9.1 Introduction

Infertility is defined as a failure of spontaneous conception after one year of regular sexual intercourse in the absence of contraceptive measures [1]. This entity represents a rising medical complaint since one out of eight couples find it difficult to conceive a child for the first time, and up to one in six find it difficult to conceive twice. Currently, 70 million couples of reproductive age suffer from infertility worldwide, accounting for an estimated overall prevalence of 15% [2].

Age remains the leading cause of infertility among women (its incidence abruptly increasing above the age of 35). However, multiple factors including a number of environmental exposures have been identified for the male patient [3]. Reactive oxygen species (ROS) are the result of cellular aerobic metabolism. Physiologic amounts of ROS are required for adequate cell defense against these exposures [4]. However, its excessive accumulation may overcome the natural antioxidant agent concentration levels, thus inducing cellular plasmatic membrane peroxidation, DNA damage, and other oxidative stress deleterious effects [5].

Recently, a number of different studies have linked the excessive accumulation of ROS in seminal liquid to male infertility. Conversely, antioxidant oral supplementation therapy would play a role in counterbalancing the excess of ROS in seminal liquid, thus improving the quality of the sperm of subfertile men [6]. This chapter aims to provide an updated review on this controversial topic.

9.2 Reactive Oxygen Species and Fertility

Aerobic organisms depend on oxygen for vital functions. ROS are the result of this aerobic metabolism [4]. The main source of ROS in the seminal liquid are different oxidative reactions related to the electron transporting chain located at the mitochondrial membrane of the cellular seminal component [7], particularly within the white blood cells [8], producing 1,000-fold more quantity than the remaining cellular populations, but also spermatozoa, and tubular epithelial cells [5].

Physiologic amounts of ROS are required for adequate seminal cellular function. They facilitate spermatozoa chromatin condensation, thus playing an important role in the regulation of germ cell population by inducing apoptosis or enhancing spermatogonia proliferation [9]. In the mature spermatozoon, ROS favor sperm capacitation, acrosome reaction, zona pellucida binding, and sheath stability/mobility; all of them of capital importance for fertility [4,10]. ROS also have an important role as second intracellular messengers for functions other than fertilization [11].

Optimal ROS levels are crucial for cellular defense against a number of different environmental exposures (including pollution, electromagnetic radiation, pesticides, and increased testicular local temperature among others), toxic habits (tobacco and alcohol), lifestyle factors (physical activity and obesity), infections, chronic processes (hypertension and diabetes), and autoimmune diseases [12]. Furthermore, immature spermatozoa and those with altered morphology produce higher amounts of ROS than structurally normal mature spermatozoa, thus decreasing the fertilizing potential of the semen [13]. Hence, different studies have linked ROS seminal levels with male infertility, since abnormally increased ROS concentration values in seminal liquid have been detected in up to 40% of subfertile men [6]. However, although moderately increased ROS concentration values significantly decrease spermatozoa mobility, via adenosine triphosphate (ATP) excessive consumption and phosphorylation reduction of the axonemal proteins encharged for spermatozoa movement, do not seem to alter sperm viability to a greater extent [10].

Varicocele (i.e. varicose dilation of the pampiniform venous plexus of the testes – see Chapter 15) merits special attention. It represents a relatively common anomaly (11.7% of all adult males) and a well-known etiologic factor for infertility in young males, thus being present in 25.4% of men with an abnormal seminal analysis [1]. Although oxidative stress induced by increased local temperature in the testicular environment is still considered the main cause for seminal damage in these men [14], its exact mechanism of action has not been clearly elucidated to date.

9.3 Oxidative Stress and Infertility

Oxidative stress appears as soon as ROS production exceeds the antioxidant agent levels in the sperm, thus inducing cellular plasmatic membrane peroxidation [5]. Spermatozoa plasmatic membranes are rich in polyunsaturated fatty acids with a small proportion of scavenging enzymes [15]. This structural composition provides the cell membrane with flexibility, but makes it vulnerable to ROS-related oxidative damage. Increased ROS levels induce a peroxidation of the lipid chains located at this level, thus producing a loss of integrity that alters the plasmatic membrane permeability, which in turn affects spermatozoa morphology, mobility, and some of its vital functions (i.e. eventually resulting in cell death) [16].

Malondialdehyde (MDA) is the final byproduct of the above-mentioned lipidic peroxidative reactions. Since this metabolite is stable at room temperature, its concentration in semen has been widely used as a diagnostic tool to estimate the degree of oxidative harm to the sperm [17,18]. In this way, MDA seminal concentrations in males suffering from astheno-zoospermia have been shown to be twice as high as those of individuals with normal seminal values. In addition, previous studies have demonstrated that a significant reduction in MDA concentration improves the chance of a successful conception [19].

9.4 The Physiologic Antioxidant System

In aerobic cells, ROS must be adequately counterbalanced by natural plasmatic antioxidant agents to avoid their potential deleterious oxidative effects [5]. The antioxidant physiologic system consists of enzymatic factors (superoxide dismutase, catalase, and glutathione peroxidase), non-enzymatic factors (coenzyme Q10, L-carnitine, vitamins E and C), micronutrients (selenium, zinc, copper), and other factors [19]. The combined interaction between all these elements provides optimal protection against the toxic oxidative effects induced by ROS (Figure 9.1). Likewise, a significant reduction in the antioxidant ability of this system (secondary to the complete absence or even the critical reduction in the seminal concentration of any of the components included) facilitates the accumulation of ROS in the seminal liquid, a fact that explains a detrimental parallel effect on its fertile capacity [19,20]. Conversely, a direct relationship between antioxidant oral therapy and improvement of sperm quality has already been established [2]. The recommended oral supplementation doses for different antioxidant agents are summarized in Table 9.1.

Figure 9.1 Zn: zinc; Vit C: vitamin C, Vit A: vitamin A, Vit E: vitamin E; ROS: reactive oxygen species; SOD: superoxide dismutase; NAC: N-acetyl-cysteine; Se: selenium; ALA: Alpha-lipoic acid; CAT: catalase; Q10: coenzyme Q10; GPX: glutathione peroxidase; LC: L-carnitine

9.4.2 Non-Enzymatic Factors

Non-enzymatic antioxidants can be either a byproduct of endogenous metabolism or directly incorporated from diet, mainly acting as coenzymes for the enzymatic factors previously detailed.

9.4.2.1 Q10-coenzyme

Q10-coenzyme is a vitamin-like liposoluble ubiquinone commonly found in different lipoproteins and the cellular membrane [7]. Most of the Q10-coenzyme in the human body is obtained directly through oral intake from a number of dietary sources including meat, fish, nuts, and vegetable oils [16]. However, a minor proportion of endogenous Q10-coenzyme is synthesized via cholesterol metabolism. Its antioxidant activity relies on adequate seminal concentrations and aims to protect the cell membrane from lipidic peroxidation [16]. As one of the components of the electron transporting chain, it participates in the mitochondrial cell respiration (i.e. dedicated to energy production for tail mobility), thus being found predominantly in the mitochondrial-rich middle zone of the spermatozoon [2,7].

An ordinary Q10-coenzyme oral intake from diet has not been linked to any change in seminal parameters [16]. Nevertheless, numerous studies have analyzed the impact of supplementary oral doses of Q10-coenzyme on different seminal characteristics (Table 9.2). All these clinical trials agree to identify an improvement in overall spermatic concentration and mobility [7,25–27]. However, a recent meta-analysis conducted by Thakur and colleagues [28] found that although spermatic concentration and mobility were significantly improved with 150 mg daily dose of oral Q10-coenzyme supplementation, a parallel increase in pregnancy or live-birth rates was not observed using this strategy.

Table 9.2 Summary of the most important literature evidence regarding oral supplementation with antioxidant agents to improve the quality of semen.

Author	Year	Sample	Type of study	Treatment	Time	End-points	Results
Suleiman et al. [17]	1996	110 males with asthenozoospermia	Double-blinded controlled clinical trial	– 300 mg Vit E – Placebo	26 weeks	Spermatic mobility and lipidic peroxidation level	Improvement in mobility in male with asthenozoospermia and reduction of lipidic peroxidation level
Scott et al. [50]	1998	69 males with asthenozoospermia	Randomized double-blinded controlled clinical trial	– 100 mcg Se – 100 mcg Se + 1 mg Vit A +10 mg Vit C + 15 mg Vit C	3 months	Concentration, mobility, morphology and Se in blood	Improvement in mobility
Keskes-Ammar et al. [34]	2003	54 infertile males	Randomized double-blinded controlled clinical trial	– Vit E 400 mg + 225 mcg Se – Vit B	13 weeks	Concentration, mobility, morphology, volume, MDA viability, Vit E and cholesterol in blood	Improvement in mobility
Lenzi et al. [37]	2004	60 males with OAT	Randomized double-blinded controlled clinical trial	–2 g/d LC + 1 g/d LAC	6 months	Concentration, mobility, morphology and volume	Rise in mobile sperm cells and in progressive sperm cell mobility
Cavallini et al. [40]	2004	219 males with oligoastheno-zoospermia + varicocele	Randomized double-blinded controlled clinical trial	– 2 g/d LC + 1 g/d LAC – Placebo	6 months	Concentration, mobility, morphology and testicular volume	Significant rise of spermatic mobility, concentration and morphology. No in varicocele grades IV and V
Greco et al. [30]	2005	64 males with idiopatic infertility and DNA fragmentation.	Double-blinded controlled clinical trial	– 1 g/day Vit E + 1 g/day Vit C – Placebo	2 months	Concentration, mobility, morphology and DNA fragmentation.	DNA damage reduction and improvement in results in patients with previous DNA damage
Balercia et al. [25]	2005	60 males with asthenozoospermia	Double-blinded controlled clinical trial	– 3 g/d LC – 3 g/d LAC – 2 g/d LC + 1 g/d LAC – Placebo	6 months	Concentration, mobility, morphology, volume and total antioxidant capacity	LC and LAC raise progressive sperm cell mobility. and total antioxidant capacity. 9 pregnancy during treatment with LC and 5 after combined treatment
Ebisch et al. [43]	2005	– 47 fertile males – 40 subfertile males	Double-blinded controlled clinical trial	– 5 mg folic acid + 66 mg Zn – Placebo	26 weeks	Seminal characteristics.	Seminal concentration improvement
Galatioto et al. [36]	2005	42 males with oligospermia	Randomized controlled clinical trial	– 600 mg NAC + Zn + vitamins and minerals – No treatment	3 months	Concentration, mobility, morphology and volume	Rise in perm cell count
Sigman et al. [39]	2006	21 males with asthenozoospermia	Randomized double-blinded controlled clinical trial	– 2 g/d LC + 1 g/d LAC – Placebo	24 weeks	Volume, mobility, concentration, progressive mobility and carnitine levels in semen	No improvement
Tremellen et al. [49]	2007	60 males with morphology, motility or membrane integrity and>25% of sperm cells with DNA fragmentation.	Randomized double-blinded controlled clinical trial	– 6mg/d lycopene + 400 IU Vit E+ 100 mg Vit C+25 mg de Zn+ 26 mcg SE+ 0.5 mg folate, + 1,000 mg garlic – Placebo	3 months	Embryo quality and pregnancy results during IVF-ICSI	Higher success in pregnancy in ICSI vs IVF
Safarinejad et al. [51]	2009	468 males with OAT	Randomized double-blinded controlled clinical trial	– 200 mcg Se – 600 mg NAC – 200 mcg Se + 600 mg NAC – Placebo	30 weeks	Concentration, mobility, morphology, volume, viscosity, liquefaction time and oxidative status.	Improvement in all seminal parameters after Se and NAC administration
Balercia et al. [7]	2009	60 males with asthenozoospermia	Double-blinded controlled clinical trial	– 200 mg Q10 – Placebo	6 months	Concentration, mobility, morphology, volume and total antioxidant capacity	Rise in spermatic mobility in patients that received treatment. 12 spontaneous pregnancies during the study
Moslemi et al. [45]	2011	690 males with asthenoteratozo-spermia	Non-controlled clinical trial	– 200 mcg Se + 400 IU Vit E	100 days	Seminal characteristics and pregnancy rate	52.6% improvement in sperm cell mobility, morphology or both, and 10.8% of spontaneous pregnancy after oral treatment vs patients with no treatment
Safarinejad et al. [26]	2012	228 males with OAT	Randomized double-blinded controlled clinical trial	– 200 mg Ubiquinone – Placebo	26 weeks	Seminal parameters and total antioxidant capacity	Density, mobility and spermatic morphology improvement vs control group
Hadwan et al. [44]	2012	– 37 infertile males – 37 males with asthenozoospermia	Double-blinded controlled clinical trial	– 220 mg Zn sulphate twice a day	3 months	Quantitative and qualitative semen characteristics	Rise in seminal volume, sperm cell count and spermatic mobility
Abad et al. [58]	2013	20 males with asthenoteratozoo-spermia	Non-controlled, non-blinded study	– 1500 mg de LC+ 60 mg de VITC+ 20 mg de q10+10 mg de VIT E+ 10 mg de ZN,+200 mcg de SE +1 mcg de B12	3 months	DNA fragmentation and seminal characteristics	Reduction of DNA fragmentation. Significant raise in concentration, mobility, vitality and spermatic morphology
Nadjarzadeh et al. [27]	2014	47 males with OAT	Randomized double-blinded controlled clinical trial	– 200 mg q10 – Placebo	3 months	Effects over CAT and SOD	Rise in CAT and SOD level in the seminal liquid with an important positive relation between Q10, CAT, SOD and the normal sperm cell morphology
Haghighian et al. [54]	2015	44 males with asthenozoospermia	Randomized triple-blinded controlled clinical trial	– 600 mg/day ALA – Placebo	12 weeks	Seminal characteristics and oxidative stress markers in semen. Total antioxidant capacity	Rise in sperm cell count, concentration and spermatic mobility. Improvement in total antioxidant capacity and MDA levels

OAT: oligoastheno-teratozoospermia; mcg: micrograms; mg: milligrams; IVF: in vitro fertilization, ICSI: intracytoplasmic sperm injection; IU: international units; Se: selenium; Zn: zinc; ALA: Alpha-lipoic acid; LC: L-carnitine; LAC: L-acetyl-carnitine; NAC: N-acetyl-cysteine.

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Related posts:

1. Chapter 4 – The Effect of Endocrine Disruptors and Environmental and Lifestyle Factors on the Sperm Epigenome
2. Chapter 5 – Lifestyle Factors and Sperm Quality
3. Chapter 12 – Perinatal Outcomes from IVF and ICSI
4. Chapter 18 – Prevention of Male Infertility: From Childhood to Adulthood

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