Nutraceutical Therapy in Male Infertility

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Nutraceutical Therapy in Male Infertility
Ranjith Ramasamy, Lucas Campos, and Marlon Martinez, University of Miami, Miami, FL, United States
r2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
This is an update of Pratik Kanabur, Ranjith Ramasamy, Nutraceutical Therapy in Male Infertility, Editor(s): Michael K. Skinner, Encyclopedia of
Reproduction (Second Edition), Academic Press, 2018, Pages 333–339, ISBN 9780128151457, https://doi.org/10.1016/B978-0-12-801238-
3.64787-6.
Background 1
Overview 2
Reactive Oxygen Species and Reactive Nitrogen Species 2
Mitochondria’s Role in ROS 2
Sources of ROS 2
ROS, Male Infertility and MOSI 3
Nutraceutical Therapy 3
Overview of Nutraceuticals 3
Specific Nutraceuticals 3
Arginine 4
CoEnzyme Q-10 4
l-Carnitine 4
Lycopene 5
Vitamin E 5
Vitamin C 5
Zinc 5
Selenium 5
N-acetylcysteine 6
Polyunsatureted Fatty Acids (PUFAs) 6
Overall Effects of Nutraceuticals 6
Adverse Effects (Arcaniolo et al., 2014) 6
Treatment 7
Female Considerations (Walker and Tobler, 2023) 7
Male Considerations 7
Conclusion 7
References 7
Further Reading 9
Abstract
Oxidative stress from reactive oxygen and subclasses can affect male fertility. Sources of reactive oxygen species include but are not limited to
lifestyle factors, environmental toxins, medications, and infections. Specifically, in the male genital tract, mitochondria from leukocytes and
immature sperm cells create reactive oxygen species. The imbalance of reactive oxygen species and antioxidants can lead to DNA damage,
resulting in decreased sperm motility morphology, count, and viability. Infertile men have been found to have an increased level of reactive
oxygen species compared to fertile controls. To protect against reactive oxygen species, some have turned to nutraceuticals, products derived
from food that have health benefits (Ko and Sabanegh, 2014). They may include amino acids, isolated nutrients, or dietary supplements.
Many of these products have antioxidant properties and can help scavenge reactive oxygen species (De Ligny et al., 2022), thus shifting the
balance. Some of the antioxidants that have been studied include CoEnzyme Q10, l-carnitine, vitamin C, vitamin E, zinc, selenium,
lycopene, and N-acetylcysteine. Supplementation of the majority of these antioxidants in infertile men has been shown to improve semen
parameters (Ko and Sabanegh, 2014a); however, the evidence has been limited and is of uncertain quality. Fortunately, there is no apparent
evidence that nutraceuticals cause an elevated risk of miscarriage or other harmful side effects(De Ligny et al., 2022). In this article, we
evaluate the impact and potential side effects of different antioxidants on semen parameters. We recommend that men with idiopathic
infertility who have impaired semen parameters may be candidates for nutraceutical therapy.
Key Points
•Present an overview of oxidative stress and reactive oxygen species in male infertility
•Introduce the concept of nutraceutical therapy and its antioxidant effect
•Attend some specific nutraceuticals, their mechanism of action and potential adverse effects
Encyclopedia of Reproduction, 3ed doi:10.1016/B978-0-443-21477-6.00056-0 1

Background
Male infertility often involves complex etiological factors, among which oxidative stress plays an important role in affecting sperm
quality, impairing sperm motility, morphology, and DNA integrity, thus compromising fertility potential. In recent years, the
exploration of new alternative therapeutic approaches has gained traction, with nutraceutical therapy emerging as a potential for
future success. Nutraceuticals, defined as bioactive compounds derived from natural sources with antioxidant properties, offer a
promising avenue for ameliorating oxidative stress-induced damage and help restore reproductive function.
Overview
Approximately 10% to 15% of couples globally experience the inability to conceive. A recent study suggests that approxi-
mately 50% of infertility cases can be attributed to men (De Ligny et al., 2022). A relationship has been observed between the
decrease in male reproductive health (lower sperm concentration, lower total testosterone levels, and higher follicle-stimu-
lating hormone values) and the worsening of general health status. Over the last four decades, there has been a decline of over
50 percent in sperm levels among men in Western nations, according to Shanna H. Swan, epidemiologist, one of the world’s
leading environmental and reproductive epidemiologists (Swan, 2021). Specifically, nutrition and lifestyle factors, which are
currently significant public health issues, play a critical role in the normal function of thereproductivesystem(Salas-Huetos
et al., 2017). In addition to known 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 a pathophysiological explanation for idiopathic male infertility is damage to the reproductive tract
due to oxidative stress (OS) from reactive oxygen species (ROS). Studies say that anywhere from 30% to 80% of male factor
infertility is due to the 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 radical and nonradical oxygen derivatives. These
molecules 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 radicals, and hydroperoxyl.
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
maintenance 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
Mitochondria are responsible for the balance of ROS. Along with the 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 midpiece and are responsible for sperm motility and
overall functionality. Thus, an intact mitochondrial genome and metabolome are essential for sperm functionality. Maintaining an
appropriate level of ROS is essential, but an excess combined with insufficient scavenging by seminal antioxidants may lead to a
decrease in motility, abnormal sperm morphology, and decreased ATP production, further 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
spermatozoa 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.
2Nutraceutical Therapy in Male Infertility

ROS, Male Infertility and MOSI
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). 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,
hyperactivation, acrosomal reaction, and sperm-oocyte fusion reaction, all of which are necessary for successful fertilization.
Supraphysiologic ROS levels can affect sperm structural and functional integrity, including motility morphology, count, and
viability. It can 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 (Doshi et al., 2012).
The spermatozoa and seminal plasma contain multiple protective antioxidants to protect spermatozoa from OS by scavenging
the free radicals. These include both high molecular weight enzymatic antioxidants (superoxide dismutase, catalase and glu-
tathione peroxidase) as well as nonenzymatic antioxidants (ascorbic acid, a-tocopherol, pyruvate, glutathione, L-carnitine, taurine,
and hypotaurine)—which provide the bulk of antioxidant activity.
Recent studies are trying to quantify and measure this OS in patients with abnormal semen analysis (SA) and male infertility.
Male Oxidative Stress Infertility (MOSI) is one of these clinical biomarkers that should become one adjunct component of SA
(Agarwal et al., 2019). Incorporating of MOSI into routine practices poses challenges due to its expensive nature, complexity, time
sensitivity, and potential requirements for intricate instrumentation, as well as extensive technical training.
Nutraceutical Therapy
Overview of Nutraceuticals
Nutraceuticals are products derived from food or food ingredients that provide health benefits including the prevention and/or
treatment of a disease. The word “nutraceutical”is a combination of ‘nutrition’and ‘pharmaceutical,’coined by Stephen DeFelice,
MD in 1989 (Ko and Sabanegh, 2014). As a comprehensive term, nutraceutical includes plant-based foods and byproducts,
supplements, minerals, and vitamins.
Many of these products have antioxidant properties and can help scavenge ROS (Arcaniolo et al., 2014). 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 (Creta et al., 2022), nutraceutical 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
Of the different kinds of nutraceuticals, many 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
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 motilityHBV:
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 morphologyHyperthyroidism 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
Nutraceutical Therapy in Male Infertility 3

antioxidants, such as vitamins, proteins, glutathione, and ubiquinol. Some different and important antioxidants studied in
literature are discussed below and a table with the main sources follows at the end of the chapter in Table 2 (De Ligny et al., 2022;
Rodak and Kratz, 2023).
Arginine
Arginine is an amino acid precursor of nitric oxide that contributes to enhancing the cellular inflammatory response by offering a
defense against oxidative damage. The impact of arginine on semen parameters is not clear. Some studies have indicated that
regular arginine supplementation enhances sperm concentration and motility (Ko et al., 2014b). However, other studies have
found no changes in sperm parameters or conception rates for treatment groups when compared with placebo groups (Pryor et al.,
1978). There are few recent studies on the use of arginine for infertility, and in most of them, arginine is combined with other
substances. Notable adverse events have not been observed (Appleton, 2002). Nevertheless, individuals with a history of genital or
oral herpes, asthma, or cancer are advised against using arginine (De Ligny et al., 2022).
CoEnzyme Q-10
CoEnzyme Q-10 (CoQ10) is an antioxidant molecule and a component of the mitochondrial respiratory chain that 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 forms—ubiquinone, the oxidized form, and ubiquinol, the reduced form—which are constantly switching
back and forth as CoQ10 transfers 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 lipophilic
antioxidant that can regenerate other antioxidants. Ubiquinol inhibits organic peroxide formation in both the seminal fluid and
seminal plasma, which reduces the OS to which sperm cells may be subjected (Mancini and Balercia, 2011). Three clinical trials,
summarized in a meta-analysis, have shown that supplementing infertile men with CoQ10 improved sperm concentration,
motility, and concentration in the seminal plasma (Lafuente et al., 2013). Another recent study mentioned an improvement in
sperm concentration and in motility in infertile men with oligoasthenoteratospermia, but no significant changes in morphology
(Alahmar and Sengupta, 2021). However, neither study reported data on live births after treatment. Thus supplementation with
CoQ10, while not proven to increase live births or even 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 that 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 male is in the epididymis,
with the concentration being 2000 times greater than that in serum; 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 meta-analysis by Zhou et al., supplementation with l-carnitine or l-
acylcarnitine (active form) 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, a systematic review and meta-analysis (Zhang et al.,
2019)also noted improved pregnancy rate and sperm motility with the use of L-carnitine and L-acetyl carnitine but not total sperm
concentration. In contrast, a Cochrane Review reported no increase in pregnancy rates after intake of carnitines (De Ligny et al., 2022).
Table 2 Sources of various nutraceuticals
Supplement Sources
Vitamin E Vegetable oils
Vitamin C Fruits (orange, lemon) and vegetables
Vitamin A Fruits, vegetables (carrot)
Arginine Meat products, dairy, nuts and seeds
Carnitine Meat, fish, poultry and dairy
CoEnzyme Q10 Meat, fish, nuts and some oils
Glutathione Avocados, pears and green-leafy vegetables
Lycopene Green vegetables, fruits, and some vegetable oils
N-Acetyl-cysteine Cashews, sunflower seeds and meat (tuna, chicken, beef)
Selenium Fish, meat products, dairy, and soil absorption by plants
Zinc Meat products, wheat and seeds
Folic Acid Green-leafy vegetables, liver, bread, yeast and fruits
PUFAs Fish, algae, phytoplankton, plant seeds, vegetable oils, and cereal products
4Nutraceutical Therapy in Male Infertility

Lycopene
Lycopene is a compound from the carotenoid family obtained through consumption of red-colored fruits and vegetables
(Gajowik and Dobrzyńska, 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 is incorporated in
the cell membrane to protect the sperm by preventing lipid peroxidation and also by neutralizing ROS (Gajowik and
Dobrzyńska, 2014). Studies have shown that supplementation with lycopene improved OS parameters, such as the DNA
fragmentation index, and sperm-related parameters including sperm count, motility, and concentration. It did not, how-
ever, improve sperm morphology (Agarwal et al., 2014). Age, smoking, and alcohol consumption may influence the
absorption of lycopene and decrease its concentration in the body (Durairajanayagam et al., 2014).
Vitamin E
Vitamin E is commonly recognized as the bioactive variant a-tocopherol, found in vegetable oils, and there is a given upper
daily limit for supplementation based on a possible increased bleeding risk (De Ligny et al., 2022). Vitamin E is a major
chain-breaking antioxidant in sperm membranes, and it scavenges the three major types of free reactive species, namely
superoxide, hydrogen peroxide, and hydroxyl radicals (Kobori et al., 2014). In a study by Suleiman et al., treatment with alpha-
tocopherol reduced 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.,whousedboth
800 mg vitamin E and 1000 mg vitamin C, failed to confirm these findings (Rolf et al., 1999). However, no improvement in
sperm parameters or pregnancies were indicated.
Vitamin C
Vitamin C is another important chain-breaking antioxidant. It 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 vitamin C with vitamin E significantly reduces hydroxyguanine levels in spermatozoa
andalsoleadstoanincreasedspermcount(Kobori et al., 2014;Rolf et al., 1999). In contrast, high intake of vitamin C from
food sources alone was associated with a lower sperm concentration and sperm count (Zareba et al., 2013).
Zinc
Zinc is second only to iron as the most abundant metal in human tissues (Dimitriadis et al., 2023). Although Zinc is found in
most types of foods such as red meat, white meat, fish, and milk, the World Health Organization estimates that 17.3% of the world’s
population is deficient in zinc (Dimitriadis et al., 2023). 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). Zinc is found in high concentrations in seminal fluid, suggesting its numerous important functions; 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 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. Gavella and Lipovac found a 53% improvement in sperm motility, morphology, or both
and an 11% spontaneous pregnancy rates in the treatment group in comparison with no treatment (Gavella and Lipovac,
1998). Moreover, in another study, selenium and N- acetylcysteine were prescribed to infertile men. Both micronutrients
were taken together and separately. All semen parameters improved significantly with all forms of treatment, except
placebo. The administration of selenium plus N-acetylcysteine resulted in additive beneficial effects, with a strong corre-
lation between the sum of selenium and N-acetylcysteine concentrations and the average sperm concentration (Safarinejad
and Safarinejad, 2009).
Nutraceutical Therapy in Male Infertility 5

N-acetylcysteine
(Jannatifar et al., 2019)
Polyunsatureted Fatty Acids (PUFAs)
PUFAs are one of the components of spermatozoan membranes and they are important to maintaining their integrity and stability.
PUFAs can be subdivided into three groups: omega-3 (docosahexaenoic acid, DHA), omega-6, and omega-9. Omega-9 is syn-
thesized by animals, but omegas-3 and -6 needs to be ingested. PUFAs enhance the fluidity of the sperm membrane in the plasma.
However, this increased fluidity renders the sperm vulnerable to reactive oxygen species (ROS) and lipid peroxidation, potentially
causing harm to the sperm (Rodak and Kratz, 2023).
Cochrane review on overall effects of antioxidants (De Ligny et al., 2022)
A comprehensive Cochrane literature review aimed to evaluate the effectiveness (live birth, clinical pregnancy, level of sperm
DNA fragmentation, semen analysis) and safety (adverse events –including miscarriage) of supplementary oral antioxidants in
subfertile men. A total of 90 studies were included, with 19 more than the 2019 Cochrane review (Smits et al., 2019) There is
limited and very low-to-uncertain evidence indicating that the use of antioxidant supplementation in subfertile males could
potentially enhance live birth rates for couples seeking fertility treatments. Similarly, there is low-certainty evidence suggesting a
possible increase in clinical pregnancy rates. In addition, there is no apparent evidence of an elevated risk of miscarriage. However,
based on the available low-certainty evidence, it is suggested that antioxidants might be linked to an increased likelihood of
experiencing gastrointestinal discomfort. Couples facing subfertility should be informed that the current evidence is inconclusive,
attributable to inadequate detail of methodologies, absence of information regarding live births and clinical pregnancy rates,
imprecision from low event occurrences, a considerable number of dropouts, and the limited size of study groups.
Overall Effects of Nutraceuticals
Adverse Effects (Arcaniolo et al., 2014)
The estimated value of the worldwide dietary supplements market was around USD 164 billion in 2022, and there is an
anticipated growth at a compound annual growth rate (CAGR) of 9.0% from 2023 to 2030. The growth of the market is propelled
by growing consumer consciousness regarding nutrition, health, and wellness. Additionally, the consumption of premium pro-
ducts infused with nutritional elements is considered a representation of social status in numerous countries (“Dietary Supple-
ments Market Size And Share Report, 2030, 2023).
Even though nutraceuticals are considered to be benign products, excess intake can lead to adverse effects. A review of the
literature (Creta et al., 2022) revealed various adverse effects from excess intake of nutraceuticals (Table 3). The use of antioxidant
Table 3 Adverse effects of increased intake of various nutraceuticals
Supplement Reported adverse effects
Vitamin E GI distress, fatigue, muscle weakness, headache blurry vision, rash, bruising, bleeding complication
(4800 IU/d)Cardiovascular complications (4400 IU/d)
Vitamin C
(42000 mg/d)
Dyspepsia, headache, increased risk of nephrolithiasis
Vitamin A
(450,000 IU/d)
Fatigue, irritability, mental status change, visual disturbances, vertigoAnorexia, GI distress, excessive sweating, myalgia/
arthralgiaHepatotoxycity, hypoplastic, anemia
Arginine GI discomfort, hypotension, electrolyte abnormalities, renal insufficiencyIncreased bleeding risk, elevated glucose levels,
worsening symptoms of sickle cell disease, asthma
Carnitine (44 g/d) GI distress, seizures, malodorous body secretion
CoEnzyme Q10 GI distress, loss of appetite, headache, skin rash
Glutathione Not absorbed within GI tract
N-Acetyl-cysteine GI distress, rash, fever, headache, drowsinessHypotension, hepatic toxicity
Selenium GI distress, nail changes, fatigue, irritability, hair loss, garlic breath/odorMetallic taste, muscle tenderness, tremors,
facial flushing, hematologic changes, hepatic, and renal insufficiency
Zinc
(4200 mg/d) GI distress, loss of appetite, dehydration, gastric ulceration, rash; headache
(4450 mg/d) Altered iron function, low copper levels, sideroblastic anemia, reduced immune function, reduced HDL levels
Folic Acid (4
5 mg/d)
Abdominal cramps, diarrhea, and rash. Atered sleep patterns, irritability, confusion, exacerbation of seizures and nausea
PUFAs Foul breath, heartburn, reflux, diarrehea
6Nutraceutical Therapy in Male Infertility

supplements treatment for male factor infertility is linked to a statistically significant risk of headaches, dyspepsia, and nausea in
comparison to a placebo or no treatment. Nevertheless, discontinuation of treatment due to adverse effects resolved the symp-
toms, indicating a mild nature. When contemplating antioxidant supplement therapy for men dealing with infertility, it is essential
to provide specific guidance of the risk and benefit considerations (Creta et al., 2022).
One point to stands out is that a significant reduction in oxidative stress through the use of antioxidants might therefore have a
negative effect on fertility, called the “antioxidant paradox”(Tiwari, 2019). Some studies have shown the elimination of reactive
oxygen species and elevation of intracellular antioxidants might develop a pro-tumorigenic effect (Perera and Bardeesy, 2011). As
well, an increased risk of skin malignancies has been documented in women using antioxidant supplements (Tiwari, 2019). This
study suggests that an overabundance of antioxidant therapy may function as a possible immunosuppressant, compromising the
natural immune defense system and causing direct damage to cells and DNA.
Treatment
Female Considerations (Walker and Tobler, 2023)
When evaluating an infertile couple, the female factor is a crucial aspect that necessitates careful consideration. A woman’s lab
values should be within normal limits: this includes a normal follicle-stimulating hormone (FSH), luteinizing hormone (LH),
estradiol, progesterone, and even thyroid hormones. It’s always necessary, as well, to estimate the ovarian reserve, analyze anti-
Müllerian hormone (AMH) levels, antral follicle count (AFC), or ovarian volume and understand the quantity and quality of the
remaining eggs in the ovaries. An anatomical workup conducting imaging studies (ultrasound, hysterosalpingography, or hys-
teroscopy) to evaluate the condition of the uterus, endometrium, and fallopian tubes may also be warranted.
Not least of all, medical history and lifestyle factors should always be considered.
Male Considerations
Nutraceutical therapy is primarily intended for the 30% –40% of infertile men where no cause could be determined (idiopathic
infertility). According to the European Association of Urology (EAU) guidelines {Citation}on male infertility, because of the weak
strength rating for the efficacy of treatment with antioxidants, no definitive suggestion can be provided for using antioxidants to treat
individuals with unexplained infertility. Moreover, the American Urology Association (AUA) guidelines similarly mentioned the low
quality (Grade B) data regarding the efficacy of a variety of supplements (vitamins, antioxidants, nutritional supplement formulations)
for men seeking to conceive (Schlegel et al., 2020). Present data indicate that these supplements are probably not harmful, but both
agencies agree that the extent to which they can bring about substantial enhancements in fertility outcomes remains uncertain.
Conclusion
This paper offers an overview of the most recent information concerning nutraceutical therapy in male infertility. As previously
mentioned, the harm to the reproductive tract resulting from oxidative stress induced by reactive oxygen species (both intrinsic and
extrinsic) remains a primary factor in idiopathic male infertility. There is a growing endeavor to point out and to measure the OS
(e.g., MOSI). Moreover, concerted efforts are being made to develop therapeutic interventions for its mitigation.
A pertinent factor in the decision as to whether to employ antioxidants is that minute quantities of reactive oxygen species (ROS) are
necessary for capacitation and the acrosome reaction. A considerable decrease in ROS levels brought about by antioxidants might,
therefore, adversely impact fertility. Similarly, an enhancement in semen parameters does not automatically result in an elevation in
fertility, as individuals exhibiting normal sperm concentration, motility, viability, and morphology could still face subfertility.
Due to these considerations, pregnancy rate is a key outcome measure for any study in this field. However, only a limited
number of studies assess this particular outcome. It is important to note that existing nutraceutical and supplement studies exhibit
various shortcomings, such as small sample sizes, brief study durations, absence of randomization or double-blinding, and a lack
of standardized dosages. Another limitation is that most studies do not specify the external factors that contribute to ROS like
physical activity, smoking, obesity, and use of other medication, generating even more confounding factors and more bias.
Additional comprehensive randomized controlled studies are needed to determine the potential for antioxidants in treating
male infertility, especially one that integrate clearly defined inclusion and exclusion criteria. These studies should assess the impact
of standardized doses of antioxidants on pregnancy rates, encompassing both spontaneous and assisted conception. This approach
should help to identify the population that might derive benefits from oral antioxidant therapy.
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8Nutraceutical Therapy in Male Infertility

Further Reading
Attallah, D., El Nashar, I.H., Mahmoud, R., Shaaban, O.M., and Salman, S.A., 2013. N-acytelcysteine prior to intrauterine insemination in couples with isolated
athenozospermia: a randomized controlled trial. Fertility and Sterility, 100 (3 Suppl), S462.
Barekat, F., Tavalaee, M., Deemeh, M., et al., (2016). A Preliminary Study: N-acetyl-L-cysteine Improves Semen Quality following Varicocelectomy. Royan Institute International
Journal of Fertility and Sterility, [online] 10(1), pp.120–126. 120-12
Nutraceutical Therapy in Male Infertility 9