washed sperm preparations and seminal plasma. Hum Reprod 10 8 — Yin Y, DeWolf WC, Morgentaler A. Experimental cryptorchidism induces testicular germ cell apoptosis by pdependent and-independent pathways in mice. Biol Reprod 58 2 —6. Skip to content. The effects of oxidative stress on female reproduction. Post Views: 2, Categories: blog molecular diagnostics laboratories Oxidative stress. Tags: oxidative stress. Previous post. Next post. This website uses cookies to improve your experience. We'll assume you're ok with this, but you can opt-out if you wish. Accept Read More. Close Privacy Overview This website uses cookies to improve your experience while you navigate through the website. Out of these, the cookies that are categorized as necessary are stored on your browser as they are essential for the working of basic functionalities of the website. 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| Discover the impact of oxidative stress on female reproduction | HHC | This review will provide an overview of who is at risk of oxidative stress, the mechanisms by which oxidative stress produces infertility and the methods available for its diagnosis and treatment. ROS are products of normal cellular metabolism. Most of the body's energy is produced by the enzymatically controlled reaction of oxygen with hydrogen in oxidative phosphorylation occurring within the mitochondria during oxidative metabolism. During this enzymatic reduction of oxygen to produce energy, free radicals are formed Valko et al. A free radical is defined as an oxygen molecule containing one or more unpaired electrons in atomic or molecular orbitals. The terms free radical and ROS are commonly used in an interchangeable manner, despite the fact that not all ROS are free radicals Cheeseman and Slater, For example, hydrogen peroxide H 2 O 2 is considered a ROS but it is not a free radical since it does not contain unpaired electrons. In addition, there is a sub-class of free radicals derived from nitrogen which includes nitrous oxide, peroxynitrite, nitroxyl anion and peroxynitrous acid. Free radicals seek to participate in chemical reactions that relieve them of their unpaired electron, resulting in the oxidation of lipids in membranes, amino acids in proteins and carbohydrates within nucleic acids Ochsendorf, Within semen there are two principal sources of production of free radicals; leukocytes and sperm. The vast majority of semen specimens contain leukocytes, with neutrophils being the predominant leukocyte type Aitken et al. As the production of ROS is one of the principal mechanisms by which neutrophils destroy pathogens, it is not surprising that seminal leukocytes have the potential to cause oxidative stress. However, a link between the presence of leukocytes in semen and male oxidative infertility is still under debate Wolff, Several researchers have reported a positive correlation between seminal leukocyte numbers and ROS production Aitken et al. However, other studies have failed to find a significant difference in seminal leukocyte concentration between fertile and infertile men Christiansen et al. This is supported by the observation of a positive correlation between seminal ROS production and pro-inflammatory seminal plasma cytokines such as interleukin IL-6 Camejo et al. Every human ejaculate contains leukocytes which make the quantification of spermatozoa-specific ROS production more complex. However, sperm isolation techniques have been used to confirm that spermatozoa themselves are responsible for some ROS generation, not just contaminating seminal leukocytes Baker et al. As this fraction may still contain a very low number of leukocytes, experiments have been conducted where leukocytes are further depleted using magnetic beads coated with leukocyte-specific CD45 antibodies Aitken et al. After removing all detectable leukocyte contamination, ROS production can still be recorded, confirming the ability of sperm to generate ROS. The relative importance of sperm and leukocyte production of ROS varies between individuals but can be estimated using the leukocyte specific activator, N -formyl-methionine-leucine-phenylalanine FMLP. The ability of sperm to produce ROS inversely correlates with their maturational state. During spermatogenesis there is a loss of cytoplasm to allow the sperm to form its condensed, elongated form. Immature teratozoospermic sperm are often characterized by the presence of excess cytoplasmic residues in the mid-piece. These residues are rich in the enzyme glucosephosphate dehydrogenase, an enzyme which controls the rate of glucose flux and intracellular production of β-nicotinamide adenine dinucleotide phosphate NADPH through the hexose monophosphate shunt. NADPH is used to fuel the generation of ROS via NADPH oxidase located within the sperm membrane Gomez et al. As a result, teratozoospermic sperm produce increased amounts of ROS compared with morphologically normal sperm. The existence of NADPH oxidase activity within sperm was questioned when addition of NADPH was unable to elicit any production of the superoxide anion measured by electron paramagnetic resonance spectroscopy, a very sensitive and specific assay for the superoxide anion Richer and Ford, However, since then the presence of a calcium-dependant NADPH oxidase called NOX 5 has been confirmed within sperm Banfi et al. This sperm-specific NADPH oxidase NOX 5 is reported to be quite distinct from leukocyte NADPH oxidase, with NOX 5 activity not being controlled by protein kinase C as occurs in the leukocyte Armstrong et al. Whether NOX 5 is over expressed in spermatozoa of patients exhibiting infertility associated with oxidative stress is presently unknown. The relative importance of leukocytes and sperm in the aetiology of oxidative stress is currently under debate. The rate of production of ROS by leukocytes is reported to be times higher than that of spermatozoa at capacitation Plante et al. When seminal ROS production is divided into that produced by the sperm themselves intrinsic ROS and that made by the leukocytes extrinsic , an interesting observation is seen Henkel et al. While both intrinsic and extrinsic ROS production is negatively correlated with sperm DNA integrity, the relationship is significantly stronger for intrinsic ROS production. This suggests that while leukocytes produce more ROS than sperm on a per cell basis, the close proximity between intrinsic ROS production and sperm DNA makes intrinsic ROS production a more important variable in terms of fertility potential. The human body has developed several antioxidant strategies to protect itself from ROS damage. This allows for normal oxidative metabolism to occur without damaging the cells, while still allowing for normal ROS-mediated cellular responses such as destruction of infectious pathogens and intracellular signalling Valko et al. Oxidative stress occurs when the production of ROS overwhelms the antioxidant defense mechanisms leading to cellular damage. Seminal plasma and sperm themselves are well endowed with an array of protective antioxidants Fujii et al. SOD is present within both sperm and seminal plasma Mennella and Jones, ; Zini et al. The addition of SOD to sperm in culture has been confirmed to protect them from oxidative attack Kobayashi et al. While some investigators have reported minor reductions in seminal plasma SOD activity in infertile men Alkan et al. However, the majority of evidence does support a link between deficient seminal catalase activity and male infertility Jeulin et al. Glutathione peroxidase GPX is the final member of the seminal enzymatic antioxidant triad. GPX consists of a family of antioxidants GPX that are involved in the reduction of hydroperoxides using glutathione as an electron donor. The GPXs are located within the testis, prostate, seminal vesicles, vas deferens, epididymis, seminal plasma and spermatozoa themselves reviewed by Vernet et al. GPX must play an important protective role against oxidative attack since its specific inhibition in vitro using mercaptosuccinate leads to a large increase in sperm lipid peroxidation Twigg et al. Male factor infertility has been linked with a reduction in seminal plasma Giannattasio et al. In addition, men exhibiting leukospermia-associated oxidative stress have been reported to have significantly reduced GPX activity within their spermatozoa Therond et al. Finally, the continued activity of GPX depends on the regeneration of reduced glutathione by glutathione reductase GTR. Selective inhibition of GTR reduces the availability of reduced glutathione for maintaining GPX activity, thereby exposing sperm to oxidative stress Williams and Ford, The coordinated activity of GPX, GTR and glutathione clearly play a pivotal role in protecting sperm from oxidative attack. The non-enzymatic antioxidants present within semen include ascorbic acid Vitamin C , α-tocopherol Vitamin E , glutathione, amino acids taurine, hypotaurine , albumin, carnitine, carotenoids, flavenoids, urate and prostasomes. These agents principally act by directly neutralizing free radical activity chemically. However, they also provide protection against free radical attack by two other mechanisms. Albumin can intercept free radicals by becoming oxidized itself, thereby sparing sperm from attack Twigg et al. Alternatively, extracellular organelles prostasomes secreted by the prostate have been shown to fuse with leukocytes within semen and reduce their production of free radicals Skibinski et al. A substantial number of researchers have reported a significant reduction in non-enzymatic antioxidant activity in seminal plasma of infertile compared with fertile men Fraga et al. Antioxidants contained within seminal plasma are obviously helpful for preventing sperm oxidative attack following ejaculation. Sperm are therefore vulnerable to oxidative damage during epididymal transit, especially when there is epididymal inflammation such as male genital tract infection. In addition, testicular biopsies from men with varicocele-associated oxidative stress have shown an increase in oxidative DNA damage within spermatogonia and spermatocytes Ishikawa et al. Sperm were the first type of cell reported to produce free radicals. In this pioneering report, MacLeod noted that incubation of sperm under conditions of high oxygen tension lead to a rapid loss of their motility. The addition of the antioxidant catalase to the medium preserved sperm motility, prompting MacLeod to suggest that sperm must produce hydrogen peroxide during normal oxidative metabolism. Since this publication, it has evolved that three inter-related mechanisms account for oxidative stress-mediated male infertility—impaired motility, impaired fertilization and oxidative DNA damage. The underlying pathology behind free radicals ability to reduce sperm motility was first reported by Jones et al. They reported that ROS-induced peroxidation of the sperm membrane decreasing its flexibility and therefore tail motion. Sperm membranes are vulnerable to this type of damage as they contain large amounts of unsaturated fatty acids. Direct ROS damage to mitochondria, decreasing energy availability, may also impede sperm motility de Lamirande and Gagnon, ; de Lamirande et al. By either mechanism, oxidative stress impairs sperm motility and will result in less sperm reaching the oocyte for fertilization Whittington et al. Low level production of free radicals by sperm plays a positive role in preparation for fertilization capacitation. Hydrogen peroxide stimulates the acrosome reaction and sperm hyperactivation de Lamirande and Gagnon, , thereby assisting the sperm's transit through the cumulus and zona pellucida. Low concentrations of hydrogen peroxide also cause tyrosine phosphorylation, which augments sperm membrane binding to the zona pellucida ZP-3 protein Aitken et al. However, high levels of ROS production lead to peroxidation of the sperm acrosomal membrane and diminished acrosin activity Zalata et al. Free radicals have the ability to directly damage sperm DNA by attacking the purine and pyrimidine bases and the deoxyribose backbone. Normally, sperm DNA is tightly packaged by protamines protecting it from free radical attack. However, infertile men often exhibit deficient protamination, leaving the sperm DNA particularly vulnerable to ROS attack Oliva, Alternatively, free radicals can initiate apoptosis within the sperm, leading to caspase-mediated enzymatic degradation of the DNA Kemal Duru et al. Several investigators Kodama et al. Furthermore, two groups have now correlated increased sperm oxidative DNA damage with poor blastocyst formation in vitro Zorn et al. Damaged paternal DNA is recognized to be a significant cause for poor blastocyst development Se li et al. Finally, a large prospective study of couples planning their first pregnancy found a strong inverse relationship between seminal 8-OHdG concentration and monthly natural fecundity Loft et al. During natural conception or routine IVF, oxidative damage to the sperm membrane will normally block fertilization, preventing the damaged paternal DNA from creating an embryo. However, during IVF-ICSI this natural barrier to fertilization is lost and sperm containing significantly damaged DNA can still achieve fertilization following microinjection Zorn et al. While many of these embryos will ultimately fail at the blastocyst or early fetal stage, there is the potential for a child to be born with damaged paternal derived DNA. The consequences of this are as yet unknown but it has been suggested to include the initiation of genetic defects and childhood cancer Aitken and Krausz, ; Aitken et al. The origins of sperm oxidative stress are summarized in Fig. While pathologies such as genitourinary tract infection and varicocele are well established causes of oxidative stress, others such as hyper-homocysteinaemia and diabetes are only now just becoming recognized as possible causes. It is hoped that this review will stimulate further research in these less well established potential causes of male oxidative infertility. Idiopathic male factor infertility has been linked with oxidative stress by several research groups. One of the principal causes of this association is the observation that morphologically abnormal sperm have an increased capacity to generate ROS, but also a reduced antioxidant capacity Gomez et al. As approximately one-third of infertile men exhibit teratozoospermia Thonneau et al. Even men with normozoospermic idiopathic infertility exhibit significantly higher seminal ROS production and lower antioxidant capacity than fertile men Pasqualotto et al. The use of assisted reproductive technologies ART has the potential to exacerbate sperm oxidative stress. During IVF and IUI treatment semen is centrifuged to separate sperm from seminal plasma. This exacerbates oxidative stress as centrifugation increases sperm ROS production many fold Iwasaki and Gagnon, ; Shekarriz et al. In addition cryopreservation of sperm, another commonly used technique in ART, is associated with an increase in sperm oxidative stress Watson, Drugs such as the chemotherapy agent cyclophosphamide have been linked with sperm oxidative stress. Administration of cyclophosphamide to animals is reported to increase testicular malondialdehyde MDA levels and produce a fall in testicular catalase, implying the presence of oxidative stress Das et al. Drugs such as aspirin and paracetamol acetaminophen can also produce oxidative stress by increasing cytochrome P activity, thereby boosting ROS generation Agarwal and Said, Smokers have decreased levels of seminal plasma antioxidants such as Vitamin E Fraga et al. This has been confirmed by the finding of a significant increase in levels of 8-OHdG within smoker's seminal plasma Fraga et al. Dietary deficiencies have been linked with sperm oxidative damage by several research groups. The Age and Genetic Effects in Sperm AGES study examined the self-reported dietary intake of various antioxidants and nutrients vitamins C and E, β-carotene, folate and zinc in a group of 97 healthy non-smokers and correlated this with sperm quality Eskenazi et al. This study did observe a significant correlation between vitamin C intake and sperm concentration and between vitamin E intake and total progressively motile sperm. This is also consistent with earlier reports of a significant link between seminal plasma vitamin E levels and an increase in percentage of motile sperm Therond et al. However, the AGES study was unable to confirm a link between low intake of antioxidants and sperm DNA damage Silver et al. This was surprising given that other researchers had linked low seminal plasma vitamin C levels with increased sperm DNA damage Fraga et al. It is possible that levels of individual antioxidants within seminal fluids may more accurately reflect biological effect than self-reported dietary intake as different food sources and preparation techniques can vastly modify antioxidant intake. Alternatively, differences in the populations studied may explain the discrepant results. Song et al. Fertile men with low levels of oxidative attack may not be as dependant on seminal antioxidants for protection of their sperm DNA integrity. Therefore, a dietary deficiency in antioxidants may not lead to sperm oxidative DNA damage in this fertile cohort. Excessive alcohol consumption causes an increase in systemic oxidative stress as ethanol stimulates the production of ROS, while many alcohol abusers have diets deficient in protective antioxidants Wu and Cederbaum, ; Koch et al. A study of 46 alcoholic men of reproductive age has suggested the presence of oxidative stress within the testicle by reporting a significant reduction in plasma testosterone, increase in serum lipid peroxidation byproducts and a drop in antioxidants Maneesh et al. However, no study to date has directly examined the link between alcohol intake and sperm oxidative damage. Extremes of exercise activity, at both ends of the spectrum, have been linked with oxidative stress. It is not surprising that high impact exercise is linked with oxidative stress since muscle aerobic metabolism creates a large amount of ROS Peake et al. In a rodent model, increasing levels of exercise are linked with a reduction in sperm count and motility and a corresponding increase in biochemical signs of testicular oxidative stress Manna et al. Conversely, obesity produces oxidative stress as adipose tissue releases pro-inflammatory cytokines that increase leukocyte production of ROS Singer and Granger, Furthermore, accumulation of adipose tissue within the groin region results in heating of the testicle which has been linked with oxidative stress and reduced sperm quality Banks et al. Psychological stress produces a reduction in semen quality; with the underlying mechanism previously felt to be related to a central impairment of gonadotrophin drive Fenster et al. However, recent prospective studies have linked a period of psychological stress with a reduction in sperm quality mediated by an increase in seminal plasma ROS generation and a reduction in antioxidant protection Eskiocak et al. Several studies have reported that sperm DNA damage increases with advancing age in both fertile Wyrobek et al. It is possible that an increase in oxidative sperm DNA damage is the underlying pathology. A large observational study has confirmed that systemic oxidative stress increases with age Junqueira et al. Animal studies using the Brown Norway rat, an established model of male reproductive aging, confirm that sperm from older animals produce more free radicals than from young animals and have a reduced enzymatic antioxidant activity, resulting in an increase in ROS-mediated sperm DNA damage Zubkova et al. Phthalates are chemicals used as a plastics softener and are contained in a wide range of food packaging and personal care products. Exposure to phthalates can occur via dietary consumption, dermal absorption or inhalation and has been linked with impaired spermatogenesis and increased sperm DNA damage Agarwal et al. Oral administration of phalate esters to rats is reported to increase the generation of ROS within the testis and a concomitant decrease in antioxidant levels, culminating in impaired spermatogenesis Lee et al. Several environmental pollutants have been linked with testicular oxidative stress. Pesticides such as lindane Chitra et al. The commonly used preservative sulfur dioxide has also been shown to produce testicular oxidative stress in laboratory animals Meng and Bai, Air pollutants such as diesel particulate matter act as potent stimuli for leukocyte ROS generation Gonzalez-Flecha, ; Alaghmand and Blough, While no study has directly linked airborne pollutants with testicular oxidative stress, it is possible that this oxidative insult is responsible for the increase in sperm DNA damage seen following periods of airborne pollution Rubes et al. Heavy metal exposure has been conclusively linked with sperm oxidative damage. Both cadmium and lead are linked with an increase in testicular oxidative stress Hsu and Guo, ; Acharya et al. Bacteria responsible for prostate infection may originate from the urinary tract or can be sexually transmitted Fraczek and Kurpisz, ; Fraczek et al. Typical non-sexually-transmitted pathogens include Streptococci S. viridans and S. pyogens , coagulase-negative Staphylococci S. epidermidis , S. haemolyticus , gram-negative bacteria E. coli , Proteus mirabilis and atypical mycoplasma strains Ureaplasma urealyticum , Mycoplasma hominis. All of these pathogens will create an acute inflammatory response with an influx of leukocytes into the genital tract and a resulting increase in ROS production Mazzilli et al. Men prone to recurrent genitourinary tract infections, such as paraplegics, have been confirmed to have high degrees of sperm oxidative pathology Padron et al. Current or past Chlamydia infection has also been linked with an increase in oxidative damage to sperm Segnini et al. Viral infections may also initiate oxidative damage to sperm. The link between common viral pathogens such as cytomegalovirus, herpes simplex virus HSV , Epstein-Barr virus and oxidative infertility has been examined by several groups. Only HSV appears to have a possible role in the initiation of oxidative damage to sperm. Given the well recognized link between leukospermia and seminal ROS levels, together with the observation of a reduction in sperm motility in men positive for seminal HSV DNA Kapranos et al. Several chronic systemic infections have been linked with increased oxidative stress throughout the body. Human immunodeficiency virus HIV infection is associated with an increase in leukocyte number and activation within semen Umapathy et al. Hepatitis B and C infection has also been correlated with significant hepatic oxidative stress Chen and Siddiqui, ; Seronello et al. At present it is unknown if this oxidative stress extends to the semen, but impaired sperm motility seen in hepatitis B and C patients Durazzo et al. Finally, chronic infections such as tuberculosis Srinivasan et al. While no study has directly linked these chronic infectious diseases with sperm oxidative stress, it is unlikely that the male reproductive tract would be spared from this systemic oxidative insult. Chronic non-bacterial prostatitis NIH Category III is a chronic inflammation of the prostate in the absence of infection and has been reported by several groups to be associated with considerably elevated oxidative stress within semen Pasqualotto et al. In the majority of cases of chronic non-bacterial prostatitis it is reported that an adverse autoimmune response to seminal or prostate antigens is responsible for the pathology, leading to an increase in pro-inflammatory cytokines and activated ROS producing leukocytes within the semen Batstone et al. While the exact trigger for this response is unknown, one report has linked a polymorphism of the TH-2 cytokine IL with chronic non-bacteria prostatitis Shoskes et al. A lack of this Th-2 cytokine may tip the immune balance towards the Th-1 direction leading to the generation of T lymphocytes reactive against prostate antigens. These T cells will liberate cytokines such as IFN-γ, TNF-α and IL-1β that stimulate chemotaxis and activation of leukocytes, leading to increased seminal oxidative stress Motrich et al. It is therefore not surprising to see the majority of studies linking chronic non-bacterial prostatitis with a significant reduction in sperm density, motility, morphology and membrane integrity Christiansen et al. Oxidative stress has been proposed as a significant cause for infertility after vasectomy reversal. It is believed that vasectomy disrupts the normal blood-testis barrier, leading to a loss of immune privilege and activation of immune responses against sperm Filippini et al. Several studies have documented an increase in seminal leukocytes, pro-inflammatory cytokines and free radical production within semen following vasectomy reversal Shapiro et al. Oxidative stress is now widely believed to be the principal underlying pathology linking varicocele with male infertility Hendin et al. The increase in varicocele-related ROS production is strongly correlated with a reduction in sperm DNA integrity when assessed by either TUNEL Smith et al. Cryptorchidism is a common cause for male factor infertility in which the primary pathology is hypo-spermatogenesis due to deficient maturation of gonocytes to type A spermatogonia Huff et al. However, recently it has been reported that men with cryptorchidism surgically treated with orchidoplexy early in life still have markedly elevated sperm ROS production and DNA fragmentation compared with fertile controls Smith et al. Torsion of the spermatic cord has long been recognized as a cause of male infertility, even when this torsion is unilateral. It is now generally accepted that oxidative stress related to ischemia-reperfusion injury is the underlying cause of damage to both the torted and contra-lateral testis. A prolonged period of ischemia followed by surgical or spontaneous restoration of blood flow leads to an influx of activated leukocytes into both testis Turner et al. Oxidative stress then leads to necrosis of the germinal cells with resulting subfertility or infertility. Diabetes has long been recognized to impair male fertility by interfering with both spermatogenesis and erectile function. Recently it has been reported that diabetic men have significantly higher levels of sperm DNA fragmentation than normal controls Agbaje et al. While this study did not directly measure oxidative stress, the authors proposed that the most likely mechanism for the observed increase in sperm DNA damage was an increase in oxidative stress as this is now recognized as a key pathology underlying many chronic complications of diabetes. In support, studies using the Streptozotocin-induced diabetic rat model have found a significant increase in testicular oxidative stress within 6 weeks of initiation of the diabetic state Shrilatha and Muralidhara, Chronic inflammation and oxidative stress are highly prevalent in patients with chronic kidney disease and end-stage renal disease Oberg et al. Surprisingly, even when uraemia is reversed by haemodialysis, a persisting state of chronic inflammation and oxidative stress persists Danielski et al. Furthermore, renal transplant patients with stable renal function and no obvious signs of immune rejection of their graft also have elevated levels of oxidative stress Moreno et al. Patients with haemaglobinopathies such as beta-thalassemia major have high degrees of systemic oxidative stress Livrea et al. The likely cause of oxidative stress is iron overload from multiple blood transfusions. Iron is a potent pro-oxidant capable of redox cycling when not safely bound to transferrin in the blood or stored as ferritin in tissue. The toxic accumulation of homocysteine may cause reproductive dysfunction and oxidative stress within the testis Forges et al. Hyper-homocysteinaemia usually occurs due to suboptimal re-methylation of homocysteine to methionine by the enzyme methyl tetrahydrofolate reductatse MTHFR caused by a dietary deficiency of folate or a single-nucleotide polymorphism SNP in the MTHFR gene Selhub, ; Matthews, Several investigators have reported that SNPs CT and others in the MTHFR gene are more commonly found in the infertile men Bezold et al. One of the main reasons why screening for oxidative stress is not routine in andrology laboratories is the cost and complexity of testing and the lack of a single standardized measure of oxidative stress. At present there are over 30 assays of oxidative stress Ochsendorf, , broadly divided into three different types. This review will focus on the most popular and clinically useful assays currently being performed. These assays measure damage created by excess free radicals against the sperm lipid membrane or DNA. As oxidative stress is the result of an in balance between ROS production and total antioxidant capacity TAC , direct tests reflect the net biological effect between these two opposing forces. The most widely used method of assessing sperm membrane peroxidation is the measurement of MDA levels in sperm or seminal plasma with the thiobarbituric acid assay. MDA levels in sperm are quite low and therefore require the use of sensitive high-pressure liquid chromatography HPLC equipment Li et al. Seminal plasma levels of MDA are 5—fold higher than sperm, making measurement on standard spectrophotometers possible Sanocka et al. Measurement of MDA appears to be of some clinical relevance since its concentration within both seminal plasma and sperm is elevated in infertile men with excess ROS production, compared with fertile controls or normozoospermic individuals Sanocka et al. Furthermore, in vitro impairment of motility, sperm DNA integrity and sperm—oocyte fusion capacity by ROS is accompanied by an increase in MDA concentration Aitken et al. Other direct tests of sperm membrane lipid peroxidation such as measurement of the isoprostane 8-Iso-PGF2α Khosrowbeygi and Zarghami, and the cBODIPY assay Aitken et al. It is well recognized that oxidative stress is one of the major causes of sperm DNA damage Aitken et al. However, measurement of sperm DNA damage by TUNEL or SCSA is an imperfect assessment of oxidative stress as sperm DNA can be damaged by non-oxidative mechanisms such as aberrant apoptosis and incomplete sperm protamination Ozmen et al. This can be measured in sperm or seminal plasma by HPLC Fraga et al. Since a large prospective study has reported that chances of natural conception is inversely correlated with sperm 8-OHdG levels Loft et al. Chemoluminescence assays using either Luminol or Lucigenin are the most commonly described technique to detect ROS production within semen. These probes are very sensitive and have the advantage of relatively well established reported ranges for both the fertile and infertile population Ochsendorf et al. However, general uptake by clinical andrology laboratories has been hampered by expensive equipment luminometer and difficulties with quality control created by assay confounders such as incubation time, leukocyte contamination and presence of seminal plasma contamination Kobayashi et al. Furthermore, Lucigenin has been shown to undergo auto-oxidization which itself leads to the production of superoxide anions Liochev and Fridovich, This makes chemoluminescent probes such as Lucigenin less than ideal reagents for measurement of sperm superoxide anion production. A simpler alternative may be light microscopy quantification of nitroblue tetrazolium NBT activity. NBT is a yellow water soluble compound that reacts with superoxide anions within cells to produce a blue pigment diformazan. The amount of diformazan crystals seen within a leukocyte or sperm reflects its superoxide anion production. The NBT assay has been shown to correlate well with traditional chemoluminescence techniques Esfandiari et al. First, the NBT assay is inexpensive to set up as it only requires a light microscope. Secondly, the NBT assay can discriminate between production of ROS by sperm and leukocytes without the need for addition of activating peptides FMLP used in chemoluminescence assays WHO manual, Measurement of TAC within semen can be conducted in a variety of ways. The ability of seminal plasma to inhibit chemoluminescence elicited by a constant source of ROS horse-radish peroxidase is a commonly used technique. The TAC is usually quantified against a Vitamin E analogue Trolox and expressed as a ROS-TAC score Sharma et al. Antioxidants present within seminal plasma suppress this colour change to a degree that is proportional to their concentrations. Again the antioxidant activity is quantified using Trolox. While a reduction in any of the sperm parameters count, motility, morphology is more commonly seen in men with oxidative stress, asthenozoospermia is probably the best surrogate marker for oxidative stress in a routine semen analysis Aitken and Baker, ; Aitken et al. A link between impaired sperm motility and oxidative stress also extends to the sperm DNA as a recent study has identified a highly significant correlation between oxidation of sperm DNA and reduced motility Kao et al. Hyperviscosity of seminal plasma is associated with increased levels of seminal plasma MDA Aydemir et al. Infection of the semen with Ureaplasma urealyticum is associated with increased seminal plasma viscosity Wang et al. It is possible that these infections may damage the prostate and seminal vesicle, altering the substrates required for creation of normal semen viscosity. A large number of round cells within semen may suggest the presence of oxidative stress as they may represent seminal leukocytes Sharma et al. However, round cells may also be immature sperm rather than leukocytes, so formal identification of leukocytes requires ancillary tests such as the peroxidase test, CD45 staining or measurement of seminal elastase WHO manual, ; Zorn et al. Finally, poor sperm membrane integrity assessed by the hypo-osmolar swelling test has been linked with the presence of sperm oxidative stress Dandekar et al. Once an individual has been identified as having oxidative stress related infertility, treatment should be aimed at identification and amelioration of the underlying cause before considering antioxidant treatment. The following paragraphs are the author's suggestions for investigation and management based on the underlying causes of oxidative stress outlined in previous paragraphs. These recommendations are summarized in Table II. This may include stopping smoking, improved diet, losing weight. Direct treatment of the underlying stimulus for sperm oxidative stress. For example, antibiotic treatment of Chlamydia or Mycoplasma infection. This would include ligation of a varicocele or the use of testicular derived sperm during IVF to improve sperm DNA quality. Vitamin and antioxidant supplements, with or without the addition of anti-inflammatory medications to decrease leukocyte ROS production. Surgical extraction of sperm. If conservative methods such as lifestyle modification, antioxidant therapy fail use of testicular sperm extraction may be justified. Optimize laboratory procedures. Minimization of iatrogenic oxidative stress can be achieved by limiting semen centrifugation times and avoidance of use of cryo-preserved sperm if possible. Lifestyle behaviours such as smoking, poor diet, alcohol abuse, obesity or psychological stress have all been linked with oxidative stress. Exposure to heat, pollution and toxins heavy metals and plasticizers have all been linked with oxidative stress. Men should be advised to avoid activities which may heat the scrotum such as long baths and saunas. Proper ventilation and use of personal protective equipment at work will hopefully reduce men's exposure to chemical and metal vapours linked with oxidative stress. Infection of the semen and male accessory sex glands with Chlamydia and Ureaplasma has been conclusively linked with an increase in oxidative stress. As both of these infections are treatable with antibiotics, it makes sense to screen all men with known oxidative stress for these bacterial pathogens. Two studies have now confirmed the ability of antibiotic treatment to reduce sperm oxidative stress and subsequently improve sperm quality Omu et al. One relatively large and well-conducted study randomized men with Chlamydia or Ureaplasma infection to either 3 months of antibiotics or no treatment Vicari, Compared with 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 Krause et al. 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 male accessory gland infections 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 randomized to either a NSAID or carnitine antioxidant and monitored for improvements in sperm quality over the next 4 months Vicari et al. In addition, a one month course of a COX-2 anti-inflammatory has been shown to significantly reduce sperm leukocyte count, while improving sperm motility, morphology and viability Gambera et al. 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. Several investigators have reported that surgical treatment of a varicocoele can reduce seminal ROS levels and improve sperm DNA integrity Mostafa et al. While the most recent meta-analysis examining the effect of varicocelectomy on spontaneous conception shows a significant benefit Marmar et al. Well-conducted randomized studies measuring oxidative end-points sperm lipid peroxidation and oxidative DNA damage and pregnancy rates need to be performed before routine use of varicocelectomy can be advocated in men with oxidative stress. Elevated homocysteine has been linked with oxidative stress. The B group vitamins folate, Vitamin B 6 and Vitamin B 12 are known to increase the enzymatic efficiency of the MTHFR and cystathionine β-synthase enzymes responsible for removing homocysteine from the circulation Matthews, While yet to be proven to enhance sperm quality, the use of a B group vitamin supplement 5 mg folate, mg Vitamin B 6 and µg Vitamin B 12 is probably warranted in any man found to have hyper-homocysteinaemia and oxidative stress as this treatment is inexpensive and without significant side effects. To date, over 30 studies have been published examining the effect of various antioxidant treatments on sperm parameters and pregnancy outcome. With such a large body of evidence it would be expected that firm conclusions regarding the clinical effectiveness of oral antioxidants on sperm function and pregnancy outcome would be available. Unfortunately this is not the case because of the use of different types and doses of antioxidants, lack of proper prospective placebo controlled study design and small sample sizes. Many small non-controlled trials report significant improvements in sperm count, motility and morphology while on antioxidant therapy reviewed in Agarwal et al. However, as these studies are open to bias this review will only consider properly conducted placebo controlled trials or prospective trials measuring oxidative stress end points sperm peroxidation and DNA damage. Several studies have reported that levels of ROS within semen can be reduced by augmenting the scavenging capacity of seminal plasma using oral antioxidant supplements. The oral antioxidant Astaxanthin Comhaire et al. Furthermore, a combination of mg of Vitamin E and µg of selenium Keskes-Ammar et al. Finally, a well-designed RCT of 2 months treatment with 1 g of Vitamin C and Vitamin E reported a very significant reduction in sperm DNA damage Greco et al. This finding is supported by non-controlled studies which have also reported a reduction in sperm DNA damage with the use of a combination of Vitamin C and E mg each , β-carotene 18 mg , zinc and selenium Menezo et al. While many relatively poorly designed studies have shown antioxidant supplements to boost sperm count and morphology, the majority of good-quality studies do not Agarwal et al. The only parameter that appears to be possibly improved with oral antioxidant therapy is sperm motility. Many well-conducted studies have shown small but significant improvements in sperm motility with supplementation of carnitine Lenzi et al. However, two prospective RCT comparing Vitamin C and E supplementation with placebo have found antioxidants to have no ability to improve sperm motility Rolf et al. While many studies have show improvements in sperm quality with antioxidant treatment, the ability of these changes to translate into improved chances of pregnancy is less clear. Suleiman et al. Conversely, Rolf et al. Finally, a recent RCT comparing the antioxidant formulation Menevit with placebo reported a significant increase in clinical pregnancy rate if the antioxidant was taken for 3 months prior to IVF-ICSI treatment Tremellen et al. The Menevit nutraceutical is postulated to improve sperm quality by three complimentary mechanisms. First, it contains traditional antioxidants such as Vitamins C and E, selenium and lycopene to protect sperm from ROS already produced. Second, it contains garlic which is known to have an anti-inflammatory effect, thereby potentially reducing seminal leukocyte ROS production Hodge et al. Finally, Menevit contains zinc, selenium and folate that are believed to play a role in augmenting protamine packaging of sperm DNA Kvist et al. While it is yet to be proven that combinational therapy such as Menevit improves sperm DNA integrity, it appears logical that using several antioxidants with different modes of action, together with an agent to reduce leukocyte ROS production Vicari et al. It has been suggested that while sperm are in contact with Sertoli cells they are relatively protected from oxidative attack Greco et al. Two studies have compared sperm DNA quality in the same individual using either ejaculate Greco et al. Both of these studies report significant improvements in sperm DNA quality in the testicle derived samples. Unfortunately neither of these studies assessed oxidative damage to sperm so it is presently uncertain if protection from epididymal oxidative stress is the sole reason for the observed improvements in DNA quality. As such, resort to the use of testicular derived sperm in men with poor DNA quality should only occur if more conservative treatments such as lifestyle modification and antioxidant therapy have failed. Centrifugation of a semen sample prior to its use in IUI or IVF can exacerbate sperm oxidative stress. This can be limited by reducing the time that the semen is centrifuged Shekarriz et al. Avoiding use of cryopreserved sperm for fertilization is also ideal since ROS are produced during freezing and thawing of the sperm, thereby decreasing sperm quality Watson, Sperm preparation media may also be supplemented with a variety of antioxidants to guard against oxidative stress. At the present moment commercial sperm preparation media does not contain any antioxidants aside from albumin and amino acids. Optimized culture media for sperm is unfortunately lagging well behind the complex sequential media developed for embryos and certainly needs intensive research as soon as possible. An expanding body of evidence now supports a role for oxidative stress as a significant cause of male infertility summarized in Table III. However, despite being a common pathology in infertile men, oxidative stress is ignored by many infertility practitioners. Antioxidant supplements have now been shown in randomized placebo controlled studies to protect sperm from oxidative related DNA damage and to boost pregnancy rates. It may therefore be prudent to consider using antioxidants in all infertile men exhibiting oxidative stress. Presently, one-third of men in infertile relationships already take such therapies Zini et al. Of course, antioxidants should be offered in combination with changes in lifestyle such as avoiding toxins cigarette smoke, pollutants, heavy metals and excessive heat. While a role for oxidative stress in male infertility is now established, many unanswered questions still remain. First, there is a clear need to develop inexpensive assays to identify sperm oxidative stress that can be easily conducted in any andrology laboratory. Secondly, large RCTs are needed to confirm the effectiveness of surgical interventions varicocelectomy, testicular biopsy in the management of oxidative stress. Further research is also required to determine what combination and dose of antioxidant supplement provides sperm with maximal protection against oxidative stress. Finally, the development of new sperm culture media that can better protect sperm from the ravages of ROS damage is clearly required. Dr Tremellen is a recipient of funding from the University of Adelaide Colin Matthews research grant and Bayer Australia. Google Scholar. Advertisement intended for healthcare professionals. Navbar Search Filter Human Reproduction Update This issue ESHRE Journals Critical Care Reproductive Medicine Books Journals Oxford Academic Mobile Enter search term Search. Issues More Content Advance articles Grand Theme Reviews Submit Author Guidelines Submission Site Reasons to Publish Open Access Purchase Alerts About About Human Reproduction Update About the European Society of Human Reproduction and Embryology Editorial Board Advertising and Corporate Services Journals Career Network Self-Archiving Policy Dispatch Dates Terms and Conditions Contact ESHRE Journals on Oxford Academic Books on Oxford Academic. ESHRE Journals. Issues More Content Advance articles Grand Theme Reviews Submit Author Guidelines Submission Site Reasons to Publish Open Access Purchase Alerts About About Human Reproduction Update About the European Society of Human Reproduction and Embryology Editorial Board Advertising and Corporate Services Journals Career Network Self-Archiving Policy Dispatch Dates Terms and Conditions Contact ESHRE Close Navbar Search Filter Human Reproduction Update This issue ESHRE Journals Critical Care Reproductive Medicine Books Journals Oxford Academic Enter search term Search. Advanced Search. Redox homeostasis and antioxidant signaling: A metabolic interface between stress perception and physiological responses. The Plant Cell. Bayr H. Reactive oxygen species. Critical Care Medicine. Salvemini D, Cuzzocrea S. Oxidative stress in septic shock and disseminated intravascular coagulation. Free Radical Biology and Medicine. Mani S. 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Vitamins and minerals functioning as antioxidants with supplementation considerations. In: Florida Ruminant Nutrition Symposium. Gainesville, FL, USA: Best Western Gateway Grand; Sekhon L, Gupta S, Kim Y, Agarwal A. Female infertility and antioxidants. Current Women's Health Reviews. Written By Moyinoluwa Comfort Onaolapo, Samuel Chibueze Nzekwe, Lateef Okeleji Olabisi, Victor Oluwaseyi Amos, Oluwatobi Hezekiah Ajayi and Ayodeji Folorunsho Ajayi. Continue reading from the same book View All. IntechOpen Importance of Oxidative Stress and Anti Chapter 9 Antioxidant Phytochemicals as Novel Therapeutic St By Bhavana Gangwar, Santosh Kumar and Mahendra P. Chapter 10 Involvement of Antioxidant in the Prevention of Ce By Olalekan Bukunmi Ogunro, Aderonke Elizabeth Fakayo Chapter 1 The Role of Oxidative Stress in the Onset and Deve By Emina Čolak, Lepša Žorić, Miloš Mirković, Jana Mir |
| Author Information | Research needs in oxidative stress and reproductive health area include prospective studies on the influence of snd factors related to energy balance ooxidative fertility oxicative. Under normal conditions, oxicative molecules known as antioxidants convert Oxidative stress and reproductive health to H 2 Oxidatice to prevent overproduction of ROS. In a healthy body, ROS reactive oxygen species and antioxidants remain in balance. Studies determining normal TAC levels of the follicular fluid in unstimulated cycles are lacking. In the future, a strategy to reinforce the antioxidant defense system and target the mitochondria will be a huge step. PubMed CAS Google Scholar Richards JS. This may include stopping smoking, improved diet, losing weight. |
| How Does Oxidative Stress Impact Reproductive Health? | Infertility is a disease defined as reprodyctive inability to conceive following 12 or more months of unprotected sex oxidative stress and reproductive health an investigation is undertaken reproduuctive the Energy boosting tips for weightlifters history and physical findings dictate oxidative stress and reproductive health oxidahive and and treatment [ 67 ]. Impaired fertilizing ability of superoxide dismutase 1-deficient mouse sperm during in vitro fertilization. Sperm were the first type of cell reported to produce free radicals. Article PubMed CAS Google Scholar Menon R, Fortunato SJ, Yu J, Milne GL, Sanchez S, Drobek CO, Lappas M, Taylor RN. Antioxidants to the rescue Antioxidants are an important weapon in the fight against oxidative stress. By Emina Čolak, Lepša Žorić, Miloš Mirković, Jana Mir |
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