Nutritional e�ects of micronutrients on male fertility

Literature Report

Summaries

of recent studies

Preface

About 40% of men all over the world su�er from impaired fertility due to insu�cient sperm quality− frequently without even knowing it. Male infertility is a multifactorial disease with a number ofcontributing causes, such as environmental and dietary factors.

Sperm production is a highly complex biological process which takes several weeks and may easilybe a�ected by adverse factors of in�uence. In the process of spermatozoa maturation the body needsspeci�c auxiliary agents These include various amino acids, trace elements, vitamins and vitamin-likesubstances. Studies support the fact that optimal conditions for normal and healthy spermdevelopment are only possible when these special nutrients are present.

Many individual agents which are important for sperm maturation were already scienti�cally testedin numerous clinical trials and described by renowned researchers. It could be shown that certainnutrients, such as L-carnitine, zinc and vitamin E, may have a favorable e�ect on the number andmotility of sperms and ultimately on fertility.

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Micronutrient Combinations

Vitamins

Trace Elements

L-Carnitine and Coenzyme Q10

N-Acetylcysteine

Polyunsaturated Fatty Acids

Content

Micronutrient CombinationsWong WY, Merkus HMWM, Thomas CMG, et al. Effects of folic acid and zinc sulphate on male factor subfertility: a double-blind, randomized, placebo-controlled trial.

Fertil Steril 2002;77(3):491-8.

Sinclair S. Male infertility: nutritional and environmental considerations.Altern Med Rev 2000;5(1):28-38.

Sheweita SA, Tilmisany AM, Al-Sawaf H. Mechanism of male infertility: role of antioxidants.Curr Drug Metab 2005;6(5):495-501.

VitaminsSuleiman SA, Ali ME, Zaki ZMS, et al. Lipid peroxidation and human sperm motility: protective role of vitamin E.J Androl 1996;17(5):530-7.

Akmal A, Qadri JQ, Noori S, et al. Improvement in human semen quality after oral supplementation of vitamin C.J Med Food 2006;9(3):440-2.

Wallock LM, Tamura T, Mayr CA, et al. Low seminal plasma folate concentration are associated with low sperm density and count in male smokers and nonsmokers.Fertil Steril 2001;75(2):525-9.

Gupta NP, Kumar R. Lycopene therapy in idiopathic male infertility – a preliminary report.Int Urol Nephrol 2002;34(3):369-72.

Boxmeer JC, Smit M, Weber RF, et al. Seminal plasma cobalamin significantly correlates with sperm concentration in males undergoing IVF or ICSI procedures.J Androl 2007;28(4):521-7.

Trace Elements Tikkiwal M, Ajmera RL, Mathur NK. Effect of zinc administration on seminal zinc and fertility of oligospermic males.Indian J Physiol Pharmacol 1987;31(1):30-4.

Netter A, Hartoma R, Nahoul K. Effect of zinc administration on plasma testosterone, dihydrotestosterone, and sperm count.Arch Androl 1981;7(1):69-71.

Foresta C, Flohé L, Garolla A, et al. Male fertility is linked to the selenoprotein phospholipid hydroperoxide glutathione peroxidase.Biol Reprod 2002;67:967-71.

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L-Carnitin und Coenzym Q10

Matalliotakis I, Koumantaki Y, Evageliou A, et al. L-carnitine levels in the seminal plasma of fertile and infertile men: Correlation with sperm quality. Int J Fertil Womens Med 2000;54(3):236-40.

Khademi A, Alleyassin A, Safdarian L, et al. The effects of L-carnitine on sperm parameters in smoker and non-smoker patients with idiopathic sperm abnormalities.J Assist Reprod Genet 2005;22(11-12):395-9.

Balercia G, Mosca F, Mantero F, et al. Coenzyme Q10 supplementation in infertile men with idiopathic asthenozoospermia: an open, uncontrolled study.Fertil Steril 2004;81(1):93-8.

Lenzi A, Sgrò P, Salacone P, et al. A placebo-controlled double-blind randomized trial of the use of combined carnitine and L-actyl-carnitine treatment in men with asthenozoospermia.Fertil Steril 2004;8(6):1578-84.

N-acetylcysteineOeda T, Henkel R, Ohmori H, et al. Scavenging effect of N-acety-L-cysteine against reactive oxygen species in human semen: a possible therapeutic modality for male factor infertility.Andrologia 1997;29(3):125-31.

Polyunsaturated Fatty AcidsAksoy Y, Aksoy H, Altinkaynak K, et al. Sperm fatty acid composition in subfertile men.Prostaglandins Leukot Essent Fatty Acids 2006;75(2):75-9.

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Folic acid and zinc in male subfertifility: randomized double-blind placebo-controlled trialEffects of folic acid and zinc sulphate on male factor subfertility: a double-blind, randomized, placebo-controlled trialWong WY, Merkus HMWM, Thomas CMG, et al. Fertil Steril 2002;77(3):491-8.

BackgroundThe decrease in semen quality may result from interactions between genetic and environmental

factors. Recent food consumption surveys show that dietary intakes of folic acid and zinc are

insufficient. Folate which is mainly present in green leafy vegetables, is essential for DNA, transfer

RNA and protein synthesis. Zinc is essential in spermatogenesis and, as a cofactor of

metalloenzymes, involved in DNA transcription, and the expression of steroid receptors.

Authors conducted the present study to determine whether administration of folic acid and zinc

could have an influence on sperm quality and thus male fertility.

Study design, patients and methodsThe study was conducted as a randomized, placebo-controlled double-blind trial. A total of 108

fertile and 103 subfertile men took part in the 26-week intervention. The two study groups were

randomly assigned to receive one of four treatments: 5 mg folic acid and placebo, 66 mg zinc

sulphate and placebo, a combination of 66 mg zinc sulphate and 5 mg folic acid, and two placebos.

Before and after treatment, semen and blood samples were obtained (according to World Health

Organization guidelines) to determine sperm concentration, motility, and morphology.

Folate and vitamin B12 were measured by radio assay both in blood and seminal plasma. Zinc was

measured by using flame atomic absorption spectrophotometry, and follicle-stimulating hormone

was quantitatively determined in serum using an immunoassay

ResultsPreintervention concentrations of folate and zinc in blood and seminal plasma did not signifi cantly

differ between fertile and subfertile men. In subfertile men the combination of folate and zinc

resulted in a 74% increase in total normal sperm count (p<0.05) and to an increased number of

normally shaped sperm cells (p=0.002).

ConclusionTotal sperm count increased after combined folate and zinc sulfate treatment in both subfertile and

fertile men. Although the beneficial effect of the micronutrients on fertility remains to be

established, this finding opens avenues of future fertility research and treatment of fertility disorders.

1Micronutrient Combinations

Male infertility: nutritional and environmental considerationsMale infertility: nutritional and environmental considerationsSinclair S. Altern Med Rev 2000;5(1):28-38.

BackgroundAn estimated 6% of adult males are thought to be infertile. Infertility is defined as the inability to

achieve a pregnancy after one year of unprotected intercourse. Certain cases of male infertility are due

to anatomical abnormalities, and 40-49% of cases are due to deficient sperm production of unknown

etiology.

There is a growing body of scientific evidence supporting the idea that sperm counts have declined

considerably over the last decades. While there was a sperm density of 113 million/ml in 1940, in 1990

only 66 million/ml were found on average. This demonstrates a substantial 58% decline in sperm

production. One must suspect that a combination of environmental, lifestyle, and dietary factors might

be interfering with spermatogenesis. One related aspect is the exposure to environmental estrogens

which are used in livestock, poultry, and dairy industries. In addition, many pesticides, such as DDT,

have estrogenic effects within the body and are known to interfere with spermatogenesis. Other

factors include heavy metals in the environment, chronic stress, alcohol abuse, cigarette smoking and

nutritional deficiencies.

ResultsOne of the micronutrients with a favorable influence on sperm cell maturation is L-carnitine, an amino

acid produced by the body. The administration of L-carnitine is able to improve sperm cell count

and motility. Another amino acid with a beneficial influence on sperm cell motility is L-arginine. The

trace element zinc is thought to be able to increase sperm cell count and improve sperm cell motility

through elevation of the testosterone level. Furthermore, sperm cells in the course of maturation are

sensitive to damaging influences of oxidative stress, and antioxidants may be protectors against this

stress. These include vitamin E, glutathione and selenium. The supplementation of vitamin E lowers

malondialdehyde concentrations in the seminal plasma und thus reduces oxidative stress.

The combination of vitamin E and selenium was shown to significantly increase sperm motility and

the overall percentage of normal spermatozoa. Glutathione and selenium are micronutrients essential

to the formation of phospholipid hydroperoxide glutathione peroxidase, an enzyme present in

spermatids. It is a structural protein accounting for over 50% of the mitochondrial capsule in the

midpiece of mature spermatozoa and is responsible for sperm motility.

ConclusionMale infertility is a multifactorial disease process with a number of po tential contributing causes

which include genetic, environmental and nutritional factors. There are various nutritional strategies,

e.g. L-carnitine, zinc, selenium and vitamin E, which have a beneficial impact on sperm count, motility,

and, ultimately, fertility. Therefore an optimal intake of antioxidants, trace elements, and other

micronutrients should be ensured for a normal spermatogenesis.

1Micronutrient Combinations

Mechanism of male infertily: role of antioxidantsMechanism of male infertility: role of antioxidantsSheweita SA, Tilmisany AM, Al-Sawaf H. Curr Drug Metab 2005;6(5);495-501.

BackgroundDefective sperm function is the most common cause of infertility which is difficult to treat. Many

environmental factors as well as anatomical and genetic disorders are involved in the conditions

leading to poor sperm function and infertility. Therefore it is important to identify the factors which

affect normal sperm function.

In the present study the significance of oxidative stress in infertility was examined. Additionally the

role of biological antioxidants and their associated mechanisms in the treatment of infertility were

assessed.

ResultsThe excessive generation of reactive oxygen species (ROS) by abnormal spermatozoa and by

contaminating leukocytes (leukocytospermia) has been identified as one of the few definedetiologies

of male infertility. Moreover, environmental factors, such as pesticides, exogenous estrogens and

heavy metals, may negatively impact spermatogenesis since male sperm counts were reduced. In

addition, aging is also likely to further induced oxidative stress. In contrast, limited endogenous

mechanisms exist to reverse such damage. In a normal situation, they are sufficient to quench the

ROS. However, during genitourinary infection / inflammation such antioxidant mechanisms may

lose in strength and oxidative stress may be created which can directly damage the sperm cells

by attacking and oxidizing the high content of polyunsaturated fatty acids in spermatozoa. These

processes will lead to a marked impairment of sperm cell motility, maturation and the capability

of capacitation* and acrosome reaction**.

Numerous nutritional approaches such as the administration of L-carnitine, arginine, zinc and

selenium have proven beneficial regarding sperm cell count and motility. Also vitamin E, glutathione

and coenzyme Q10 have shown favorable effects in the treatment of male infertility.

ConclusionThe multi-faceted therapeutic approaches to improving male fertility include the identification of

harmful environmental and occupational risk factors, while correcting nutritional imbalances to

encourage optimal sperm production and function.

* maturation of sperm cells in the female genital tract; without this process the fertilization of the egg cell is not possible. ** important part of procreation enabling the sperm cell’s penetration into the egg cell

1Micronutrient Combinations

Lipid peroxidation and human sperm motility: protective role of vitamin ELipid peroxidation and human sperm motility: protective role of vitamin ESuleiman SA, Ali ME, Zaki ZMS, et al. J Androl 1996;17(5):530-7.

BackgroundAsthenozoospermia is the main factor of male infertility in patients consulting the Asir Infertility

Center in Abha, Saudi Arabia. Already several years ago researchers reported that oxygen radicals

may be toxical for human sperm motility. Therefore the use of antioxidants, such as vitamin E, is

discussed in asthenospermic patients. These radicals, if left alone, will lead to peroxidation of

phospholipids and thus to ultimate immotility of sperm cells. The objectives of this study were to

determine the level of lipid peroxidation in the semen and to measure the effect of a vitamin E

supplementation on the degree of peroxidation, improvement in sperm motility and the occurrence

of pregnancy.

Study design, patients and methodsIn this randomized placebo-controlled double-blind study 110 men with asthenozoospermia and

sperm motility <40% and normal sperm cell count were included. In total 87 patients received either

100 mg vitamin E t.i.d. or placebo. Supplementation continued till the sperm quality parameters

improved (15 percent increase in sperm motility) or till the patient’s spouse became pregnant, but

up to a maximum of 6 months. The malondialdehyde (MDA) concentration in seminal plasma was

measured as an indicator of the level of lipid peroxidation.

ResultsFifty-two patients in the vitamin-E group and 35 patients in the placebo group completed the study.

Compared to the group of fertile men, patients with asthenozoospermia had a 1.7 times higher MDA

concentration in sperm cells associated with a lower sperm motility. With vitamin E supplementation

the MD level was significantly reduced (p<0.001). Simultaneously investigators observed a significant

increase in sperm motility (p<0.001). In the placebo group there were no changes. The correlation

between MDA concentration and sperm motility was highly significant after vitamin E treatment

(r=0.79). In 11 cases in the group taking vitamin E, a pregnancy occurred, however, no pregnancy was

reported in the spouses of the placebo-treated patients.

ConclusionVitamin E seems to protect against the loss of sperm motility by lipid peroxidation. Supplementation

of vitamin E improves sperm motility and increases the possibility of fertilization in asthenospermic

subjects.

2Vitamins

Oral supplementation of vitamin C improves semen qualityImprovement in human semen quality after oral supplementation of vitamin C. Akmal A, Qadri JQ, Noori S, et al. J Med Food 2006;9(3):440-2

BackgroundA therapeutic approach to improving male fertility is focused on compensating nutrition deficits.

Various antioxidants, such as vitamin C, have shown beneficial effects in studies on male fertility

disorders. In these studies, the ascorbic acid level in the seminal plasma correlates positively with the

percentage of sperms of normal morphology.

Vitamin C protects the sperms against oxidative damage and improves the sperm quality

of smokers. It is also effective in the treatment of sperm agglutination and can thus improve fertility.

In the seminal plasma ascorbic acid, together with thiolen and uric acid, is one of the strongest

antioxidants.

Studies have shown that the in-vitro administration of ascorbic acid, uric acid and alpha tocopherol

has a beneficial effect on the sperms’ DNA integrity. Vitamin C protects the sperm DNA against

oxidative stress.

Study design, patients and methodsA total of 13 men with oligozoospermia were included in the study. Patients with urogenital

infections or varicoceles were excluded. The men were between 25 and 35 years old and were given

1 g of vitamin C twice daily for a period of 2 months. A semen sample was analyzed before and after

the treatment according to WHO criteria.

ResultsTaking vitamin C led to a significant increase in the portion of motile sperms from 31.2% ± 9.61%

to 60.1% ± 8.47% (p<0.001). The sperm number also increased significantly, i.e. from 14.3 ± 7.38 x

106 to 32.8% ± 10.3% x 106 sperms per milliliter (p< 0.001). The percentage of sperms of normal

shape rose significantly from 43% ± 7.87% to 66.7% ± 4.77% (p<0.001).

ConclusionThe study has shown that the uptake of vitamin C can have a beneficial effect on sperm number,

motility and morphology in infertile men. Therefore supplementation of ascorbic acid is a useful

measure to improve semen quality and enhance the chance of conception. The beneficial effects of

vitamin C are presumably due to its antioxidative properties.

2Vitamins

Low seminal plasma folate concentration and low sperm quality in smokers and nonsmokersLow seminal plasma folate concentrations are associated with low sperm density and count in male smokers and nonsmokersWallock LM, Tamura T, Mayr CA, et al. Fertil Steril 2001;75(2):525-9.

BackgroundWhile it is well accepted that folate is essential for normal female reproduction, only few data are

available on the subject of relevance of folate to male reproduction. Studies have shown that an

adequate folate supply is important to male fertility, and correspondingly the treatment with folate

antagonists leads to impairment of fertility. Both in seminal plasma and in the prostate, high-affinity

folate binding proteins have been found. These assumptions suggest a relationship between folate

status and male fertility. As cigarette smoking has a harmful effect on male fertility, Wallock and

colleagues evaluated the potential relationships between folate status and semen quality in smokers

and nonsmokers.

Study design, patients and methodsIn total 24 smokers and 24 nonsmokers were included in the observational study conducted at the

Western Human Nutrition Research Center in San Francisco (CA). Inclusion criteria was that the

subjects had an intake of less than 3.5 takings of fruit and vegetable per day. Sperm count and

density were assessed under the microscope and folate, vitamin B12 (radioassay) and plasma

homocysteine concentration (HPLC) were measured. In seminal plasma folate concentration

(microbiological tests*), and folate levels were measured separately as 5-methyltetrahydrofolate

(5-MTHF) and non-methyltetrahydrofolate (non-MTHF) concentrations.

ResultsTotal seminal plasma folate concentrations correlated significantly with blood plasma folate levels

(r=0,76) and were on average 1.5 times higher in all men. Seminal plasma folates contained

5-methyltetrahydrofolate (74% of total) and non-methyltetrahydrofolates (26% of total). Total and

5-MTHF concentrations correlated significantly with blood plasma folate and homocysteine

concentrations (r=0,43). Low seminal plasma non-MTHF levels correlated significantly with sperm

density and total sperm count. Seminal plasma of smokers contained a proportionally lower

concentration of non-MTHF compared with nonsmokers.

ConclusionSeminal plasma total folate and 5-methyltetrahydrofolate concentrations reflect folate intake with

the diet. The non-methyltetrahydrofolate fraction of seminal plasma was associated with sperm cell

density suggesting the important role of folate for the male reproductive function.

* using bacterial species that respond in particular to folates

2Vitamins

Lycopene in idiopathic male infertilityLycopene therapy in idiopathic male infertility – a preliminary report Gupta NP, Kumar R, Int Urol Nephrol 2002;34(3):369-72.

BackgroundSperm membranes are rich in polyunsaturated fatty acids and therefore highly sensitive to lipid

peroxidation. Studies have shown that infertile men often have higher concentrations of free radicals

than healthy men. This is why elevated levels of free radicals are associated with idiopathic infertility.

Lycopin is a naturally occurring carotenoid, a component of the human redox mechanism which

neutralizes free radicals. The aim of the study was to find out whether giving lycopin could improve

the fertility of men with idiopathic infertility.

Study design, patients and methodsThirty men with oligo-, astheno- or teratozoospermia were included in the study.

During the 3-month intervention phase the patients were given 2 mg of lycopin twice daily.

Before and after the intervention, sperm analyses were made and standard parameters for the

determination of the sperm quality examined.

ResultsIn 66% of the patients an improvement in sperm concentration by an average of 22 million/ml was

found. 53% of the men had a higher sperm motility after the intervention (p<0.05), and 46% a higher

proportion of sperms of normal shape (p<0.05). Especially in men who had a sperm concentration

of > 5 million/ml before the study started demonstrated a marked improvement of sperm density.

In six spouses of these men a pregnancy was diagnosed while the study was still ongoing or in the

follow-up period.

ConclusionOxidative stress in the seminal plasma is an important factor in the origin of idiopathic infertility.

Oral supplementation of antioxidants such as lycopin led to distinct improvements in semen quality.

2Vitamins

Vitamin B12 in the seminal plasma and sperm concentration: role for IVF or ICSI proceduresSeminal plasma cobalamin significantly correlates with sperm concentration in men undergoing IVF or ICSI procedures Boxmeer JC, Smit M, Weber RF, et al. J Androl 2007;28(4):521-7.

BackgroundIt is a well-known fact that an elevated homocysteine level is associated with disorders of the

reproductive function. B-vitamins – in particular the folic acid, cobalamin, pyridoxin and

homocysteine concentrations – play a crucial role in the degradation of homocysteine. Studies

prove beneficial effects on sperm quality when B-vitamins are taken. The aim of the study was to

analyze the folic acid, cobalamin, pyridoxin and homocysteine concentrations in blood and seminal

plasma.

In addition, the study should find out whether these biomarkers correlate with the sperm parameters

of men undergoing IVF and ICSI procedures.

Study design, patients and methodsA total of 73 men who wanted to undergo IVF participated in the study. The blood and sperm

samples were tested for their B-vitamin level. Moreover, the classical parameters of sperm quality

were determined according to the WHO criteria.

ResultsTwenty-six percent of the men had a varicocele, and in 34% of the cases subfertility was diagnosed.

The folate and B12 concentrations in the blood plasma were significantly lower than they were in

the seminal plasma (p<0.001). The homocysteine concentrations in blood and seminal plasma were

comparable. The vitamin B12 concentration in blood serum and seminal serum correlated

significantly.

The vitamin B12 concentration in the seminal plasma correlated positively with the concentration in

the sperms (r=-0.42, p<0.001). The other B vitamins and homocysteine in blood and seminal plasma

did not correlate significantly with other seminal parameters.

ConclusionIn the study, a significantly positive correlation between the vitamin B12 concentration in seminal

plasma and the sperm concentration was found in men wanting to undergo IVF or ICSI. This strong

correlation supports the assumption that B12, besides folic acid, plays an important role in

spermatogenesis.

2Vitamins

Effect of zinc on fertility of oligospermic malesEffect of zinc administration on seminal zinc and fertility of oligospermic males.Tikkiwal M, Ajmera RL, Mathur NK. Indian J Physiol Pharmacol 1987;31(1):30-4.

BackgroundZinc is essential for the action of over 80 metalloenzymes and plays an important role in the polmeric

organization of macromolecules, such as RNA and DNA, protein synthesis, cell division and stability of

cell membranes. In relation to male reproduction zinc has been implicated in maintenance of

spermatogenesis, survival of germinal epithelium, survival and normal function of spermatozoa and

perhaps fertilization. A zinc-deficient diet was shown to be associated with a decrease in sperm count

and testosterone levels.

The objective of the study was to examine the effect of an oral zinc therapy on zinc levels in seminal

plasma and other seminal parameters in oligospermic infertile males with low seminal plasma zinc

levels.

Study design, patients and methodsIn the study 14 men with oligozoospermia (sperm cell count <40 million per ml or significantly

subnormal percentage of sperms with progressive motility or normal morphology) were

examined. Several parameters of sperm quality and phosphatase activity in seminal plasma were

measured. The zinc level was assessed in blood plasma and seminal plasma using AAS (atomic

absorption spectrophotometry). After two consecutive examinations at an interval of 1 month to

establish pretreatment data, patients received a supplementation of 220 mg zinc sulphate daily

over 4 months.

ResultsBefore zinc supplementation sperm cell count, percentage of sperms with progressive motility and

phosphatase activity in seminal plasma were below normal recommended values. After 4 months of

zinc sulphate therapy there was no effect on zinc plasma level, while zinc concentration in seminal

plasma increase significantly (p<0.05). In addition, sperm cell count, sperm motility and the

percentage of normally shaped sperm cells were significantly increased (p<0.01 each).

ConclusionZinc is essential for androgen production in the testes, proliferative activity of germ cells and for

capacitation* of spermatozoa. Obviously this trace element is an important factor in the treatment of

male infertility.

* maturation of sperm cells in the female genital tract; without this process the fertilization of the egg cell is not possible.

3Trace Elements

Effect of zinc on plasma testosterone, dihydrotestosterone, and sperm countEffect of zinc administration on plasma testosterone, dihydrotestosterone, and sperm count. Netter A, Hartoma R, Nahoul K. Arch Androl 1981;7(1):69-71.

BackgroundAlready in 1921, researchers observed that the herring testes were considerably richer in zinc during

the season of reproduction than in the resting season. Moreover high concentrations of zinc were

found in the testes and accessory genital glands of various mammalians including man. In view of

these data it seems likely that zinc might play an important role in reproductive physiology.

Study design, patients and methodsThirty seven patients between 20 and 40 years of age with infertility of more than 5 years were

selected. They received a treatment with 120 mg zinc twice daily for the duration of 40 to 50 days.

At baseline and after treatment zinc levels in blood plasma were measured using atomic absorption

spectrometry. Testosterone and dihydrotestosterone were determined using chromatography

and subsequent radioimmunoassay. Additionally before and after intervention, sperm count was

assessed.

ResultsFor data evaluation, patients were subdivided into two subgroups according to the basal plasma

testosterone level: Patients in group I had a plasma testosterone level of <4.8 ng/ml, group II showed

a testosterone level of > 4.8 ng/ml.

In group I, plasma zinc levels, testosterone levels, dihydrotestosterone levels and sperm counts increased

significantly (p<0.01 each). In group II, there was a significant increase ofdihydrotestosterone levels

(p<0.01).

During the study period, nine wives of the patients in group I became pregnant.

ConclusionMen with idiopathic fertility disorders showing a low plasma testosterone level can be successfully

treated by oral zinc supplementation also increasing sperm count. Additionally, increased

testosterone and dihydrotestosterone levels due to zinc effects have a beneficial impact on

spermatogenesis.

3Trace Elements

Male fertility and the selenoprotein phospholipid hydroperoxide glutathione peroxidaseMale fertility is linked to the selenoprotein phospholipid hydroperoxide glutathione peroxidase. Foresta C, Flohé L, Garolla A, et al. Biol Reprod 2002;67:967-71.

BackgroundThe selenoprotein phospholipid hydroperoxide glutathion peroxidase (PGHPx) accounts for almost

the entire selenium content of mammalian testes. PHGPs is abundantly expressed in spermatids as

active peroxidase but is transformed to an oxidatively inactivated protein in mature sperm. There it

is a major constituent of the mitochondrial capsule in the midpiece. Male infertility which is

characterized by impaired sperm motility and morphological midpiece alterations is considered to

result from insufficient PHGPx content. Therefore the authors of the present article studied the

relationship between sperm PHGPx, measured as rescued activity, and male fertility.

Study design, patients and methodsSperm specimens from 75 infertile men and 37 controls were analyzed for various fertility parameters

according to World Health Organization criteria. The PHGPx protein content was estimated after

reductive solubilization of the spermatozoa by measuring the rescued PHGPx activity.

ResultsRescued PHGPx activity of 93.2 mU/mg in the infertile group ranged significantly (p<0,001) below

that of controls (187.5 mU/mg sperm protein) and was particularly low in oligoastheno zoospermic

specimens (61.93 mU/mg; p<0.001 compared with controls and asthenozoo spermic samples).

Rescued PHGPx activity was correlated positively with viability (r=0.35), morphological integrity

(r=0.44), and most profoundly forward motility (r=0.45).

ConclusionIn humans, an adequate level of PHGPx appears to be indispensable for structural integrity of

spermatozoa and to codetermine sperm motility and viability. As the content of PHGPx, irrespective

of the cause of alteration, is associated with fertility-related parameters, PHGPx can be considered a

predictive measure for fertilization capacity.

3Trace Elements

L-carnitine levels and infertility: correlations with sperm qualityL-carnitine levels in the seminal plasma of fertile and infertile men: Correlation with sperm quality Matalliotakis I, Koumantaki Y, Evageliou A, et al. Int J Fertil Womens Med 2000;54(3):236-40.

BackgroundL-carnitine is a vitamin-like substance (so-called vitaminoid) found in human tissues and cells. It is

important for the transfer of long-chain fatty acids across the internal mitochondrial membrane

leading to beta-oxidation during the production of energy. L-carnitine is concentrated in the

epididymis, and an increased L-carnitine and L-acetylcarnitine content in the spermatozoa during

the epididymal passage is related with progressive motility of the sperms.

In this study the L-carnitine concentration in the seminal plasma of fertile and infertile men was

measured and the potential relationships between L-carnitine and various parameters of sperm

quality was determined.

Study design, patients and methodsThe study group included 101 men between the ages of 19 and 53 years. Semen samples were

obtained after 3 to 6 days of sexual abstinence. The semen samples were divided in two groups on

the basis of normal or abnormal spermiogram, i.e. a fertile and infertile group of subjects. Sperm

density, motility and morphology as well as L-carnitine concentration in seminal plasma were

measured.

ResultsL-carnitine levels in seminal plasma of fertile men were significantly higher than in infertile men (478.4

µmol/l vs. 100.6 µmol/l). The L-carnitine concentration correlated positively with the sperm cell count

(r=0.71), the sperm cell motility (r=0.58) and the sperm morphology (r=0.59).

ConclusionThe L-carnitine concentration is decreased in semen of infertile men and correlates with various

quality parameters of spermiograms. The higher seminal carnitine content in subjects with good

sperm quality supports the claim that carnitine may be a marker for good sperm cell quality.

L-carnitine is also able to improve motility of sperm cells.

4L-Carnitine and Coenzyme Q10

The effects of L-carnitine on idiopathic sperm abnormalities in smokers and nonsmokersThe effects of L-carnitine on sperm parameters in smoker and non-smoker patients with idiopathic sperm abnormalitiesKhademi A, Alleyassin A, Safdarian L, et al. J Assist Reprod Genet 2005;22(11-12):395-9.

BackgroundOne couple in 10 seeks medical help because of infertility. Offering some type of treatment in order

to improve male fertility may help approximately half of the couples with infertility. L-carnitine has

beneficial effects on the quality of sperms in patients with asthenozoospermia and plays a role in

the metabolism of sperm cells.

The objective of this study was to determine the effect of L-carnitine on sperm parameters in patients

with idiopathic sperm abnormalities and to examine the role of smoking as a risk factor for infertility.

Study design, patients and methodsTotally 170 men with infertility (including 48 smokers and 122 nonsmokers) participated in this study.

Before taking L-carnitine, 3 semen analyses covering a period of 3 months were performed and

assessed according to the WHO classification. Subsequently, participants took L-carnitine orally at a

dose of 1 g every 8 hours for 3 months. At the end of treatment another two semen analyses were

performed. Test parameters included sperm cell concentration, motility and morphology.

ResultsAll patients showed teratozoospermia (<14% normal shapes). No patient had sperms with normal

motility, and oligozoospermia was diagnosed in 58 patients.

The intake of L-carnitine during a period of 3 months led to a significant increase in total motility

(p=0.02) and the proportion of sperms with linear progressive motility (p<0.001) in nonsmokers. In

the group of smokers, there was an increase of sperm cells of normal shape (p=0.03).

ConclusionL-carnitine effectively improves the percentage of motile sperm cells in semen, the proportion of

sperms with linear progressive motility as well as sperms of normal morphology.

4L-Carnitine and Coenzyme Q10

Coenzyme Q10 supplementation in infertile men with idiopathic asthenozoospermiaCoenzyme Q10 supplementation in infertile men with idiopathic asthenozoospermia: an open, uncontrolled study. Balercia G, Mosca F, Mantero F, et al. Fertil Steril 2004;81(1):93-8.

BackgroundCoenzyme Q10 has antioxidative features and is able to neutralize excessive reactive oxygen species

(ROS) which are known to impair sperm cell function. Coenzyme Q10 biosynthesis is predominantly

active in testes and high levels of its reduced form QH2 (ubichinol) are present in semen (sperm

cells and seminal plasma). The objective of the study was to clarify if the oral intake of coenzyme

Q10 could increase its concentration in semen, and improve seminal kinetic parameters in men with

idiopathic asthenozoospermia.

Study design, patients and methodsA total of 22 patients with idiopathic asthenozoospermia were enrolled in the study. They

underwent a dietary intervention with coenzyme Q10 200 mg/day twice daily orally for 6 months.

At baseline and after 6 months of treatment a semen analysis (spermiogram) was performed and

the concentration of coenzyme Q10 assayed in sperm cells and seminal plasma using high pressure

liquid chromatography (HPLC)

ResultsCoenzyme Q10 levels increased significantly both in seminal plasma and in sperm cells after

treatment (p<0.05). The proportion of sperm cells with progressive motility (9.13% vs. 16.34%; p<0.05)

and their straight progressive velocity (15.2 µm/s to 20.40 µm/s; p<0.05) increased significantly.

ConclusionThe supplementation of coenzyme Q10 obviously plays a positive role in the treatment of astheno-

zoospermia. This is probably the result of both its action in mitochondrial bioenergetics and the

antioxidative properties of this vitaminoid.

4L-Carnitine and Coenzyme Q10

Combined L-carnitine and L-acetylcarnitine treatment in men with astenozoospermiaA placebo-controlled double-blind randomized trial of the use of combined carnitine and L-acetyl-carnitine treatment in men with astenozoospermia.Lenzi A, Sgrò P, Salacone P, Paoli D et al, Fertil Steril 2004;8(6):1578-84.

BackgroundL-carnitine protects the cell membrane and DNA against damage induced by free oxygen radicals. The

highest L-carnitine concentrations in the human body are found in the epididymal fluid. Initiation

of sperm motility occurs in parallel to an increase in L-carnitine in the epididymal lumen and the

concentration of L-acetylcarnitine in spermatozoa. In this study the efficacy of combined L-carnitine

and L-acetylcarnitine therapy in infertile men with oligoastheno-teratozoo spermia was to be

determined.

Study design, patients and methodsIn this placebo-controlled double-blind randomized clinical trial 60 infertile men were included and

divided into two groups. The study protocol consisted of a 2-month washout phase, a 6-month

administration of both substances, or a placebo, respectively, and a 2-month follow-up phase. The

carnitine group of patients took 2 g L-carnitine and 1 g L-acetylcarnitine daily.

ResultsAll parameters of sperm quality were improved after the combined carnitine treatment. The most

significant improvement in sperm motility was present in patients who had lower initial absolute

values of motile sperms (<5 x 106). In these patients the progressive motility (2.7 x 106 vs. 7.5 x 106

progressively motile sperms per ejaculate; p<0.043) and total motility (3.4 x 106 vs. 6.9 x 106 total

motile sperms per ejaculate; p<0.038) were also significantly increased.

In the group of patients who had received the carnitine combination, four of the spouses achieved

spontaneous pregnancies during the observation period.

ConclusionCombined treatment with L-carnitine and L-acetylcarnitine in this controlled study of efficacy was

effective in increasing sperm motility. This was especially noticeable in the patients with lower

baseline levels in the spermiogram.

4L-Carnitine and Coenzyme Q10

N-Acetylcysteine as radical scavenger in semen: therapeutic relevance for infertility?

Scavenging effect of N-acetyl-L-cysteine against reactive oxygene species in human semen: a possible therapeutic modality for male factor infertility. Oeda T, Henkel R, Ohmori H, et al. Andrologia 1997;29(3):125-31.

BackgroundMany studies have demonstrated that reactive oxygen species impair sperm function. This is a big

problem since low fertilization rates may be the consequence. Spermatozoa are particularly sensitive

to oxidative stress as their plasma membranes have a high content of omega-3 fatty acids. Membrane

lipids are damaged by reactive oxygen species (ROS). This damage affects membrane stability, fluidity

and permability, because the physico-chemical characteristics play an important role for normal sperm

functioning. N-acetylcysteine (NAC) acts as precursor of glutathione which as glutathione peroxidase is

the most important cellular antioxidant.

Study design, patients and methodsTo investigate the relevance of NAC, semen samples of 83 patients referred to the andrological

department of the university were examined. The semen samples were incubated with or without

N-acetylcysteine at room temperature. The amount of reactive oxygen species was assessed using

a chemiluminescent assay, and the effect of NAC on functional sperm parameters, such as motility,

vitaliy and acrosome reaction, was studied.

ResultsThe results demonstrated a significant effect of NAC on the formation of free radicals. The authors of

the study observed a significant decrease of ROS activity compared with controls, which was tested

at 20, 40, 60, and 120 minutes after incubation in the NAC group.

The ROS levels decreased significantly after 20 minutes of incubation with NAC. This reduction was

greater in the group with high ROS levels.

ConclusionNAC significantly reduced the amount of ROS in human semen. It also improved sperm function.

NAC might be a useful therapeutic option for the treatment of male infertility patients.

5N-Acetylcysteine

Fatty acid pattern of sperms in subfertile menSperm fatty acid composition in subfertile men.Aksoy Y, Aksoy H, Altinkaynak K, et al. Prostaglandins Leukot Essent Fatty Acids 2006;75(2):75-9.

BackgroundThe fatty acid composition in the cell membranes regulates the activity of various membrane-bound

enzymes as well as the resistance of the membranes to physical and chemical stress. The membrane

structure of the sperms plays an important role in successful fertilization. The sperms‘ lipids are relevant

to the vitality, maturation and function of the sperms.

Apparently the proportion of polyunsaturated fatty acids (PUFA) in the sperm membrane has also an

effect on sperm fluidity. High concentrations of docosahexaenoic acid (DHA) are associated with an

increase in sperm motility. Studies have also shown that men with oligo- or asthenozoospermia had

lower DHA levels than normal men.

Study design, patients and methodsIn total, the ejaculate of 79 men was examined. Using their spermiograms the men were divided in

three groups: one group each for normozoospermia, asthenozoospermia and oligozoospermia. The

spermatooa were separated from the seminal plasma, and the fatty acid profile was assayed in all

three groups. With these tests the association between traditional sperm parameters and fatty acid

composition was to be investigated.

ResultsThe DHA concentration was significantly lower in men with asthenozoospermia (p<0.01) or

oligoasthenozospermia (p<0.05) than in healthy men. Also patients with oligozoospermia showed

decreased DHA levels compared with healthy controls (p<0.05). There were no significant

differences found related to omega-6 fatty acid levels. The omega-6 : omega-3 ratio was significantly

higher in patiens with asthenozoospermia than in healthy controls (p<0.05). The PUFA content was

lower in cases of oligozoospermia (p<0.05) and asthenozoospermia (p<0.01) as compared with

healthy men. The DHA concentration also correlated positively with sperm motility, sperm

density and normal sperm morphology. Furthermore, investigators found an association between

the content of polyunsaturated fatty acids and sperm motility (r=0.50, p=0.0001), sperm density

(r=0.35, p=0.002) and normal morphology (r=0.28, p<0.01).

ConclusionThe altered content of DHA, PUFA, omega-6 : omega-3 ratio in sperms of patients with oligo- or

asthenozoospermia is presumably related to male infertility. Therefore in these cases supplementation

of polyunsaturated fatty acids can be useful in order to improve sperm quality.

6Polyunsaturated Fatty Acids

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