Harvesh Kumar Rana, Amit Kumar Singh, Abhay K. Pandey
Department of Biochemistry, University of Allahabad, Prayagraj, India
The success of pregnancy is the consequence of a complex interaction between males and females physiological systems. Any disruption in this interactive system, whether in a man or a woman, has the potential to prevent the birth of a biological child. Infertility is described as the inability to conceive after a year of frequent unprotected intercourse. Infertility affects around 15–20% of couples of reproductive age, and it can be caused by both male and female causes.
Oxidative stress (OS) has been linked to infertility in both men and women. It is a situation that occurs when the generation or buildup of reactive oxygen species (ROS) exceeds the biological system’s antioxidant capability. John MacLeod was the first to notice that OS might be a significant cause of male infertility in 1943 (MacLeod, 1943). The major sources of ROS in the male reproductive system are neutrophils, macrophages, and immature sperm. The generation of ROS in leukocytes after the beginning of infection and inflammation might result in an increase in ROS levels in the surrounding tissues (Sharma et al., 1999). Depending on the amount of the OS, ROS can cause varying levels of sperm problem. ROS can cause DNA fragmentation in sperm from infertile men in two ways: first, it can cause single or double stranded DNA breaks, which can lead to infertility (Kodama et al., 1997). Aitken et al. (1995) demonstrated that low levels of H2O2 had no effect on sperm motility but did inhibit sperm–egg fusion. Second, higher levels of ROS may cause damage by causing lipid peroxidation of the sperm plasma membrane through a sequence of chemical processes (Alvarez, 1987). Lack of membrane fluidity, which is crucial for sperm motility and sperm–oocyte fusion, is caused by lipid peroxidation. According to Griveau and Le Lannou (1997), the acrosome response in human spermatozoa is susceptible to ROS. Several studies have shown that the levels of ROS are inversely related to sperm motility.
OS because of free radicals load impacts the exceptional of gametes and affects oocytes, spermatozoa, embryos, and their situations. The microenvironments of follicular fluid, hydrosalpinges fluid, and peritoneal fluid have an immediate impact on oocyte quality, sperm–oocyte contact, sperm-mediated oocyte activation, implantation, and early embryo development. OS has an effect on early embryo development and implantation, which has an effect on the likelihood of becoming pregnant (Agarwall et al., 2005).
Antioxidants (vitamins C and E, folic acid, zinc, selenium, carnitine, and carotenoids) are ROS scavengers, and their usage as a therapy has been demonstrated to counteract the negative effects of high ROS levels on sperm and blood parameters in female infertility. Those with a high dietary intake of antioxidants had a reduced incidence of sperm aneuploidy and higher sperm quality than men with a lower consumption, according to studies (Silver et al., 2005; Young et al., 2008). Women with unexplained infertility had greater ROS levels than their fertile counterparts (Ruder et al., 2008). The normal buildup of free radicals with ageing may explain why older women’s egg cells are of lower quality (Agarwal et al., 2012). The current understanding of the role of ROS in the normal functioning of male and female fertility, as well as their role in infertility, is summarized in this chapter.
Infertility is defined as the inability to achieve a medical pregnancy after 12 months of typical unprotected intercourse or decline in a person’s fertility, either as an individual or with their partner, and it is an essential factor of pregnancy beginning. Infertility, according to the most recent WHO definition, is a condition that results in impairment due to a decline in function (Zegers-Hochschild et al., 2017). Infertility is a major issue. OS may play a role in endometriosis, tubal, and peritoneal issues, and unexplained infertility. Infertility affects 15% of couples of childbearing age. Only male factors can account for a quarter of these occurrences, whereas male and female factors can account for up to half of them (Sharlip et al., 2002).
The male physiological condition has traditionally been defined as an anomaly in one or more of the commonly studied spermatozoa characteristics, namely, concentration, morphology, and motility. Normal sperm analysis, on the other hand, has been proven to be ineffective in distinguishing between men with high and low fertility (Bonde et al., 1998). Furthermore, there appears to be a considerable overlap in observed sperm concentration, morphology, and motility between infertile individuals and men with confirmed fertility (Guzick et al., 2001). The considerable intraindividual variability of these measures, even during a spermatogenic cycle (about 10 weeks), might explain why conventional sperm parameters have a limited predictive value for diagnosing male infertility (Alvarez et al., 2003). It is commonly recommended that an abnormal humor analysis be performed at least once. Another possible causal factor is that regular spermatozoon analysis is often done manually using light research on a spermatozoa sample distribution (usually 200–400). This results in a high level of perspicacity as well as the possibility of significant interlaboratory and intralaboratory variance.
Aitken et al. (1989) presented that the ability of human sperm to fuse with egg cells with increased OS decreased in a dose-dependent manner, which can be inverted in the addition of vitamin E. Hughes et al. (1998) found that the addition of antioxidants to Percoll sperm preparation for an aided copy improved the DNA integrity of the sperm. However, the majority of those studies include uncontrolled, fertilized males, and pregnancy is rarely used as a prognosis indication (Kefer et al., 2009; Lewis and Agbaje, 2008).
Infertility in reproductive-elderly women is expected to affect one out of every seven couples in the Western world, and one out of every four couples in developing countries. Infertility rates may reach 30% in several parts of the world, including South Asia, a few countries in Sub-Saharan Africa, Middle East, North Africa, Central and Eastern Europe, and Central Asia (Mascarenhas et al., 2012). Males are shown to be entirely responsible for 20–30% of infertility cases, while they contribute to 50% of cases overall. However, such numbers no longer accurately represent all parts of the globe. Male infertility rates were highest in Africa and Central/Eastern Europe, according to Agarwal et al. (2015), whereas rates in North America, Australia, Central, and Eastern Europe ranged from 4.5 to 6%, 9%, and 8–12%, respectively.
Infertility can also be classified as primary or secondary. The main infertile female is a woman who has never been diagnosed with a clinical pregnancy yet satisfies the criteria for being classified as infertile. Secondary female infertility refers to a woman who is unable to have a clinical pregnancy but has previously been diagnosed with a clinical pregnancy (Zegers-Hochschild et al., 2017). The same classification is likely to apply to the male in terms of his involvement in the conception of a child.
To improve sperm quality and, as a result, male reproductive potential, a type of medication was developed (Kamischke and Nieschlag, 1999). In the age of evidence-based medicine, accurate control of infertility must be based on identifying reversible causes of infertility and treating them with suitable medications. This, however, will be a difficulty because, despite extensive research, no specific explanation for infertility in over 25% of infertile guys can be found (March and Isidori, 2002). More couples are seeking medical treatment for infertility, including pharmacological therapies, as infertility treatment continues to improve in the United States. According to the National Survey of Family Growth from 2002, 12% (7.3 million) of reproductive-elderly women (15–44 years) in the United States said they have used infertility treatments. According to the Centers for Disease Control and Prevention and the American Pregnancy Association, around 6 million women aged 15–44 have difficulty becoming or remaining pregnant. Because age is a significant risk factor for infertility, the requirements for an infertility analysis are based on the patient’s age.
In more than 90% of cases, infertility in men is caused by low sperm counts, poor sperm quality, or both. Anatomical issues, hormone abnormalities, and genetic anomalies are among the other causes. Hypothalamic hypophyseal tract, testicular issues of the seminal tract, immunological, psychosomatic, prior cancer treatments (chemotherapy), and various drugs like testosterone supplements, anabolic steroids, antifungals like ketoconazole, and a few antihypertensives are all factors that contribute to male infertility (Table 5.8.1).
Table 5.8.1
| Causes of male infertility | |
|---|---|
| Hypothalamic hypophyseal | Pituitary insufficiency, hyperprolactinemia, Kallmann syndrome, hemochromatosis, pituitary tumors, chronic illness (Dohle et al., 2002) |
| Testicular disorders | Infection, Klinefelter syndrome, testicular atrophy, Y chromosome deletions, systemic disorders (Dohle et al., 2002) |
| Seminal tract disorders | Retrograde ejaculation, obstructive azoospermia (Quinn et al., 1996) |
| Immunological disorders | Autoimmunity to sperm. This antibody hobby may be detected through some of the methods, inclusive of agglutination, immobilization, cytotoxicity, and immunofluorescence (Shulman, 1972). |
| Psychosomatic disorders | Psychological attitudes associated with neuroticism, melancholy, etc. Clinical observations advocate that remedy of subjective anxiety or strain can enhance fertility (Urry, 1977) |
| Causes of female infertility | |
| Chromosome abnormalities | Within the phenotypic lady, sex chromosome defects include gonadal dysgenesis (including Turner’s disease) and androgen insensitivity (David et al., 1994) |
| Ovulatory disorders | Hirsutism, obesity, and endometrial cancer are all linked to anovulatory disorders (David et al., 1994) |
| Oocyte factor | Weakening of oocyte first-rate inflicting a decrease being pregnant price and an expanded abortion price can be chargeable for massive age-associated lower in woman fecundity (Shoham et al., 1993) |
| Tubal infertility | Tubal infertility is caused by pelvic inflammatory disease (PID) caused by sexually transmitted bacteria such as gonococci, chlamydia, or other infections (David et al., 1994) |
| Implantation failure | The role of implantation failure as an infertility cause. The common belief is that insufficient progesterone secretion causes a nonreceptive endometrium in some women (Klentzeris et al., 1993) |
| Endometriosis | With the help of pelvic adhesions, altered anatomy, and ovarian or tubal damage, severe endometriosis can impair fertility (David et al., 1994) |
| Recurrent miscarriage | Parental chromosomal abnormalities, antiphospholipid antibodies, and uterine hollow space abnormalities are all linked to recurrent abortion. Polycystic ovaries may be the single most significant reason (Clifford and Regan, 1993) |
| Life style, physiological, and occupational factors | Tobacco smoking in ladies will increase the threat of infertility, the eggs of people who smoke have reduced IVF capacity. In females, occupational publicity to fabric dyes, lead, mercury, and cadmium were related to infertility (Rosevar et al., 1992) |
The reasons for female infertility may also range from one topographical and community place to another. A WHO task force identified the following reasons for female infertility: tubal component 36%, ovulatory problems 33%, endometriosis 6%, and no apparent explanation 40%. In Asia, Latin America, and the Middle East, a similar pattern emerges, but in Africa, tubal infertility was the most common cause of infertility. Unprecedented infertility (considering each companion) has been documented in 8–28% of couples. Causes of infertility in females are also given in Table 5.8.1.
Within the male duplicate system, physiological levels of ROS play an important function (Agarwal et al., 2008). Moderately higher ROS concentrations cause sperm immobility by depleting intracellular ATP and then lowering axonemal phosphorylation, whereas ROS concentrations above physiological levels cause lipid peroxidation and sperm cell death (Misro et al., 2004). Spermatozoa membranes are vulnerable to free radical damage because they are rich in polyunsaturated fatty acids and have limited antioxidant enzyme activity (Maneesh and Jayalekshmi, 2006). Furthermore, spermatogenesis in the testes is a highly energetic replicative mechanism for rapidly producing sperm. This rapid pace of cell division is accompanied with an increase in the production of free radicals as a result of an increase in mitochondrial oxygen intake through the usage of germinal epithelium (Aitken and Roman, 2008). As a result, an imbalance of free radical production and detoxification in sperm and testicular tissues causes injury to cell lipids, proteins, amino acids, sugars, nucleic acids, and mid-portions, resulting in next-to-worst semen characteristics. In male animals, poor semen characteristics are responsible for more than 80% of fertilization and embryogenesis failures, miscarriage, and infertility (Gadea and Matas, 2000).
Spermatozoa are liable to oxidative harm for some of the reasons. First, plasma membranes of sperm comprise a huge range of polyunsaturated fatty acids, compounds that might be intrinsically liable to OS. Second, the bulk of the cytoplasm of the cell is eliminated throughout spermatogenesis alongside cytoplasmic enzymes which include catalase and glutathione peroxidase, which commonly serve to scavenge loose radicals. Third, excessive ranges of ROS are related each with sperm DNA harm (Agarwal et al., 2003) and reduced capacity to restore such harm. Damaged sperm in flip produce extra ROS, thereby perpetuating this cycle.
Free radicals are produced in the female reproductive system in a variety of ways, according to in vivo and in vitro studies. ROS are produced directly from oocytes and embryos, as well as their environment, and they mediate embryonic development strategies (Guérin et al., 2001). RNS are involved in oocyte meiotic maturation in rats, pigs (Chmelková et al., 2009), cattle (Matta et al., 2009), and sheep, in addition to ROS generation (Amale et al., 2011). In the female replica system, free radicals play two roles, one of which is ovulation (Shkolnik et al., 2011). In addition the everyday technology of free radicals in vivo, many in vitro elements reason OS and harm to replica system. For example, better ambient temperature and numerous pollution are the most important methods inducing OS. Changes in membrane properties, chromatin structure, and the meiotic spindle are among the reactions of oocytes or embryos to heat shock (Ju, 2005). Animal embryonic and larval stages are often the most vulnerable stages of the living cycle to heavy metals and pollution (Daka, 2002). There is a link between high blood and milk lead concentrations and ovarian dysfunction in cattle (Ahmed et al., 2010), and OS has been linked to the development of lead- and cadmium-related reproductive illnesses in animals (Patra et al., 2011).
Free radicals, like males, have a dual role in the pathophysiology of preeclampsia (Buhimschi et al., 1998), endometriosis (Uchiide et al., 2002), hydatid shape mole, delivery abnormalities (Williams, 2010), infertility (Celi, 2011), and abortion in the female reproductive system. Vandaele et al. (2010) discovered that short-term exposure to H2O2 during oocyte maturation accelerated bovine embryo development. Extra free radicals, on the other hand, had negative consequences. Furthermore, research in cattle has found that early stages of embryonic development, such as the two-cell and four-cell stage, are more susceptible to free radical-induced strain than oocytes, morulas, and blastocysts, due to the presence of more active mitochondria (Tarazona et al., 2006).
If the antioxidant device has been depleted due to excessive ROS production, female genital tract features may be altered. Oocyte maturation, steroidogenesis, and ovulation can all be affected by this. Furthermore, it has the potential to increase granulosa cell apoptosis, which is a well-known phenomena in terms of programmed cell death. In vitro studies have shown that an ovarian glutathione deficit accelerates antral follicle atresia, a condition in which antral follicles are too sensitive to OS (Mulla et al., 2018).
Humans have devised a complex antioxidant defense system to protect the body’s cells and organ structures from ROS (Kumar and Pandey, 2015). It consists of a variety of chemicals, both endogenous and foreign in origin, that work together to neutralize free radicals in an interactive and synergistic manner. These additives include: (a) antioxidants derived from food, such as ascorbic acid (vitamin C), tocopherols and tocotrienols (vitamin E), carotenoids, and various low molecular weight compounds, as well as glutathione and lipoic acid; (b) antioxidant enzymes, such as superoxide dismutase (SOD), glutathione peroxidase, and glutathione reductase; (c) ferrous binding proteins, including as ferritin, lactoferrin, albumin, and ceruloplasmin, which sequester loose iron and copper ions that may catalyze oxidative reactions; and (d) a variety of antioxidant phytonutrients found in a variety of plant foods (Kumar and Pandey, 2014).
While O2 percent and H2O2 combine with ferric ion (Fe3+), SOD inhibits the production of hydroxyl radical (HO) (Kumar et al., 2015). O’Flaherty (2014) found that the HO is highly reactive with lipids, promoting lipid peroxidation in human sperm membranes. According to one study, the best stage for keeping sperm alive is 50 units of SOD per milliliter. SOD supplementation has also been shown to increase the vitality of spermatozoa in other studies (Perumal, 2014). Catalase increases the price of sperm acrosome response and lowers the price of spermatozoa DNA fragmentation (Chi et al., 2008). Glutathione peroxidase (GPX), in combination with selenium as selenocysteine, protects cells when glutathione (GSH) is present. Within the reproductive system, GSH is the most important nonenzymatic antioxidant. After giving 600 mg of GSH per day intramuscularly in a 2-month pilot study, it was shown that patients’ sperm characteristics improved (Lenzi et al., 1993). In humans, the failure to express a GPX inside the spermatozoa is linked to infertility (Imai et al., 2001). GPX becomes the leading defense against H2O2-mediated attack on spermatozoa and male genital tract tissues when catalase expression is compromised or absent entirely (Drevet, 2006). Peroxiredoxins (PRDXs) are the first line of defense against OS damage in spermatozoa, regulating the local movement of ROS to maintain sperm function (Manandhar et al., 2009). In human spermatozoa, they are crucial defenders against H2O2 and other ROS (hydroperoxides, peroxynitrite; Zini et al., 1993). Coenzyme Q10 (CoQ10), or its reduced metabolite ubiquinol, is an antioxidant that is abundant in the mitochondria of the sperm midpiece (Lewin and Lavon, 1997). CoQ10 levels in seminal plasma and spermatozoa of infertile men with idiopathic- and varicocele-related asthenospermia were shown to be lower in several studies (Balercia et al., 2002).
Carnitine is an antioxidant that accumulates explicitly in the epididymis (Tang et al., 2008) and protects the cell DNA harm brought on via way of means of free oxygen radical precipitated male infertility (Dokmeci, 2005). L-carnitine elements strength to the sperms (Ruiz-Pesini et al., 2001) via way of means of transferring and breaking or oxidizing the fatty acids into the mitochondria, ensuing in power generation. In the treatment of individuals with prostate-vesicular-epididymitis, carnitine is a third-line medication having antibacterial and anti-inflammatory properties (Vicari and Calogero, 2001). Following copper poisoning, a recent animal study discovered that L-carnitine reduced ROS production and improved sperm quality in Wistar rats (Khushboo et al., 2017). Vitamin E (α-tocopherol) is a lipid-soluble antioxidant that acts as a sequence breaker rather than a ROS scavenger (Sharma et al., 2001). Vitamin E has been shown to be effective in reducing sperm dependency and infertility in several studies (Eskenazi et al., 2005). The use of oral vitamin E was reported to improve in vitro fertilization and semen characteristics (Suleiman et al., 1996). Ascorbic acid (vitamin C) is a water-soluble antioxidant that protects spermatozoa DNA from oxidative damage (Fraga et al., 1991). It increases sperm quality and characteristics such as attentiveness, motility, and dependability. In low quantities, ascorbic acid is a strong antioxidant, but a higher dose of vitamin C may cause auto-oxidation (Kumar and Pandey, 2014). For 2 months, 64 infertile guys were given 1 g of vitamin C and 1 g of vitamin E, together with faster attention to unusual spermatozoa in their ejaculates, resulting in reduced DNA-fragmented spermatozoa (Greco et al., 2005). In a group of individuals, co-administering vitamin E with selenium resulted in similar results and improved sperm motility (Keskes-Ammar et al., 2003). A recent study discovered that combining vitamin E with flaxseed oil reduced ROS and improved the semen quality of cloned goats (Kargar et al., 2017).
Because of their antioxidant properties, isoflavones are phytoestrogens that include genistein and equol antioxidants and help with male fertility. Adding dose-structured amounts of genistein or equol to sperm has shown to have protective effects on sperm. Cai and Wei (1996) reported that genistein increased antioxidant interest in mice and suppressed H2O2 production in vitro and in vivo (Wei et al., 1993). Pentoxifylline is a methylxanthine by-product that improves the cAMP level in human sperm and functions as a sperm motility activator. In a dose-based awareness, it is a fantastic superoxide anion radical inhibitor (Gavella et al., 1991). In vitro treatment with pentoxifylline resulted in reduced ROS production in 15 patients’ spermatozoa (Okada et al., 1997). It was recently discovered that inexperienced tea has the capacity to prevent OS inside the male reproductive apparatus (Roychoudhary et al., 2017). Polyphenols (catechins) and flavonoids are the two primary bioactive components in inexperienced tea. Catechins are 20 times more powerful antioxidants than vitamin C, and they help to reduce OS by quenching free radicals and chelating transition metals (Saeed et al., 2017). Catechins in green tea increase sperm awareness inside the epididymis, reduce lipid peroxidation and DNA damage, and improve enzymatic activity in the testis of mice. In individual rats, however, a higher dosage of inexperienced tea causes spermatogenesis suppression. Quercetin is a bioflavonoid with strong antioxidant effects. It boosts antioxidant enzymes while lowering NADPH oxidase and NADH-structured oxidoreductase activity (Kumar et al., 2019). Tempol is a SOD mimetic antioxidant and transforms superoxide into much less poisonous H2O2 (Santiani et al., 2013). Tempol protects OS from DNA breakage and lipid peroxidation caused by cryopreservation. Tempol and N-acetyl-cysteine were shown to reduce sperm motility in thawed ram spermatozoa in one study. Tempol is also used to protect cells against OS in molecular cultures techniques. When administered alone, 10 M Quercetin or 5 M Tempol increased the motility and viability of cryopreserved sperm, however adjunct therapy revealed no significant changes in semen parameters (Azadi et al., 2017).
OS has been suggested to be one of the important causes of infertility in males and females affecting varying degrees of sperm dysfunction and adversely affects fertilization, implantation and embryo viability. Antioxidant supplementation of natural origin (phenolic compounds and vitamins) has shown marked effect in reducing infertility in both the sexes.
H.K.R. acknowledges UGC New Delhi for providing financial support in the form of UGC-CRET fellowship. A.K.S. acknowledges the CSIR New Delhi for providing Senior Research Fellowship. All the authors gratefully acknowledge DST-FIST and UGC-SAP facilities of the Department of Biochemistry, University of Allahabad, India.
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