Nutraceutical Therapy in Male Infertility

Pratik Kanabur and Ranjith Ramasamy, University of Miami, Miami, FL, United States
© 2018 Elsevier Inc. All rights reserved.

Background
Overview
Global rates of male infertility range from 2.5% to 12%. Males are found to be solely responsible for 20%–30% of infertility cases
and contribute to 50% of cases overall (Jungwirth et al., 2012). The management of male infertility includes assessing and identi-
fying a patient’s potential health problems. Decreased general health status has been associated with lower sperm concentration,
lower total testosterone levels and higher follicle-stimulating hormone values. Specifically, nutrition and lifestyle factors, which
are currently huge public health issues, play a critical role in the normal function of the reproductive system. Aside from evident
factors such as smoking (Saleh et al., 2002) and heavy alcohol consumption (Condorelli et al., 2015), male obesity and high fat
diets (Taha et al., 2016) have also been implicated in male infertility. One of the leading hypotheses for pathophysiological expla-
nation for idiopathic male infertility is damage to the reproductive tract due to oxidative stress from reactive oxygen species (ROS).
Studies say that anywhere from 30% to 80% of male factor infertility are due to damaging effects of oxidative stress (Ko et al., 2014).

Reactive Oxygen Species and Reactive Nitrogen Species

ROS represent a broad category of molecules that indicate the collection of radicals and nonradical oxygen derivatives. These mole-
cules have an unpaired electron in their outer orbit, and thus are highly reactive and interact with a variety of lipids, proteins, and
nucleic acids in the body (Agarwal et al., 2008). Free radicals include superoxide, hydroxyl radical, and hydropreoxyl. Nonradicals
include hydrogen peroxide, singlet oxygen, iron oxygen complexes, and hypochlorite. A subclass of ROS is reactive nitrogen species
(RNS) such as nitric oxide and peroxynitrate. These molecules, which are prominent in different areas of the male reproductive
system, are responsible for contributing to nitrosative stress. RNS have multiple physiologic functions, which include regulation
of multiple signaling pathways, assembly of the tight junctions in the blood testis barrier, production of hormones, and mainte-
nance of vascular tone. Specifically RNS also are essential for conducting various sperm functions such as capacitation, acrosomal
reaction, zona pellucida binding, as well as sperm motility, morphology, and viability (Doshi et al., 2012).

Mitochondria’s Role in ROS

The mitochondria are responsible for balance of reactive oxygen species. Along with production of ATP, initiation of apoptosis,
production of heat, and hereditary contribution, mitochondria produce ROS during the formation of superoxide in the electron
transport chain. In sperm, 25–75 mitochondria are arranged in tubular structures in the mid piece and are responsible for sperm
motility and overall functionality. Thus an intact mitochondrial genome and metabalome is essential for sperm functionality. While
a controlled level of ROS is necessary, an imbalance between ROS and ROS scavenging by seminal antioxidants results in seminal
oxidative stress which may lead to a decrease in motility, abnormal sperm morphology, and decreased ATP production leading to
overall decreased sperm viability as well as increased sperm DNA damage (Amaral et al., 2013).

Sources of ROS
Human semen consists of different types of cells such as mature and immature spermatozoa, round cells from different stages of the
spermatogenic process, leukocytes and epithelial cells. Of these, leukocytes (neutrophils and macrophages) and immature sperma-
tozoa are the two main sources of ROS. ROS come from multiple extrinsic and intrinsic sources in the semen. Intrinsic sources
include activated leukocytes from inflammation (i.e., diabetes, renal failure) and infection, immature spermatozoa with abnormal
morphology, and varicoceles, which are abnormal dilations of the veins in the testicles. Extrinsic sources include smoking, alcohol,
obesity, radiation exposure, and other environmental toxins such as pesticides, heavy metals, and plastics (Agarwal et al., 2016).
These exposures are summarized in Table 1.

ROS and Male Infertility

In 30%–40% of cases, no male-infertility-associated factor is found. However, even in these cases of idiopathic normozoospermic
male factor infertility, up to 25% of men have significantly higher levels of ROS when compared with fertile controls (Zini and
Al-Hathal, 2011). In addition, the decreased levels of antioxidant capacity found in this population further synergize this state
of oxidative stress. The delicate balance of oxidation and reduction is required for all major sperm functions such as capacitation,
hyperactivation, and sperm-oocyte fusion; ROS may also disrupt sperm by fragmenting its DNA and interfering with normal
chromatin packing. Normal chromatin compaction is required for sperm maturation during epididymal transit, capacitation, hyper-
activation, acrosomal reaction, and sperm-oocyte fusion reaction, all of which are necessary for successful fertilization. Supraphy-
siologic ROS levels can affect sperm structural and functional integrity including motility morphology, count and viability. It can

Encyclopedia of Reproduction, 2nd edition, Volume 4 https://doi.org/10.1016/B978-0-12-801238-3.64787-6 333

334 Treatment: Medical j Nutraceutical Therapy in Male Infertility

Table 1 Sources of ROS

Category Exposure Results

Lifestyle Smoking Decrease in sperm motility and normal morphology

Alcohol Decrease in sperm concentration, motility, and normal morphology
Obesity/high fat diet Decrease in sperm concentration, motility, normal morphology, and vitality
Environmental Air pollution No significant changes in ejaculate volume, sperm concentration, motility, or normal morphology
Pesticides Decrease in sperm motility and normal morphology and an increase in pH of seminal fluid
Plastics Decrease in sperm concentration, motility, and normal morphology
Infection Genitourinary Decrease in sperm concentration
Systemic HIV: Leukocytospermia (increased white blood cells ➔ increased ROS) and decreased sperm
motility
HBV: Decrease in ejaculate volume, sperm concentration, motility, vitality, and a decrease in pH of
seminal fluid
Testicular Varicocele Decrease in sperm concentration
Cryptorchidism Decrease in sperm concentration, motility, normal morphology, and vitality
Chronic disease Diabetes Decrease in ejaculate volume
Renal failure Decrease in sperm concentration and motility
Thyroid dysfunction Hypothyroidism associated with statistically significant decrease in sperm concentration, motility,
and normal morphology
Hyperthyroidism associated with statistically significant decrease in sperm motility
Medications Opioids Decrease in sperm concentration, motility, and normal morphology
SSRI Decrease in sperm motility and normal morphology

induce apoptosis, resulting in low sperm counts characteristic of men with idiopathic infertility. Sperm DNA damage may also
decrease fertilization rates, reduce implantation, impair embryonic development, and increase miscarriage/pregnancy loss and
the potential for birth defects.
The spermatozoa and seminal plasma contain multiple protective antioxidants to protect spermatozoa from oxidative stress by
scavenging the free radicals. These include both high molecular weight enzymatic antioxidants (superoxide dismutase, catalase and
glutathione peroxidase) as well as nonenzymatic antioxidants (ascorbic acid, a-tocopherol, pyruvate, glutathione, L-carnitine,
taurine, and hypotaurine)dwhich provide the bulk of antioxidant activity.

Nutraceutical Therapy
Overview of Nutraceuticals
Nutraceuticals are products derived from food that have health benefits, and may include amino acids, isolated nutrients, or dietary
supplements. Many of these products have antioxidant properties and can help scavenge ROS. Since seminal oxidative stress may be
due in part to deficiency in seminal antioxidants and there is a lack of serious side effects related to antioxidant therapy, nutraceut-
ical therapy may be used in men with clinical subfertility, as well as in men with normal semen parameters who have been unable to
conceive for 6–12 months.

Specific Nutraceuticals
Many different antioxidants have been investigated in the literature. It is important to distinguish between enzymatic antioxidants
such as superoxide dismutase, catalase, and glutathione peroxidase and nonenzymatic antioxidants such as vitamins, proteins,
glutathione, and ubiquinol. The different nutrients and their respective key role in infertility are summarized in Table 2. Some
of the important antioxidants studied in literature are discussed below. Overall, research has demonstrated that a decrease in the
seminal levels of these antioxidants is associated with infertility. In addition, when given to men with infertility, these supplements
or nutraceuticals can improve semen parameters.

CoEnzyme Q-10
CoEnzyme Q-10 (CoQ10) is an antioxidant molecule and a component of the mitochondrial respiratory chain, which participates,
in aerobic cellular respiration. It plays an important role in energy metabolism, as well as functioning as a liposoluble chain-
breaking antioxidant for cell membranes and lipoproteins (Gvozdjáková et al., 2015). At the cellular level, CoQ10 exists as a redox
pair, that is, it is found in two formsdubiquinone, the oxidized form, and ubiquinol, the reduced formdwhich are constantly
switching back and forth as CoQ10 transfers a hydrogen in the electron transfer chain in the mitochondria. As a supplement there
is no difference in taking ubiquinone or ubiquinol. Specifically, ubiquinol, which is the reduced state of CoQ10 is a strong lipo-
philic antioxidant that can regenerate other antioxidants. Ubiquinol inhibits organic peroxide formation in both the seminal fluid
and seminal plasma, which reduces the oxidative stress to which sperm cells may be subjected (Mancini and Balercia, 2011). Thus
 Treatment: Medical j Nutraceutical Therapy in Male Infertility 335

Table 2 Different nutraceutical therapies and role in infertility

Ingredient Key role in infertility

Co-Enzyme Q-10 Energy, antioxidant, sperm parameter benefits

L-Carnatine Energy, sperm parameter benefits
Lycopene Antioxidant, sperm parameter benefits
Beta carotene Antioxidant
Vitamin C Antioxidant
Vitamin E Antioxidant
Methylcobalmin Sperm parameter benefits
Astaxanthine Sperm parameter benefits
Alpha lipoic acid Antioxidant
Zinc Sperm parameter benefits
Selenium Antioxidant

there is a strong positive correlation between CoQ10 concentration and sperm count and motility. Three clinical trials, summarized
in a metaanalysis by Lafuente et al. have shown that supplementing infertile men with CoQ10 improved sperm concentration,
motility, and concentration in the seminal plasma (Lafuente et al., 2013). However, this is no reported data on live births after treat-
ment. Thus supplementation with CoQ10, while has not been proven to help increase pregnancy rates, has been shown to improve
semen parameters.

L-Carnitine
L-Carnitine is a molecule that is necessary for beta-oxidation of fatty acids in the mitochondria and helps to continue the energy
supply through the transfer of fatty acids from cytosol to mitochondria. It also protects DNA and cell membranes from the damage
caused by ROS (Agarwal and Said, 2004). The highest concentration of L-carnitine in the human is in the epididymis, with the
concentration being 2000 times greater than that in serum and infertile men have been found to have lower levels of seminal
L-carnitine. Supplementation of L-Carnitine in infertile men demonstrated an improvement in sperm concentration, mobility,
viability, and morphology (Sofimajidpour et al., 2016). In a metaanalysis by Zhou et al., supplementation with L-carnitine or L-acyl-
carnitine versus placebo led to a significant improvement in pregnancy rate and sperm motility but not total sperm concentration or
atypical sperm forms (Zhou et al., 2007). In addition, one study showed that in men with a grade 2 varicocele, which are varicoceles
that are palpable on clinical examination, men who chose between 250 mg L-carnitine four times a day for 6 months or varicoce-
lectomy showed improvement in sperm concentration, motility, and morphology similarly in both groups (Sofimajidpour et al.,
2016).

Lycopene
Lycopene is a compound from the carotenoid family obtained through consumption of red-colored fruits and vegetables (Gajowik
and Dobrzy nska, 2014). It is found in higher concentrations in semen and the concentration of lycopene was significantly decreased
in infertile men (Ghyasvand et al., 2015). Lycopene is a lipophilic molecule that incorporates in the cell membrane to protect the
sperm by preventing lipid peroxidation and also neutralizing ROS (Gajowik and Dobrzy nska, 2014). Studies have shown that
supplementation with lycopene improved oxidative stress parameters such as DNA fragmentation index and sperm related param-
eters including sperm count, motility, and concentration. It did not, however, improve sperm morphology (Agarwal et al., 2014).

Vitamin E
Vitamin E is a major chain-breaking antioxidant in sperm membranes and this effect appears to be dose dependent. Naturally occur-
ring vitamin E is actually a mixture of four tocopherols (alpha, beta, gamma, and delta) and four tocotrienols (again, alpha, beta,
gamma, and delta). Most vitamin E supplements consist solely of a synthetic form of pure alpha tocopherol. Vitamin E scavenges
the three major types of free reactive species, namely superoxide, hydrogen peroxide, and hydroxyl radicals (Kobori et al., 2014). In
a randomized, double blind, placebo-controlled trial by Kessopoilou et al., in vitro functional tests of human spermatozoa
improved after 3 months of alpha-tocopherol (600 mg/day) therapy (Kessopoulou et al., 1995). In another study by Suleiman
et al., treatment with alpha-tocopherolreduced levels of malondialdehyde, a marker of lipid peroxidation, and 11 out of the 52
(26%) men treated were able to impregnate their spouses and 9 of those ended up in live births (Suleiman et al., 1996). While
many studies have demonstrated a potential role for vitamin E in the management of male infertility, another randomized trial
by Rolf et al. who used both 800 mg vitamin E and 1000 mg vitamin C failed to confirm these findings (Rolf et al., 1999).

Vitamin C
Vitamin C is another important chain-breaking antioxidant and is present at a higher concentration in seminal fluid than in plasma
as well as being present in low but detectable amounts in sperm cells. Vitamin C neutralizes hydroxyl, superoxide, and hydrogen
peroxide reactive species and prevents sperm agglutination, while preventing lipid peroxidation, recycling vitamin E, and protecting
against DNA damage induced by hydrogen peroxide radicals (Angulo et al., 2011). It has been suggested that oral administration of
336 Treatment: Medical j Nutraceutical Therapy in Male Infertility

vitamin C with vitamin E significantly reduces hydroxyguanine levels in spermatozoa and also leads to an increased sperm count
(Kobori et al., 2014; Rolf et al., 1999)

Zinc
Zinc is second only to iron as the most abundant element in human tissues. Although Zn is found in most types of foods such as red
meat, white meat, fish, and milk, the World Health Organization estimates that one-third of the world’s population is deficient in
zinc. Zinc and citrate are excreted from the prostate gland as a low-molecular-weight complex; thus, it is estimated that the zinc
levels in seminal plasma typically represent prostatic secretory function (Zhao et al., 2016). Since zinc is found in high concentra-
tions of seminal fluid, it has numerous important functions, and it is essential for conception, implantation, and a favorable
pregnancy outcome. On a more molecular level, zinc influences the fluidity of lipids and, thus, the stability of biological
membranes. Zinc is a co-factor for superoxide dismutase, one of the important enzymatic antioxidants found in the semen. It
also helps stabilize sperm chromatin. Lastly zinc has been found to play a regulatory role in the process of capacitation and the
acrosome reaction (Gavella and Lipovac, 1998). Studies on the curative effects of zinc with respect to male infertility have shown
that zinc supplementation can significantly increase the percentage of normal sperm morphology, sperm motility and semen
volume. However, there were no significant effects of zinc supplementation on the sperm viability, sperm concentration, sperm
count or percentage of abnormal sperm morphology (Zhao et al., 2016).

Selenium
Selenium (Se) is an essential element for normal testicular development, spermatogenesis, and spermatozoa motility and function.
The predominant biochemical action of Se in both humans and animals is to serve as an antioxidant via the Se-dependent enzyme
glutathione peroxidase and thus protect cellular membranes and organelles from peroxidative damage. In one study, infertile men
with idiopathic asthenoteratospermia were treated with 200 mg of selenium with 400 U of vitamin E for at least 100 days. There was
a 53% improvement in sperm motility, morphology, or both and an 11% spontaneous pregnancy rates in comparison with no
treatment (Gavella and Lipovac, 1998). In another placebo controlled clinical trial carried out in Iran and Tunisia, selenium supple-
mentation improved sperm counts, concentration, motility and morphology as well as sperm concentration in infertile men
(Gavella and Lipovac, 1998).

N-Acetylcysteine
N-Acetyl cysteine is a naturally occurring compound, which comes from amino acid L-cysteine, and functions as a precursor of
glutathione peroxidase. One study investigated the effect of selenium and N-acetyl-cysteine on infertile men with idiopathic
oligo-asthenoteratospermia. These men were treated with the combinational therapy for 30 weeks. All semen parameters signifi-
cantly improved with selenium and N-acetyl-cysteine treatment (Gavella and Lipovac, 1998).

Overall Effects of Nutraceuticals

Dosages(Ko and Sabanegh, 2014)
Although the doses that are prescribed vary between physicians and different sources, review of literature revealed a range of dosages
that are recommended for various nutracueticals (Table 3).

Cochrane review on overall effects of antioxidants (Showell et al., 2017)

The Cochrane review was a large literature review of multiple studies, aimed to quantify the effect of nutraceutical therapies on
sperm motility, sperm count, and ability to achieve a pregnancy and/or a live birth. The results are summarized in Table 4.

Table 3 Doses of various nutraceuticals

Supplement Daily dose

Vitamin E 300–1000 IU
Carnitines 1–2 g/day
Zinc 40 mg/day
CoEnzyme Q10 200–300 mg
N-Acetylcysteine 600 mg
Vitamin C 1000 mg
Vitamin D 1000–4000 IU
Selenium 60–400 mg
Glutathione 600 mg
Lycopene 10–30 mg
 Treatment: Medical j Nutraceutical Therapy in Male Infertility 337

Table 4 Review on effects of various antioxidants

Fertility improvement Antioxidants used Findings

Live birth rate Vitamin E; zinc Increased

Pregnancy rate L-Carnitine, L-acetetyl carnitine, co-enzyme Q10, magnesium, vitamin E plus vitamin C, Increased
zinc, combined antioxidants
Sperm DNA fragmentation Vitamin E plus vitamin C Decreased
Sperm concentration
- < 3 months Docosahexaenoic acid, magnesium, vitamin C plus E, N-acetylcysteine, pentoxifylline, No difference
L-carnitine
- 6 months L-Carnitine, selenium, N-acetylcysteine, CoEnzyme Q10, pentoxifylline Increased
- 9 months or more L-Carnitine, CoEnzyme Q10 Increased
Sperm motility
- 3 months or less Vitamin C, vitamin E, L-carnitine, selenium, N-acerylcysteine, magnesium, zinc, No difference
docohexamandic acid, pentoxifylline
- 6 months L-Carnitine, selenium, N-acetylcysteine, CoEnzyme Q10, vitamin E Increased
- 9 months or more L-Carnitine, L-acetylcarnitine, CoEnzyme Q10 Increased

Adverse effects(Arcaniolo et al., 2014)

Even though nutraceuticals are benign products, excess intake can lead to adverse effects. Review of the literature revealed various
adverse effects from excess intake of nutraceuticals. Since men often take these medications for an extended period of time, it is
important to ensure that the dosages are not large enough to cause adverse effects (Table 5).

Treatment
Ideal Couple
Ideal couple should want to attempt natural conception or intrauterine insemination. For patients that want to proceed with intra
cytoplasmic sperm injection or in vitro fertilization, surgical therapy may be preferred over administration of nutraceutical therapy.

Female Considerations
Full female workup should be considered. Female lab values should be within normal limits. This includes a normal AMH, a normal
day 3 FSH, good follicle count. An anatomical workup with a hysterosalpingogram should be normal as well.

Male Considerations
Nutraceutical therapy is primarily intended for the 30%–40% of infertile men where no cause could be determined (idiopathic
infertility). According to EAU Guidelines on male infertility, there is little evidence for empiric treatment using naturaceuticals.
However, medical therapy should be reserved only in men with hypogonadotropic hypogonadism, which is low gonadotropins
and sex steroid hormone levels in the absence of any problems in the hypothalamic-pituitary-gonadal axis.
Male sperm count should be between 5 and 15 million/cm3, which is an intermediate range of sperm. A patient is considered to
have oligospermia with a concentration < 5 million/cm3. On the other hand a normal sperm count is > 15 million. Thus for men
with sperm count that is decreased but not enough to be considered as oligospermia, nutraceutical therapy should be considered.
Sperm motility should be < 40% but > 20%. Sperm motility is more important for natural conception or intra uternine insem-
ination but not as important for artificial techniques.
Male should also have no other correctible causes of abnormal semen parameters. These include varicoceles, cryptorchidism,
infection, and inflammation. In general a male with idiopathic oligoasthenozoospermia is an ideal candidate for nutraceutical
therapy. Overall these men who choose to take nutraceutical therapy will need to do so for over 6 months at the dosages required.
The end goal of treatment with nutraceutical therapy is to help increase the motility of the sperm.

Conclusion

This article provides an overview of various causes of seminal oxidative stress, use of specific nutraceutical therapies to help in men
with idiopathic infertility, and the selection of an ideal couple for nutraceutical therapy. The causes of oxidative stress include but
are not limited to lifestyle, drugs, infections, chronic diseases, and iatrogenic causes. Various nutraceuticals have been studied in
literature and include CoEnzyme Q10, carnitine, lycopene, vitamin E, vitamin C, zinc, and selenium. In a review of the literature
338 Treatment: Medical j Nutraceutical Therapy in Male Infertility

Table 5 Adverse effects on increased intake of various nutraceuticals

Supplement Reported adverse effects

Vitamin E GI distress, fatigue, muscle weakness, headache blurry vision, rash, bruising, bleeding complication (>800 IU/d)
Cardiovascular complications (>400 IU/d)
Vitamin C (>2000 mg/d) Dyspepsia, headache, increased risk of nephrolithiasis
Vitamin A (>50,000 IU/d) Fatigue, irritability, mental status change, visual disturbances, vertigo
Anorexia, GI distress, excessive sweating, myalgia/arthralgia
Hepatotoxycity, hypoplastic, anemia
Arginine GI discomfort, hypotension, electrolyte abnormalities, renal insufficiency
Increased bleeding risk, elevated glucose levels, worsening symptoms of sickle cell disease, asthma
Carnitine (>4 g/d) GI distress, seizures, malodorous body secretion
CoEnzyme Q10 GI distress, loss of appetite, headache, skin rash
Glutathione Not adsorbed within GI tract
N-Acetyl-cysteine GI distress, rash, fever, headache, drowsiness
Hypotension, hepatic toxicity
Selenium GI distress, nail changes, fatigue, irritability, hair loss, garlic breath/odor
Metallic taste, muscle tenderness, tremors, facial flushing, hematologic changes, hepatic, and renal insufficiency
Zinc
(>200 mg/d) GI distress, loss of appetite, dehydratation, gastric ulceration, rash; headache
(>450 mg/d) Altered iron function, low copper levels, sideroblastic anemia, reduced immune function, reduced HDL levels

on nutraceutical therapies, it was found that taking these various supplements for over 6 months at certain doses increases chance to
improve sperm count and motility. Overall, an infertile man with oligioasthenozoopermia is the best candidate for nutraceutical
therapy.

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