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Nutritional Supplementation for the Treatment of Male Infertility

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235
11 Nutritional Supplementation
for the Treatment of
Male Infertility
Saad Alshahrani, Ashok Agarwal,
DavidCollins, and Sebo Ling Wang
11.1 INTRODUCTION
11.1.1 Male InfertIlIty
Infertility is a common healthcare problem affecting nearly 15% of couples. Although previous
studies have focused on female factors as the primary cause, current research indicates that about
25% of cases are exclusively caused by a male factor, and nearly 30–40% of all infertility cases have
direct contributions from male factor insufciency [1]. Several research groups have also noted a
steady decrease in sperm quality over the past 50 years, further contributing to male factor infertil-
ity [2,3].
CONTENTS
11.1 Introduction .......................................................................................................................... 235
11.1.1 Male Infertility ........................................................................................................ 235
11.1.2 Reactive Oxygen Species and Male Infertility ....................................................... 236
11.1.3 Oxidative Stress ......................................................................................................237
11.2 Antioxidants ......................................................................................................................... 237
11.2.1 Vitamins A, C, and E .............................................................................................. 237
11.2.2 Carnitines ................................................................................................................ 2 41
11.2.3 Coenzyme Q10 .........................................................................................................242
11.2.4 Lycopene ................................................................................................................. 242
11.2.5 Arginine .................................................................................................................. 243
11.2.6 Folic Acid ................................................................................................................243
11.2.7 Glutathione ..............................................................................................................244
11.2.8 N-Acetylcysteine ..................................................................................................... 244
11.2.9 Selenium ..................................................................................................................244
11.2.10 Zinc .........................................................................................................................244
11.2.11 Combination Antioxidant Therapy .........................................................................245
11.3 Herbal Therapy for Male Infertility ..................................................................................... 246
11.4 The Role of Nutritional Supplementation in the Treatment of Chronic Prostatitis ............. 247
11.5 Conclusion ............................................................................................................................248
11.6 Key Points Summary ........................................................................................................... 249
Acknowledgment ...........................................................................................................................250
References ...................................................................................................................................... 250
236 Nutrition, Fertility, and Human Reproductive Function
11.1.2 reactIve Oxygen SpecIeS and Male InfertIlIty
The etiology of male infertility is often varied and may include environmental, endocrine, and
genetic factors. One signicant cause of male factor deciency is the generation of reactive oxygen
species (ROS), which can damage sperm DNA, membranes, and proteins. If not properly neutral-
ized, ROS can lead to impaired motility, cytoskeleton damage, disruption of membrane uidity,
and even sperm apoptosis [4]. ROS include oxygen-containing compounds that have one or more
unpaired electrons (free radicals) as well as non-radical oxygen compounds. The most frequently
produced free radical is the superoxide radical
O2
, but other common free radicals include HClO
and OH. Ozone and hydrogen peroxide (H2O2) are examples of non-radical ROS [5].
Numerous sources of ROS exist. The two most prevalent sources are leukocytes and abnor-
mal sperm [6,7]. Leukocytes (particularly macrophages and neutrophils) produce ROS such as
O2
and H2O2 as part of the natural host immune defense against pathogens. Neutrophils also produce
HOCl through the action of oxygen-dependent myeloperoxidase. Abnormal sperm may retain more
cytoplasm than developmentally normal ones, leading to increased ROS production [5]. NADPH
oxidase in the sperm membrane produces ROS, and the concentration of this enzyme may increase
with abnormal cytoplasmic retention [6]. Along with this, diaphorase (a mitochondrial NADH-
dependent oxidoreductase) may also increase sperm ROS production [8]. Lastly, H2O2 generated
by superoxide dismutase (SOD) may temporarily inactivate glucose-6-phosphate dehydrogenase,
which decreases the amount of NADPH available to neutralize ROS [5].
Under normal physiological conditions, the amount of ROS produced does not exceed the rate
at which the sperm are able to neutralize these compounds. The production of ROS is imperative
for cellular functions in a limited capacity. O2
may serve as a metabolite for signal transduction
within the sperm [9,10]. A natural overproduction of ROS also occurs during sperm hyperactiva-
tion, capacitation, and fertilization [6,9,11,12]. Signicantly elevated levels of ROS, however, may
cause 30–80% of all male infertility cases [10]. Specic risk factors for the development of ROS
Smoking
Pollution
Cancer
Prolonged stasis of
spermatozoa in the
epididymis or in transit
Immature/abnormal
spermatozoa
Protein
damage
Lipid
peroxidation
Biomembrane
damage
Sperm damage
Infertility
DNA
damage
Male accessory
gland infections
• Prostate glands
Seminal vesicle
Epididymis
Drugs
O2
H2O2
OH
Varicocele
Oxidative
stress
FIGURE 11.1 Causes, mechanisms, and effects of oxidative stress on male infertility.
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237Nutritional Supplementation for the Treatment of Male Infertility
are diverse, and common examples include lifestyle (obesity, stress, alcohol, tobacco), environment
(heat, pollution), infection (acute, chronic), and inammation [13]. Figure 11.1 illustrates the effect
of oxidative stress on male fertility.
11.1.3 OxIdatIve StreSS
When the generation of ROS surpasses the sperm capacity to eliminate the free radicals and reac-
tive metabolites that are generated, oxidative stress (OS) occurs. Figure 11.1 illustrates the mecha-
nism of oxidative stress. OS can lead to a decrease in semen quality, resulting in a pathological
decline in several sperm parameters as a result of free radical damage. For example, it may lead to
a decrease in sperm motility as a result of reduced ATP production or damaged axonemal proteins
[14,15]. The ability of sperm to undergo capacitation and induce fertilization may also decrease
owing to reduced membrane uidity, increased membrane peroxidation, and loss of membrane ATP
[16]. OS can also lead to a loss of membrane integrity as well as DNA damage and apoptosis [4,7,17].
The functional morphology of sperm increases its susceptibility to OS and subsequent oxidative
damage. Sperm are vulnerable to oxidative damage owing to their abundance of polyunsaturated fatty
acids (PUFAs), which are at a high risk for lipid peroxidation. In addition, sperm maturation leads to a
reduction in cytoplasmic content, limiting the amount of enzymes and antioxidants available to counter
ROS production and repair ROS-induced nuclear and mitochondrial DNA damage[5].
11.2 ANTIOXIDANTS
Semen naturally contains antioxidants to counter ROS. Antioxidants are molecules that scavenge
free radicals and prevent deleterious cell damage due to chain reactions involving unpaired elec-
tions. Sperm contain two broad categories of antioxidants: enzymatic antioxidants, including SOD,
catalase, and glutathione peroxidase [18–20], and nonenzymatic antioxidants including vitamin C,
vitamin E, glutathione, amino acids, albumin, carnitines, carotenoids, avenoids, and prostasomes
[13]. The nonenzymatic antioxidants can be further divided into synthetic and dietary antioxidants.
Dietary antioxidants can be found in natural foods. These foods often contain multiple antioxi-
dants and other enzymatic cofactors that may act synergistically within the body to eliminate ROS.
In contrast, synthetic antioxidants are manufactured dietary supplements. For this reason, isolated
supplementation with a synthetic antioxidant may limit the synergistic effect commonly observed
with dietary antioxidants, and therefore, these compounds may offer suboptimal protection against
ROS in certain cases [21,22]. The effective use of synthetic antioxidants may require combination
supplementation to achieve a signicant ROS-scavenging ability [23].
Because of the prominent role OS plays in male infertility and the promising ability of dietary
and synthetic antioxidants to neutralize ROS, signicant research has been performed to assess
their efcacy. A substantial number of these studies have reported diminished ROS levels on sup-
plementation and improved semen parameters. However, other trials have found that many of the
same antioxidants had little or no effect on ROS and/or semen quality.
Sections 11.2.1–11.2.10 review the most common antioxidants, together with their recommended
dosing and possible value in improving sperm function and male fertility potential. Table 11.1 shows
the effects of antioxidants on male fertility.
11.2.1 vItaMInS a, c, and e
Vitamins are metabolic cofactors needed in a variety of biochemical processes for synthesis of
essential nutrients. Vitamins A, C, and E have been heavily researched in the last two decades
and possess antioxidant activities. Vitamin A is lipid soluble and necessary for visual acuity, and
it may also act as a growth factor [24]. Vitamin A also helps maintain the mucous membranes of
the genitourinary tract, gastrointestinal tract, eye, and skin [25]. The mechanism of action as an
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238 Nutrition, Fertility, and Human Reproductive Function
TABLE 11.1
Effects of Antioxidants on Male Fertility
Study Antioxidant Effects on Semen Quality Reproductive Outcomes
Scott et al. [26] Vitamin A (withselenium,
vitaminsC and E)
Increased motility N/A
Ehrenkranz [27] Vitamin C (with vitamin E) No change No change
Palamanda and Kehrer [28] Vitamin C (with vitamin E) No change No change
Kessopoulou et al. [29] Vitamin C No change No change
Thiele et al. [30] Vitamin C Increased normal morphology N/A
Baker et al. [31] Vitamin C (with vitamin E) No change No change
Rolf et al. [32] Vitamin C (with vitamin E) No change No change
Kessopoulou et al. [29] Vitamin E No change No change
Suleiman et al. [33] Vitamin E Decreased MDA, increased motility Improved pregnancy rate
Geva et al. [34] Vitamin E No change No change
Keskes-Ammar et al. [35] Vitamin E Increased motility No change
Menchini-Fabris et al. [36] Carnitine Increased motility with increased
supplementation
N/A
Bornman et al. [37] Carnitine Increased motility with increased
supplementation
N/A
Moncada et al. [38] Carnitine Increased progressive motility N/A
Costa et al. [39] Carnitine Improved count, motility, and morphology N/A
Vitali et al. [40] Carnitine Increased motility N/A
Lenzi [41] Carnitine Increased concentration and motility N/A
Cavallini et al. [42] Carnitine Increased concentration, motility, and
morphology
N/A
De Rosa et al. [43] Carnitine Increased motility, count, and membrane
integrity
Increased cervical mucus
penetration
Balercia et al. [44] Carnitine Increased motility velocity No change
Sigman et al. [45] Carnitine No change N/A
Zhou et al. [46] Carnitine Increased motility Improved pregnancy rates
Balercia et al. [47] CoQ10 Increased motility Improved pregnancy rates
Balercia et al. [48] CoQ10 Increased motility No change
Mancini et al. [49] CoQ10 No change No change
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239Nutritional Supplementation for the Treatment of Male Infertility
Lewin and Lavon [50] CoQ10 No change Increased IVF/ICSI success rates
Safarinejad [51] CoQ10 Increased concentration, morphology, and
motility
N/A
Safarinejad et al. [52] CoQ10 Increased count, motility, morphology,
acrosome reaction efciency. Increased
inhibin B and FSH
N/A
Nadjarzadeh et al. [53] CoQ10 Increased morphology, concentration, and
activity of catalase and SOD
N/A
Gupta and Kumar [54] Lycopene Increased motility, morphology, and
concentration
Improved pregnancy rates
Mendiola et al. [55] Lycopene Decreased semen quality with decreased
supplementation
N/A
Vicari et al. [56] NSAIDs Increased motility and viability, decreased
ROS
Improved pregnancy rates
Cavallini et al. [42] NSAIDs Increased concentration, motility, and
morphology
Improved pregnancy rates
Srivastava and Agarwal [57] Arginine Improved motility N/A
Landau et al. [58] Folic acid No effect N/A
Wong et al. [59] Folic acid Improved sperm concentration, no
improvement in sperm motility or
morphology
N/A
Ebisch et al. [60] Folic acid Decrease in folic acid in seminal plasma
caused by increase in DNA fragility and
sperm DNA damage
N/A
Tremellen et al. [61] Folic acid N/A Improved pregnancy rate
Imhof et al. [62] Folic acid No effect N/A
Lenzi et al. [63–65] GSH Increased sperm motility and morphology N/A
Kodama et al. [12] GSH Increased sperm concentration N/A
Atig et al. [66] GSH Maintained good sperm quality and
motility
N/A
Oeda et al. [67] NAC Preserved sperm motility N/A
Erkkila et al. [68] NAC Improved germ cell survival N/A
Comhaire et al. [24] NAC Decreased ROS. No effect on semen
motility and morphology
N/A
(Continued)
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240 Nutrition, Fertility, and Human Reproductive Function
TABLE 11.1 (Continued)
Effects of Antioxidants on Male Fertility
Study Antioxidant Effects on Semen Quality Reproductive Outcomes
Ciftci et al. [69] NAC Increased sperm volume, concentration,
motility and viscosity
N/A
Safarinejad and Safarinejad [70] NAC Improved sperm motility and morphology N/A
Noack-Fuller et al. [71] Selenium Preserved normal sperm morphology N/A
Scott et al. [26] Selenium Sperm concentration unchanged,
increased sperm motility
N/A
Tremellen et al. [61] Selenium N/A Improved pregnancy rates
Safarinejad and Safarinejad [70] Selenium Improved sperm motility and morphology N/A
Wong et al. [59] Zinc Improved concentration and sperm count N/A
Colagar et al. [72] Zinc Improved sperm parameters, increased
seminal antioxidant capacity, and reduced
oxidative stress
N/A
Atig et al. [66] Zinc Fertile men have greater concentration of
zinc than infertile men. Decreased amount
of zinc correlated with poor sperm
production, concentration, and motility
N/A
Tremellen et al. [61] Menevit No effect Increased pregnancy rates
Tunc and Tremellen [73] Menevit No change in concentration, motility, or
morphology. Increased DNA integrity and
protamine packaging
N/A
Omu et al. [74] Vitamin E, zinc Increased motility Increased fertilization capabilities
Note: CoQ10, coenzyme Q10; FSH, follicle-stimulating hormone; GSH, glutathione; IVF/ICSI, in vitro fertilization/intracytoplasmic sperm injection;
MDA, malondialdehyde; NAC, N-acetylcysteine; NSAIDs, nonsteroidal anti-inammatory drugs; ROS, reactive oxygen species; SOD, super-
oxide dismutase.
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241Nutritional Supplementation for the Treatment of Male Infertility
antioxidant is not yet wellunderstood, but studies have shown that it can reduce ROS levels and
improve semen parameters [24,26]. Studies on vitamin A as a monotherapy have yet to be per-
formed, and therefore, its efcacy as a sole agent remains unknown [25].
Vitamin A has been studied in combination with other antioxidants including zinc, N-acetylcysteine
(NAC), selenium, and vitamins C and E. Scott et al. reported a 30% increase in motility after a
3-month regimen of vitamin A supplementation combined with vitamins C and E and selenium
[26]. Galatioto et al. found seminal Xuid analysis showed that the median value of sperm count was
14.42 (11.75–15.45) millions/mL before treatment and 32.58 (18.75–35.25) millions/mL after anti-
oxidant treatment (P = 0.009) [75]. Over-supplementation (above 10,000 IU/day) is associated with
decreased visual acuity, skin dryness, hepatotoxicity, gastrointestinal (GI) distress, and other side
effects [76]. Vitamin A is found in many foods including meat, dairy products, eggs, sh, fruits, and
vegetables such as carrots and leafy greens [25].
Vitamin C is a water-soluble antioxidant that is available in semen at a concentration 10 times
higher than that in in serum [77]. It functions in the generation of biomolecules such as collagen,
proteoglycans, and other essential intercellular proteins [69]. Vitamin C also prevents peroxyl attack
by lipoproteins, sustains vitamin E in its reduced form, and defends against oxidative DNA damage
[77,78]. Many studies have been performed to assess the efcacy of vitamin C as a supplement and
its ability to combat ROS. A study of 42 patients by Thiele et al. showed that vitamin C levels were
positively correlated with the number of morphologically normal sperm in a specimen [30]. Most
studies combined vitamin C with vitamin E and various other antioxidants [79,80]. Although some
studies have reported a possible synergistic effect when vitamins C and E are used together [31],
most have shown no efcacy. For instance, a randomized, placebo-controlled, double-blind study in
which subjects received 1000 mg of vitamin C and 800 mg of vitamin E for 56 days showed that the
regimen had no effect on sperm parameters or pregnancy rates [32]. Studies assessing vitamin E as
a monotherapy also found that it had no signicant effects [27–29,32]. Over-supplementation with
vitamin C has been associated with ROS generation and kidney stones [81,82]. The most common
sources of vitamin C are fruits and vegetables [25].
Vitamin E is the most studied vitamin antioxidant. This lipid-soluble vitamin directly blocks
lipid peroxidation in the sperm membrane by neutralizing ROS-generated free radicals. Vitamin
E may also block ROS formation by diminishing leukocyte attraction via its anti-inammatory
actions [83]. Lastly, vitamin E is similarly thought to reduce ROS by aiding the activity of other
important antioxidants in the body [27,28]. Studies contain conicting data on the efcacy of oral
vitamin E supplementation in reducing ROS levels in semen. However, two randomized controlled
studies showed that it improved semen parameters. Suleiman et al. reported an increase in sperm
motility and a 21% increase in pregnancy rates and decreased malondialdehyde (MDA) levels in
asthenozoospermic men after supplementation with vitamin E [33]. In another double-blind ran-
domized, placebo, crossover controlled trial by Kessopulou et al., a 3-month vitamin E supplemen-
tation regimen increased the efciency of sperm zona binding [29]. In addition to these studies,
Geva et al. also showed decreased MDA levels and increased fertilization rates in a prospective
study analyzing the effects of a 3-month, 200 mg/day supplementation regimen [34].
The current allowable intake of vitamin E for men is 15 mg/day, with possible side effects begin-
ning at 400 IU [82]. Common sources of vitamin E include fruits, vegetables and vegetable oil,
eggs, meat, poultry, grains, and wheat germ [25]. Because it can inhibit platelet aggregation, it is
contraindicated in patients with hemorrhagic illnesses or those currently taking anticoagulants [84].
Side effects associated with supplementation include GI distress, rashes, blurry vision, headache,
fatigue, and muscle weakness [85].
11.2.2 carnItIneS
Carnitines, which include both -carnitine and -acetyl carnitine, are important water-soluble anti-
oxidants that generate metabolic energy by shuttling long-chain fatty acids across mitochondrial
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242 Nutrition, Fertility, and Human Reproductive Function
membranes to initiate β-oxidation. This process generates reducing equivalents in the form of
NADH and FADH2 as well as the two-carbon molecule acetyl-CoA which can then be further
oxidized in the tricarboxylic acid (TCA) cycle to generate cellular energy. Carnitines provide the
principle energy source necessary for sperm motility [86]. They also play a role in protecting the
phospholipids of the mitochondrial membrane by preventing the oxidation of fatty acids located
within it [41,87]. Carnitines are synthesized in the liver, transported to the epididymal epithelium,
and carried into the lumen of the epididymis, which is an important site of sperm development
[88]. As antioxidants, they play a role in preventing membrane and DNA damage from free radicals
and subsequent apoptosis of the cells [41,42,63,89]. Supplementation with carnitines has also been
shown to increase both sperm concentration and motility [36,37]. The effects of carnitines on sperm
parameters are thought to occur in the epididymis after the sperm have left the testes [41,63].
For -carnitine or combined carnitine supplementation, many studies have reported increased
motility and/or concentration with supplementation [38–43,46,47]. For example, Vitali et al. studied
subjects on a 3-month, 3 g/day supplementation with -carnitine and found that it increased motility
in 78% of patients along with sperm density [40]. Other studies, however, indicated no improvement
in semen parameters with -carnitine supplementation [39,45].
The most prominent sources of carnitines are red meat, but they also may be found in poultry,
sh, dairy products, fruits, and vegetables [90]. Supplementation above 4 g/day is associated with
GI distress, foul-smelling body odor, and possibly seizures [85].
11.2.3 cOenzyMe Q10
Coenzyme Q10 (CoQ10) is an antioxidant involved in many biochemical reactions but most com-
monly in those related to metabolism and the electron transport chain (ETC). Within the ETC, this
lipid-soluble molecule transfers electrons from complexes I and II to complex III. Because of the
role it plays in mitochondria, it is located primarily in the midpiece of the sperm. As an antioxidant,
the active form, ubiquinol, acts as a free radical scavenger for lipoproteins and membrane lipids
[83]. This antioxidant may have a natural protective function because its concentration increases
with ROS sperm damage [49].
A study by Safarinejad et al. analyzed supplementation with CoQ10 in 228 men with idiopathic
infertility by dividing them equally into two groups: one received 200 mg of ubiquinol/day and the
other received a placebo. This study reported a signicant increase in sperm count (9.8%), motil-
ity (4.5%), and morphology (1.8%) and an improvement in the efciency of the acrosome reac-
tion. The authors also reported a signicant increase in levels of inhibin B and follicle-stimulating
hormone (FSH), indicating that CoQ10 had a positive effect on both semen and Sertoli cells [51].
Most recently, Nadjarzadeh et al. showed that supplementation with CoQ10 increased catalase and
SOD activity and improved sperm concentration and morphology [53]. Several other studies have
reported similar positive effects on motility, count, morphology, and pregnancy rates, but whether
these improvements are clinically signicant remains to be established [44,47,48,50,70]. Mancini et
al. found that CoQ10 supplementation did little to improve sperm motility and quality in subfertile
men with varicocele [91].
Although no Recommended Daily Allowance (RDA) has been established, the optimal dose is
thought to be 200–300 mg/day [25]. Common sources of CoQ10 include sh, organ meats (heart,
kidney, and liver), nuts, soybeans, grains, and vegetables [85]. Over-supplementation has been asso-
ciated with skin rashes, decreased appetite headache, and GI distress [25].
11.2.4 lycOpene
Lycopene is a natural antioxidant that is part of the carotenoid family. This compound scavenges free
radicals and prevents cellular membrane and protein damage. It plays a role in immune reactions,
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243Nutritional Supplementation for the Treatment of Male Infertility
signaling in gap junctions, modulation of cell growth, and regulation of gene expression [92]. Of
interest is the fact that lycopene is thought to have the greatest ROS-quenching rate of all the anti-
oxidants [93]. Lycopene levels are high in semen and the testes. Infertile men are noted to have
lower levels than fertile men [54].
Several studies have been performed to assess the efcacy of lycopene on semen quality. Gupta
and Kumar found that lycopene signicantly increased sperm count, motility, and normal morphol-
ogy. In addition, in the patients who had a sperm count of at least 5 million/mL, supplementation
also increased conception rates [54]. A study by Mendiola et al. compared the dietary intake of
30 men with poor semen quality to that of 31 normozoospermic men. In this study, semen quality
improved with lycopene supplementation [55].
Lycopene is found in fruits (tomatoes, grapefruits, and watermelons) and vegetables [54]. As of
yet, there are only very mild observed side effects (GI distress and skin color change) with gross
over-supplementation [25].
11.2.5 argInIne
Arginine is a semi-essential amino acid that is a precursor to nitric oxide and spermine. It is neces-
sary for spermatogenesis and sperm motility and plays a crucial role in cell division, wound heal-
ing, immune function, and hormone production [94]. Men who have arginine-decient diets may
suffer from low sperm count and have increased levels of nonmotile sperm. In a recent study by
Srivastava and Agarwal, arginine improved motility and metabolism in sperm through the nitric
oxide pathway [57]. However, the lack of a large number of randomized controlled studies exploring
the efcacy of arginine makes it difcult to gauge its effect on male fertility [95,96].
Owing to lack of human data, there is no current RDA for arginine. Sources of arginine
include animal and plant products such as dairy, turkey, beef, pork, seeds, soybeans, and nuts [96].
Commonly observed side effects associated with supplementation with arginine are GI distress,
renal insufciency, electrolyte imbalance, hypotension, and increased bleeding risk [95].
11.2.6 fOlIc acId
Folic acid is a derivative of the water-soluble vitamin B9 and is essential for the synthesis of purines
and thymidine. It also plays a role in many other important cellular functions such as the transfer
of one-carbon molecules and promoting proper spermatogenesis, although the underlying mecha-
nism for this process is currently unknown [59,62]. Folic acid also acts as a free radical scavenger
to prevent damage to lipids and proteins [86]. Infertile men may have lower concentrations of folic
acid than fertile men [97].
Several studies have noted that folic acid supplementation improves sperm quality. A study by
Wong et al. showed an increase in sperm concentration despite a lack of improvement in sperm
motility or morphology [59]. Ebisch et al. showed that a decrease in folic acid concentration in
seminal plasma correlated with an increase in sperm DNA damage [60]. These ndings underscore
the role folic acid plays in DNA synthesis and protein methylation reactions [98]. Despite these
positive results, several other studies have reported that folic acid supplementation is ineffective in
improving sperm quality. Originally, a study by Landau et al. reported that folic acid alone failed
to improve sperm concentration in subfertile men [58]. A more recent study by Imhof et al. showed
that supplementation with folic acid in fertile and subfertile men did not improve sperm parameters
[62].
Sources of folic acid include green, leafy vegetables, beans, citrus fruits, and avocados. Over-
supplementation with folic acid is associated with GI distress, rash, sleep disturbances, confu-
sion, increase in seizure frequency, allergic reaction, and increased risk for myocardial infarction
[99 –101].
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244 Nutrition, Fertility, and Human Reproductive Function
11.2.7 glutathIOne
Glutathione (GSH) is an essential antioxidant that is synthesized in the liver and transported into
the epididymis. It alleviates OS and helps maintain exogenous antioxidants in their active state. It
is the most abundant reducing agent in the body, making it vital to the intracellular defense against
ROS [86]. Its sulfydryl group directly neutralizes superoxide anions and other free radicals and
therefore protects proteins and nucleic acids against oxidative damage [26,86]. Many studies have
shown that GSH supplementation has a positive effect on semen parameters. Others have found that
it increases sperm motility, morphology, counts, and forward progression as well as prevents DNA
fragmentation [63–65,102]. Recently, Atig et al. studied the altered antioxidant status of the seminal
plasma in infertile men and found that GSH helps maintain good sperm quality and motility. These
authors showed that infertile men may have lower GSH levels than fertile men and that insufcient
amounts of GSH can lead to abnormal sperm motility. In addition, their results suggested that GSH
may enhance fertility by reducing lipid peroxidation [66].
GSH is found in fresh meat, fruits, and vegetables. The maximum RDA is 3 g/day [86], and
a deciency of GSH results in an unstable sperm midpiece, leading to defective morphology and
motility [103].
11.2.8 N-acetylcySteIne
N-Acetylcysteine (NAC) is a nontoxic derivative of -cysteine. It is a precursor of GSH and pro-
motes its production to assist in neutralizing ROS [104,105]. It can also interact directly with oxi-
dants, thiols, and hydroxyl radicals to remove free radicals and reduce oxidative stress in seminal
plasma [69]. Many studies have shown that it has a benecial effect on semen parameters. An in
vitro study by Erkkila et al. showed that NAC improved germ cell survival [68]. Several studies have
reported increased sperm motility, concentration, volume, and viscosity. Additional improvements
included decreased ROS levels, increased efciency of the acrosome reaction, and reduced oxida-
tion of the sperm DNA [24,67,69,75]. In contrast, another study found that NAC supplementation
did not improve semen parameters even though its seminal plasma concentration increased [51].
Sources of NAC include poultry, yogurt, egg yolks, oats, onions, and other vegetables. The lim-
ited side effects associated with supplementation are GI distress, rash, fever, headache, drowsiness,
hypotension, and hepatic toxicity [106].
11.2.9 SelenIuM
Selenium is an essential micronutrient necessary for normal male reproductive function, testicular
development, spermatogenesis, and spermatozoa motility and function [107]. It is a required cofac-
tor for the reduction of antioxidant enzymes. It maintains sperm structural integrity by protecting
against oxidative DNA damage. However, the exact mechanism of its action remains unknown
[5,86]. Many studies have shown a positive correlation between increased selenium levels and
increased sperm concentration, motility, and normal morphology [26,70,71,108].
Selenium is commonly found in soil, plants, and meat. The current recommended daily dose of
selenium is 55–400 mcg [86]. A selenium deciency is linked to decreased motility, breakage at the
midpiece, and sperm head morphologic abnormalities. On the other hand, over-supplementation is
associated with GI distress, nail changes, fatigue, and irritability [109]. Excessive intake has also
been linked to serious side effects such as liver cirrhosis, pulmonary edema, and even death [83].
11.2.10 zInc
Zinc is an essential micromineral that is an important cofactor for metalloenzymes, and it plays
a role in DNA transcription and protein synthesis [86]. Zinc SOD is involved in DNA repair [96]
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245Nutritional Supplementation for the Treatment of Male Infertility
and also helps increase the concentration of GSH, both of which limit the damaging effects of ROS
[86]. Many studies have reported that zinc supplementation improves sperm parameters such as
concentration, progressive motility, and sperm integrity as well as pregnancy rates. In an in vivo
study, men treated with 66 mg of zinc daily for 6 months experienced improved sperm concentra-
tion and count [59]. Omu et al. conducted a prospective study that showed zinc therapy increased
sperm parameters and antioxidant capacity and reduced sperm DNA fragmentation and apoptotic
markers. Omu’s study also showed that fertile men have a greater concentration of zinc than infer-
tile men and that a decrease in zinc concentration leads to an increase in OS and loss of sperm
integrity [74]. A study by Colagar et al. showed improved sperm parameters, an increase in seminal
antioxidant capacity, and a reduction in oxidative stress with zinc supplementation [72]. These
results suggest that zinc may be useful in reducing OS and thus helping prevent sperm membrane
and DNA damage [86].
A study by Atig et al. showed that fertile men have a greater concentration of zinc in their semi-
nal plasma than infertile men. The researchers also found that the infertile men had an increased
ROS level, which is associated with increased abnormal sperm parameters. They reported a positive
correlation between decreased zinc levels and poor sperm production and concentration as well as
motility [66]. Zinc supplementation has been shown to improve sperm parameters such as concen-
tration, progressive motility, sperm integrity, and pregnancy rates.
Zinc is found naturally in soil, plants (such as wheat and seeds), beef products, oysters, and
liver. Zinc deciency has been associated with abnormal agella and deformed midpiece [86]. The
limited amount of experimental data for humans prevents the establishment of an RDA [110]. Side
effects that may be a consequence of zinc supplementation above 200 mg/day include GI distress,
rash, headache, loss of appetite, and dehydration [85]. More severe side effects such as anemia, low
copper levels, impaired iron function, reduced immune function, and decreased high-density lipo-
protein (HDL) levels are associated with supplementation above 450 mg/day [111].
11.2.11 cOMbInatIOn antIOxIdant therapy
Many research studies have focused on the use of combination therapy to determine whether there
is a benecial synergism between individual components. Vitamin E has been studied in several
other combinations with different antioxidants. Keskes-Ammar conducted an in vivo study in which
men were given a mixture of vitamin E and selenium daily for 6 months. Sperm motility was the
only sperm parameter that improved [35]. A study by Omu et al. showed that combination supple-
mentation with vitamins C and E and zinc improved motility and fertilizing capacity [74]. Wong et
al. showed that combined supplementation with zinc and folic acid improved sperm concentration
and sperm count [59]. Other examples include combination therapies with selenium and vitamins A,
C, and E [26]; NAC with vitamins [75]; as well as nonsteroidal anti-inammatory drugs (NSAIDs)
combined with carnitines [42,56] as discussed previously in this chapter. One study showed that the
combination of NAC and selenium improved sperm count, motility, and morphology [70].
One important emerging combination supplement is Menevit, which is a synthetic compound
composed of several common antioxidants. It includes vitamin C, vitamin E, zinc, folic acid,
lycopene, garlic oil, and selenium. This supplement was designed so that the different compo-
nents would perform specic functions to reduce ROS levels synergistically and increase semen
parameters and sperm quality. To date, two studies have been performed to analyze the efcacy
of Menevit. In the rst one, Tremellen et al. studied 60 couples with known male factor infertility.
They found that Menevit supplementation increased in vitro fertilization (IVF)/intracytoplasmic
sperm injection (ICSI) pregnancy rates better than placebo [61]. In the second study, Tunc et al.
assessed the antioxidant therapy in 50 infertile male patients for 3 months. In that study, Menevit
reduced ROS levels and apoptosis in sperm cells while improving DNA integrity and protamine
packaging [73]. Neither of these studies found any improvements in sperm count, motility, or mor-
phology [61,73].
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246 Nutrition, Fertility, and Human Reproductive Function
11.3 HERBAL THERAPY FOR MALE INFERTILITY
Herbal therapy, along with other complementary and alternative therapies, is used for medicinal pur-
poses in the treatment of infertility in up to 18% of cases in the United States [112]. It has been known
to regulate systemic dysfunctions naturally and may affect levels of luteinizing hormone (LH), FSH,
and testosterone in humans. In an in vivo animal study by Abdillahi and Van Staden, aqueous stem
extracts of Bulbine natalensis were shown to increase blood testosterone concentrations in ani-
mals, thereby modifying their sexual function and behavior (especially effective for rats that have
hypotestosteronemia) [113]. In a rodent study by Wang et al., 8 weeks of supplementation with the
Wuziyanzong herbal pill lead to improvements in sperm quality. These improvements included such
parameters as sperm density and viability and mitochondria in rodents with oligoasthenozoospermia
[114]. In the in vitro study of Peng et al., human spermatozoa were incubated with Tu Si Zi, which
enhanced spermatic motility [115]. In another in vitro study, the combination of six herbal extracts
incubated with infertile male semen resulted in an increase in viability, number of progressive motile
sperm, curvilinear velocity, average path velocity, and lateral head displacement [116].
Clinical observations of married couples showed that the herb Sheng Jing Zhongzi Tang
improved spermatic density, motility, percentage of normal spermatid morphology, and pregnancy
rates [117]. This herb was also associated with a decrease in the amount of antisperm antibodies in
the semen [118]. In an investigation of Withania somnifera effects on semen, the herb effectively
reduced various oxidants, decreased OS, and increased antioxidant levels. This herbal treatment
also returned levels of testosterone, LH, FSH, and prolactin back to normal in infertile men [119]. In
another study, 219 men with varicocele-associated infertility were treated for 2 months with a daily
dose of 60 mg of Escin, an extract of Aesculus hippocastanum seed. The herb was shown to target
OS, resulting in an increase in sperm motility, density, and normal sperm morphology. In addition,
Escin signicantly improved the severity of varicocele [120]. These results were similar to those of
an older study in which infertile men treated with Bu-Zhong-yi-qi-tang for 3 months experienced
an increase in sperm concentration and motility [121]. Another herb, Rou Cong Rong, was shown
to promote the sperm generating functions of the testes as well as improve the microenvironment
of epididymis.
TABLE 11.2
Herbal Therapy for Male Infertility
Study Compound Outcome
Peng et al. [115] Tu Si Zi Improved sperm motility
Liu et al. [116] Mixed herbal (6components) Increased viability, number of motile and progressive sperm,
curvilinear velocity, average path velocity, and lateral
headdisplacement
Furuya et al. [121] Bu-Zhong-yi-qi-tang Increased concentration and motility
Sun and Bao [122] Yikang Tang Improved sperm parameters and pregnancy rates
Tijani et al. [123] Manix Improved sperm quality
Ahmad et al. [119] Withania somnifera Decreased oxidative stress and increased levels
ofantioxidants
Fang et al. [120] Escin Increased sperm motility, sperm density, and normal
spermmorphology
Yang et al. [109] Sheng Jing Zhongzi Tang Improved spermatic density, motility, percentage of normal
spermatid morphology, and pregnancy rates
Yang et al. [109] Rou Cong Rong Increased sperm generation in testes
Abdillahi and van
Staden [113]
Mixed herbal Increased serum testosterone levels
Wang et al. [114] Wuziyanzong herbal pill Increased sperm density and improved sperm viability
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247Nutritional Supplementation for the Treatment of Male Infertility
In a 6-month study, men with idiopathic oligozoospermia treated with Manix, a combination of
11 herbs with honey and sugar, experienced a signicant improvement in sperm count, motility and
density, and serum testosterone levels. The only sperm parameter that did not improve was semen
volume [123]. Another study conducted on 100 infertile men utilized an herbal combination called
Yikang Tang. The therapy increased sperm parameters and pregnancy rates while decreasing the
sperm agglutination rate [122]. Other combinations of herbs taken by infertile men have also been
shown to signicantly reduce sperm disomy [124].
In vitro studies and clinical trials have continuously found that the use of herbal treatment can
improve OS-induced male infertility [113]. Herbal treatments may become a more important fac-
tor in treating male infertility in the future, and they have been shown to signicantly increase
sperm density and sperm viability [114]. Most research indicates that these supplements have little
effect on vital signs, blood counts, and liver and kidney function [120], which may make them a
safer option than some currently prescribed medications [125]. Herbal treatments may also offer
abetter and safer method to restore sex hormones in infertile men [119]. Unfortunately, owing to a
lack of studies, the data surrounding their efcacy is very limited. More research on herbal treat-
ments should be explored to further evaluate their effects and possible clinical applications and their
potential side effects. Table 11.2 shows herbal therapy for male infertility.
11.4 THE ROLE OF NUTRITIONAL SUPPLEMENTATION IN
THE TREATMENT OF CHRONIC PROSTATITIS
Chronic prostatitis is just one of the many causes of OS-induced male infertility. We have included
it in this chapter because it is a rising problem. It affects up to 14% of men of reproductive age and
is difcult to treat. This condition, dened as inammation of the prostate gland with genitouri-
nary pain but without the presence of bacteria, is associated with increased ROS levels and sperm
damage [126]. Kullisaar et al. reported a positive correlation between chronic prostatitis and semi-
nal OS [127]. The most common symptoms involve the lower urinary tract and often include geni-
tourinary pain, dysuria, and altered frequency, although a host of other symptoms have also been
linked to this condition [128]. The National Institutes of Health (NIH) International Prostatitis
Collaborative Network divides prostatitis into four categories: (1) acute bacterial prostatitis,
(2)chronic bacterial prostatitis, (3) chronic prostatitis or chronic pelvic pain syndrome (CPPS),
and (4) asymptomatic prostatitis [129]. Of particular importance is category III (genitourinary pain
without bacteria present), which is the most prevalent among the four categories [129,130]. The
causes of CPPS may be such conditions as an unidentied bacterial infection (Ureaplasma and
Mycoplasma), autoimmune or inammatory reactions (including ROS, inammatory cytokines,
and white blood cells), and other causes such as pelvic muscle spasms and anti-inammatory drug
supplementation [131–133].
Much of the current therapy for chronic prostatitis involves a multidisciplinary approach involv-
ing dietary supplementation, acupuncture, and physical therapy. Several antioxidants have been
investigated as possible treatments, but few have been researched in great detail. In one study,
a 3-week regimen of lycopene decreased prostate-specic antigen (PSA) levels [134]. Lycopene
supplementation has also been associated with decreased interleukin-6 (IL-6) production and there-
fore decreased inammation [135]. This anti-inammatory effect may act synergistically with other
agents such as zinc, selenium, ellagic acid (EA), and epigallocatechin-3-gallate (EGCG) [116,136].
Vicari et al. described carnitines as a possible therapy for chronic prostatitis owing to their ability
to reduce ROS and oxidative damage and improve semen parameters [56].
In addition to the aforementioned dietary supplements, several compounds have also been inves-
tigated as possible treatments for chronic prostatitis. One study examined supplementation with
pollen extract (Cernilton) in patients with CPPS. Supplementation increased the patient-reported
quality of life, decreased pain, and generally improved patients’ overall well-being [128]. The use
of quercetin, a avinoid, has also been explored. Shoskes conducted a preliminary prospective,
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248 Nutrition, Fertility, and Human Reproductive Function
double-blind, placebo-controlled trial in which men with CPPS received 500 mg of quercetin twice
daily for 1 month. Mean NIH chronic prostatitis symptom scores decreased (from 21 to 13), and
67% of the patients experienced an improvement in symptoms [137]. Another study by Shoskes et
al. showed that 84% of patients with chronic prostatitis experienced an improvement in their symp-
toms after supplementation with quercetin for 26 weeks [139].
Another common nutritional supplement is saw palmetto. Kaplan et al. indicated that supplemen-
tation with saw palmetto did not have any long-term efcacy in relieving the symptoms of chronic
prostatitis [138]. Another researched nutritional supplement is prouss. Morgia et al. showed
that treatment with prouss (composed of Stylidium repens, selenium, and lycopene) effectively
improved symptoms associated with CPPS [126]. Although some trials showed improvements with
supplementations, more studies with larger, more dened cohorts are needed to draw meaning-
ful conclusions and to determine the clinical efcacy of these supplements in the management of
chronic prostatitis. Table 11.3 shows nutritional supplements for the treatment of chronic prostatitis.
11.5 CONCLUSION
Owing to the growing prevalence of infertility around the world, much research is being devoted to
understanding its underlying causes and in devising more effective treatments. Many current thera-
pies for treating OS-induced male infertility are not fully reliable and are expensive. Owing to the
ever-growing cost of medical care, alternative therapies represent a possible way to minimize costs
and improve pregnancy rates. A systematic review of the literature indicates that a wide variety of
supplementation is available for the treatment of OS. Theoretically, supplementation with antioxi-
dants should provide a valuable solution to OS-related sperm damage. Although many experiments
and trials have been performed, the efcacy of many of these antioxidants has not been proven and,
as a result, acceptable daily allowances have yet to be established. Many antioxidants decrease ROS
levels and increase sperm motility, morphology, and count with supplementation. An increase in
pregnancy rates is also often observed. Many trials, however, report conicting data for the same
antioxidant, indicating that larger trials and more well-dened studies are needed to fully uncover
the hidden mechanisms that may be present. Furthermore, even when an antioxidant is positively
correlated with sperm quality, it is often difcult to infer with a high degree of condence whether
the effect is clinically relevant. In general, little research has been performed to nd alternative,
TABLE 11.3
Nutritional Supplements for the Treatment of Chronic Prostatitis
Study Supplement Outcome
Shoskes et al. [137] Quercetin Improved NIH symptom score
Kaplan et al. [138] Saw Palmetto No long-term improvement in
prostateparameters
Herzog et al. [135] Lycopene Decreased IL-6 and inammation
Wagenlehner et al. [128] Cernilton Increased quality of life, decreased pain,
and improvement of overall condition of
chronic prostatitis
Shoskes et al. [139] Quercetin Improved pain, urinary symptoms, and
quality of life
Morgia et al. [126] Prouss (Stylidium repens,
selenium,andlycopene)
Decreased CPPS symptoms
Lombardo et al. [134] Lycopene Decreased PSA
Note: CPPS, chronic pelvic pain syndrome; IL-6, interleukin-6; PSA, prostate-specic antigen.
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249Nutritional Supplementation for the Treatment of Male Infertility
nonantioxidant treatments and herbal supplements for the treatment of OS-induced male infertility,
as these generally exist outside of current mainstream medical care. Both of these treatment strate-
gies, however, are becoming more prevalent and may one day represent the preferred treatment
option. One of the most important and fundamental issues is nding the normalized cutoff values
that dene OS and subsequent sperm damage. This has yet to be elucidated partially because cur-
rent methods for measuring ROS are expensive and unreliable.
In conclusion, studies investigating antioxidants and other nutritional supplements often suffer
from a lack of standardization, making it difcult to quantify the results of a given study. For the
efcacy of these supplements to be determined, larger trials with high-quality controls and random-
ization must be performed to establish clinically relevant guidelines for supplementation.
11.6 KEY POINTS SUMMARY
1. Infertility affects 15% of couples, with impairment in sperm function being the primary
underlying cause in up to 40% of cases.
2. Although the causes for sperm dysfunction in male infertility are many and varied, oxi-
dative stress related damage to sperm appears to be a contributing factor in up to 80% of
cases. Oxidative stress occurs when the production of reactive oxygen species (ROS) by
leukocytes or sperm themselves exceeds the neutralizing capacity of antioxidants con-
tained in the sperm or seminal plasma, resulting in damage to the sperm. This oxidative
damage impairs fertility by reducing sperm motility (direct ROS damage to the sperm
tail or mitochondrial energy source for sperm propulsion), by damaging the sperm acro-
somal membrane leading to impaired fertilization capacity, or by initiating paternal DNA
fragmentation.
3. The use of nutrition supplements with antioxidant capacity to prevent ROS-mediated dam-
age to sperm function holds promise as an effective treatment of male infertility for several
reasons. First, nutrients such as minerals (zinc, selenium), vitamins (vitamin C, folate), and
phytochemicals (lycopene), all with powerful antioxidant capacity, have been reported to
be present in lower concentrations in the serum or seminal plasma of men experiencing
infertility. Therefore, supplements of these nutrients may reverse these relative decien-
cies, bolstering natural antioxidant defenses and in turn improve sperm quality. Second,
several studies have shown that antioxidants such as vitamin C, vitamin E, and selenium
do have the capacity to reduce oxidative damage to the sperm membrane and DNA, which
theoretically should improve sperm functionality.
4. Although the theoretical basis for antioxidant supplementation to boost sperm function and
assist male fertility is strong, the quality of studies proving this point is poor for several
reasons. First, the majority of studies are not placebo controlled, making rm therapeu-
tic conclusions impossible. Second, very few studies have fertility (live birth) as the pri-
mary outcome, with the majority reporting only changes in sperm parameters. Although
an antioxidant nutritional supplement may produce a statistically signicant improvement
in sperm concentration or motility, it is not always possible to extrapolate that this will
translate into improvements in natural fertility given the limited diagnostic sensitivity of
routine semen analysis for natural fertility. Finally, although dozens of studies have been
conducted examining the effects of antioxidant herbal or nutritional supplements on sperm
quality or fertility, each has tended to use a different combination of antioxidants at various
dosages, making rm conclusions by comparison of studies impossible.
5. No universally accepted antioxidant nutritional supplement for the treatment of male infer-
tility has been agreed on. However, scientic principles would suggest that a combinational
approach using antioxidants with different modes of action would have the best chances of
success. For example, the use of a combination of vitamin C and vitamin E is likely to be
useful, as vitamin C potentiates the antioxidant effect of vitamin E by keeping it in its active
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250 Nutrition, Fertility, and Human Reproductive Function
reduced form. The nutrients zinc and selenium are likely to be useful for their direct antioxi-
dant effect and because they play an important role in protamine packaging of sperm DNA,
protecting it from ROS-mediated attack. Carnitine and coenzyme Q10 both play important
roles in sperm mitochondrial energy production, above and beyond their antioxidant effects.
Therefore, these two agents are likely to boost sperm motility and fertility potential. Finally,
the group B vitamin folate has been shown to boost sperm quality, possibly due to its anti-
oxidant effects and its important role in DNA synthesis. Although the results of clinical
studies are conicting, all of the above nutrients have been shown to boost sperm quality, as
have nutrients such as lycopene, glutathione, N-acetylcysteine, and antioxidant herbs such as
Withania somnifera and Aesculus hippocastanum.
6. Future placebo-controlled studies with clinically important end points (sperm DNA dam-
age, live birth) will need to be conducted before rm conclusions can be drawn on the
benets of antioxidant nutritional supplements for the treatment of male fertility. However,
as antioxidants are generally inexpensive and carry minimal side effects, a combination
antioxidant therapy appears to be a reasonable treatment for optimizing male fertility
potential.
ACKNOWLEDGMENT
The Center for Reproductive Medicine, Cleveland Clinic provided nancial support for this resea rch.
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