Emerging evidences on oxidative stress and male infertility. Role of antioxidants and medicinal plants.
Sara Giacaroni, Renga Barbara
Infertility is a global health problem and it is one of the most stressful conditions amongst married couples. Approximately 7% of men worldwide are affected by male infertility of which male factors contribute to 40%-50% of all infertility cases. Infertility can be caused by various problems and among men, the most common cause are sperm disorders. Sometimes it is not possible to establish a cause of male infertility and when the results of a standard infertility examination are normal, a diagnosis of unexplained or idiopathic infertility is assigned. Oxidative stress has well extablished role in the pathogenesis of explained and unexplained infertility. The present review focuses on both the role of oxidative stress as well as the impact of antioxidants and medicinal plants in improving male fertility.
Infertility is a global hearth problem and male factor infertility is responsible in not less than 50 % of the cases (1). Among men the most common cause of infertility are sperm disorders (1-2) and oxidative stress, which arises from an unbalance between reactive oxygen species and protective antioxidants, has a well-established role in the pathogenesis of explained and unexplained male infertility.
Reactive oxygen species (ROS) represent a broad category of molecules including: Oxygen free radicals (i.e superoxide anion, hydroxyl radical and hyperoxyl radical); non radical species (i.e. hypochlorous acid and hydrogen peroxide); reactive nitrogen species and free nitrogen radicals (i.e. nitroxylion, nitrous oxide, peroxynitrite) (3, 4, 5).
ROS may act as key signaling molecules in physiological processes, but in excess, uncontrolled levels may also mediate pathological processes as well as that regarding the reproductive tract/reproduction. Indeed, despite it is well documented that spermatozoa needs small amounts of ROS for capacitation, hyperactivation, motility, acrosome reaction and fertilization (6, 7), enhancement of ROS level in semen can be a main cause of male sub-fertility and even infertility. Therefore, it is necessary to create a balance between produced free radicals and its metabolism for appropriate function of testicular cells, because if the testicular biological system fails to detoxify or repair the adverse effects of free radicals, the cells and tissue will be damaged seriously (8).
In this regard, antioxidants can avoid this damage by counteracting free radicals or preventing their formation in the testicular cells. Seminal plasma has endogenous antioxidant for protecting spermatozoa from oxidative damage (9, 10). These antioxidants are divided to enzymatic and non-enzymatic antioxidant and male reproductive system has both antioxidant. Nonetheless, exogenous antioxidants (i.e. vitamin C and E, polyphenols and carotenoids) derived mainly from diets can play an important role in increasing the body’s capacity to fight free radicals. Indeed, an interaction between endogenous and exogenous antioxidants preserves and restores redox homeostasis (11-13) .
This review focuses on the role of oxidative stress in testicular function as well as the recent advances on the effect of natural and semy-synthetic antioxidants in regulating oxidative stress and sperm dysfunction.
Physiological role of ROS in male fertility
Accumulating evidence suggests that low levels of ROS are of paramount importance in the activation of intracellular pathways responsible for spermatozoa maturation, capacitation, hyperactivation, acrosomal reaction, chemotactic processes as well as fusion with the female oocyte [14-17].
Aitken and Clarkson were the first in 1987 to find that low levels of ROS promote binding ability of human sperm with zona pellucida ; since then, de Lamirande demontrated that superoxide anion participated in enhancing hyperactivation and capacitation of spermatozoa . Furthermore, other studies provided abundant evidences regarding the participation of ROS in capacitation and acrosome reaction and the potential signal transduction cascades .
Mammalian sperm maturation involves critical morphological and physiological modifications in both testes and epididymis. It is well recognized that low and controlled amounts of ROS are prerequisite for the process of fertilization. In this process, ROS might offer a substrate for phospholipid hydroperoxide glutathione peroxidase to trigger the oxidation of nuclear proteins and condensation of nucleus . Capacitation is a complex process prerequisite for next step: the acrosome reaction. During this process, spermatozoa undergo a finely tuned series of changes at the right moment and the proper location. Over the last decades, de Lamirande group did groundbreaking work in fertilization involving ROS, especially in capacitation. And it was demonstrated that among ROS, superoxide anion, hydrogen peroxide and nitric oxide, are of significant role in participating capacitation process [20, 22].
Physiological concentrations of ROS produced by capacitating spermatozoa could modulate a series of downstream events. The first event is the upregulation of intracellular cAMP levels, activation of protein kinase A, and phosphorylation of protein kinase A substrates. Subsequent events include phosphorylation of extracellular signal regulated kinase-like protein, and tyrosine phosphorylation of fibrous sheath proteins . Additionally, the involvement of ROS in human spermatozoa chemotaxis and sperm–oocyte fusion was also demonstrated [24-27].
Etiologies of sperm dysfunction by oxidative stress
Despite small amounts of ROS being a prerequisite for normal sperm–oocyte fertilization, high levels of ROS have been proved to suppress these pivotal events including sperm capacitation and acrosome reaction . Additionally, excess exposure to ROS is inversely correlated with sperm motility [29, 30]. Overexposure of spermatozoa to ROS was proposed to result in excess lipid peroxidation , which will subsequently not only lead to loss of plasma membrane fluidity and function , but also to mutagenic and cytotoxic effects as end products of the lipid peroxidation exhibit these features [33-35]. Consequently, spermatozoa not only lose their motility, but lipid peroxidation also damages the male germ cell DNA.
A wide range of internal and external factors can cause disturbance in antioxidant defense and subsequently induce oxidative stress. Some of these are described below.
Exogenous sources of ROS
Xenobiotcs and toxins
Several studies on rats and mice demonstrated that environmental exposure to toxins, such as industrial pollutants (i.e. 3,1-dinitrobenzene), plastic compounds (i.e. phthalates, that are particularly used for domestic containers) or certain pesticides (i.e. hexachlorocyclohexane) can cause an increase in ROS production in testes, which in turns causes a decline in a testicular sperm output, an increase in lipid peroxidation and finally an impairment of sperm production [36-38].
Similar to toxin effects, long term accumulation of xenobiotic compounds, which derived from the metabolism of drugs and chemicals in the body, can be associated with an increase in testicular oxidative stress a consequently with a decreased sperm quality .
Smoking and alchool consumption
Adoption of inappropriate lifestyle such as excessive use of alcohol or increased smoking can affect male fertility. Cigarette smoking is perhaps the most influential; in fact several studies have been demonstrated that smoking can increase production of free radicals in all tissues, including testes, thus affecting semen parameters [40-42]. As for the smoking, such studies recognized alcohol as a promoter of ROS production, thus interfering with body antioxidant defense, especially in the liver. However, also in testes, it has been demonstrated whether acetaldehyde, the end product of ethanol metabolism, significantly increase lipid peroxidation and decrease antioxidant defenses . Moreover a study associations between alcohol consumption, semen quality and serum reproductive hormones have shown that alcohol consumption of more than 5 units per week had adverse effects on semen quality and changes serum levels of both testosterone and SHBG . Thus, men should be advised that habitual alcohol intake could affect their fertility.
Testicular tissue is more sensitive to X-rays; therefore, exposure to X-ray can be associated with male infertility. In vitro studies demonstrated that X-ray radiation is able to produce a dose dependent production of ROS, DNA damage in human spermatozoa as well as an impairment in sperm concentration, motility and viability [45, 46]
Endogenous sources of ROS
Varicocele, dilation of spermatic vein in the left testicle, is associated with increased rate of male infertility . Oxidative stress induced by varicocele affects spermatogenesis process with various mechanisms. Some clinical trials have shown, that the oxidative stress in varicocele men could be the result of both increase in the level of ROS, and decrease in the total antioxidant capacity [48, 49]. In addition, other studies have shown the presence of Nitric oxide (NO) in spermatic vein of varicocele men, which in turns contributes to spermatozoa damage (50, 51).
Leukocytospermia refers to the presence of leukocytes in semen. It is defined by the World Health Organization (WHO) as ≥1 × 106 WBC/mL of semen  and is present in 10% to 20% of infertile men . The condition can be an indicator of male genital tract infection or inflammation. However, in the absence of infection, it may originate from etiologies such as cigarette smoking, heavy alcohol use, or age [54-57]. As reported in several studies, leukocytospermia is associated with significant elevations in seminal ROS levels and sperm DNA damage [58, 59]. These studies clearly demonstrated a positive correlation between the number of seminal leukocytes and ROS levels. Moreover, these studies shown the negative implication of ROS on sperm parameters and function by identifying negative correlations between ROS with sperm concentration and motility,
and a positive correlation with sperm DNA fragmentation [58, 59].
Immature spermatozoa are characterized by large amounts of cytoplasm that contains deposits of glucose-6-phosphate dehydrogenase. This enzyme produces nicotinamide adenine dinucleotide phosphate (NADPH) and as a result, ROS is generated from NADPH via an intramembrane-located NADPH oxidase (NOX). On the contrary, in morphologically normal spermatozoa, cytoplasm deposits in the midpiece are extruded to allow cell elongation and condensation to occur during spermiogenesis. So, immature spermatozoa are characterized by large amounts of cytoplasm that are expected to produce higher levels of ROS [60, 61]. In fact, several studies reported whether an excessive residual of cytoplasm droplet is correlated with increased ROS generation [60-62]. Mitochondria are another major source of ROS which can be amplified in spermatozoa of infertile men with mitochondrial dysfunctions .
Several studies have linked ROS overproduction with metabolic diseases such as obesity and diabetes. It has been demonstrated that obesity affects male fertility with different mechanisms: (i) it has been demonstrated that obesity results in male infertility by increasing seminal ROS levels and by inducing physical manifestations such as erectile dysfunction ; (ii) obesity causes a systemic inflammatory response which impacts semen parameters and semen quality ; (iii) the increased visceral abdominal fat can lead to alterations in adipokine secretion and the recruitment of pro-inflammatory white blood cells, and increased NADPH oxidase activity which, in turn, generates additional ROS and decreases sperm DNA integrity [66, 67]. Furthermore, men with metabolic syndrome have increased adipokine secretion (i.e. TNF‐α and interleukins) which results in the recruitment of macrophages in the seminal plasma [68, 69]. Of note, in combination with diabetes mellitus type 2, obesity‐related infertility is exacerbated by IL‐6 and TNF‐α disruption of the hypothalamic–pituitary–gonadal axis .
Oxidative stress and antioxidant defense
Seminal plasma in men with idiopathic infertility has been found to have a lower antioxidant carrying capacity compared to fertile men .
Important enzymatic antioxidants in infertility include SOD, glutathione peroxidase (GPX), and CAT (3 A). SOD scavenges superoxide anion and catalyses its conversion to H2O2 and O2. High levels of SOD have been found in Sertoli cells, whilst germ cells have high activity levels that are maintained during spermatogenesis in developing and maturing spermatozoa . SOD has also been identified throughout the epididymis and in seminal plasma . This enzyme decreases markers for oxidative stress , protects sperm against lipid peroxidation , decreases DNA damage , and is associated with motility in human spermatozoa . GPX uses glutathione as an electron donor to catalyse H2O2 and superoxide anion . High levels of GPX are present in Sertoli cells . GPX is expressed and secreted from the head of the epididymis and is found in semen . GPX primarily protects against lipid peroxidation of the plasma membrane of spermatozoa . CAT is an enzyme found in peroxisomes that converts H2O2 to H2O and O2. Although minimal CAT is present in developing sperm, there is a constant low level of activity in the testicle . Men with asthenozoospermia have lower levels of CAT in their semen compared to normospermic men , potentially demonstrating the importance of seminal plasma levels of CAT [74, 77].
Non-enzymatic antioxidants are endogenously produced or consumed from food or supplements. Glutathione is a free radical scavenger found in high levels of developing spermatocytes and spermatids  that also acts as a coenzyme for GPX. Ascorbic acid (vitamin C) is a water-soluble vitamin that neutralises ROS and may protect against DNA damage in sperm . Tocopherol (vitamin E) is a fat-soluble vitamin that reduces lipid peroxidation in spermatozoa . Selenium and zinc are trace elements. Selenium serves as a cofactor to certain isoforms of GPX  and zinc may provide protection against lipid oxidation . Lycopene, a carotenoid, is localised to the prostate and testicles and may protect against ischaemia–reperfusion tissue injury . However, lycopene has not been detected in semen . Ubiquinol, found within seminal plasma, is the reduced form of coenzyme Q10 and has been associated with lower levels of ROS and a corresponding increase in sperm count and motility .
Effect of medicinal plants on male infertility
Since ancient times, medicinal plants have been proposed for the treatment of various disorders including infertility. The efficacy of medicinal plants used in traditional Persian medicine for treatment of male infertility related to abnormal sperm parameters has been cited in multiple literature papers. Most of the herbs showed in these studies have been clinically investigated for their effects on semen parameters including sperm count, sperm motility, sperm viability, dead or abnormal spermatozoa and recovery of sperm morphology. There is little information about the exact mechanism of action of these plants in infertility, but the more investigated and mentioned mechanism is antioxidant activity . Examples of plants with antioxidant effect are : Eurycoma longifolia, Cardiospermum halicacabum, Grape Seed, Marjoram, Syzygium aromaticum, Nigella sativa, Lycium barbarum, Tribulus terrestris, Asteracantha longifolia, Polycarpea corybosa . The other proposed mechanisms for the above mentioned plats are anti‐inflammatory, anti‐oedematous, venotonic (84, 85), containing nutriments and precursors for sperm production such as saponin and stigmasterol (86), and increasing blood testosterone (87).
The active ingredients that may be responsible for improvement of fertility in targeted plants are from various chemical groups including saponins (aescin, dioscin, protodioscin and diosgenin) (88), phytosterols (stigmasterol) (86), carotenoids (crocin, saranal) (89], oxygenated volatile compounds (thymoquinone, cinnamaldehyde, carvacrol) (90, 91), phenols (ellagic acid, zingerone, gingerdiol, zingiberene, gingerols and shogaols) (92, 93), lignans (sesamin) (94), lipids (l‐sitosterol, lecithin) (96) and alkaloids (withanolides) (95).
Conclusions and future perspectives
Free radicals attack to different organs can cause the induction of oxidative stress and subsequently causing serious damage to tissues. Testicular tissue is highly predisposed to activity of free radicals and oxidative stress due to several reasons including high cell division rate, cell competition for oxygen rate, low oxygen pressure due to weakened vessels as well as high levels of unsaturated fatty acids. Furthermore, since the body’s antioxidant system, including antioxidant enzymes such as SOD, catalase and GPX is not able to neutralize all free radicals, the use of antioxidant supplements is recommended to fight adverse effects of oxidative stress, enhance spermatogenesis and increase enhance fertility. The studies on the efficacy of medicinal plants proposed for male infertility are promising; however, further studies are recommended to obtain more conclusive results in terms of efficacy and safety of these herbal medicines.
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