review article review of clinical trials on effects of...

Review ArticleReview of Clinical Trials on Effects of OralAntioxidants on Basic Semen and Other Parameters inIdiopathic Oligoasthenoteratozoospermia

Senka Imamovic Kumalic and Bojana Pinter

ReproductiveUnit, Division ofGynecology andObstetrics, UniversityMedical Centre Ljubljana, Slajmerjeva 3, 1000 Ljubljana, Slovenia

Correspondence should be addressed to Bojana Pinter; [email protected]

Received 31 January 2014; Accepted 14 March 2014; Published 31 March 2014

Academic Editor: Irma Virant-Klun

Copyright © 2014 S. Imamovic Kumalic and B. Pinter. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Infertility affects 50 to 80 million people worldwide. Male factor is a cause of infertility in almost half of cases, mainly due tooligoasthenoteratozoospermia (OAT). With common diagnostic methods no cause can be found in approximately 30% of casesof male infertility due to OAT and these are considered idiopathic. Reactive oxygen species (ROS) play an important role in maleinfertility and are proved to be higher in infertilemen; antioxidants could oppose their effect.The aim of this paper was to review theliterature on clinical trials in the period from year 2000 to year 2013 studying the effects of various types of antioxidant supplementson basic and other sperm parameters and pregnancy rates in subfertile males with idiopathic OAT. The majority of studies wererandomized and placebo controlled and confirmed beneficial effect of antioxidants on at least one of the semen parameters; thebiggest effect was determined on sperm motility. In many of these trials combinations of more antioxidants were assessed. Theoptimal dosages of one or more antioxidants were not defined.We concluded that antioxidants play an important role in protectingsemen from ROS and can improve basic sperm parameters in case of idiopathic OAT.

1. Introduction

Almost 15% of all couples trying to conceive are affected byinfertility, and in almost half of these cases male infertilityis the sole or a contributing factor [1]. While conditionssuch as varicocele, cryptorchidism, and hypogonadism aredefinable causes for infertility, no cause may be determinedfor an abnormal semen analysis in over 25% of cases [2]. Suchidiopathic infertility and oligoasthenoteratospermia (iOATs)is a condition in which sperm concentration, the proportionof motile sperms, and the proportion of morphologicallynormal sperms are below the World Health Organization(WHO) reference values [3].

Elevated reactive oxygen species (ROS) levels in thesemen may be an etiologic factor for male infertility [4]. Itis estimated that 25% of infertile men possess high levelsof semen ROS, whereas fertile men do not have high levelsof semen ROS [5, 6]. ROS are needed for capacitation, theacrosome reaction, and ultimately fertilization [7]. However,

their uncontrolled production is detrimental to cell functionas they damage a variety of biomolecules such as lipids, aminoacids, carbohydrates, protein, and DNA and adversely affectsperm function [8] due to DNA damage [9, 10], reducedmotility [11], and defective membrane integrity [12, 13].Spermatozoa are particularly susceptible to oxidative injurydue to the abundance of plasma membrane polyunsaturatedfatty acids. These unsaturated fatty acids provide fluidity thatis necessary for membrane fusion events (e.g., the acrosomereaction and sperm-egg interaction) and for sperm motility[14]. The human ejaculate contains a number of potentialsources of ROS. These include leukocytes, germ cells, orabnormal sperms [15]. At the same time, a number of cellularmolecules called antioxidants, which protect the cell fromexcessive ROS-induced lipid peroxidation, are also presentwithin the ejaculate [16]. Studies have shown that seminalantioxidant capacity is suppressed in infertile men with highROS levels compared to men with normal levels of ROS[17, 18].

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014, Article ID 426951, 11 pageshttp://dx.doi.org/10.1155/2014/426951

2 BioMed Research International

2. Materials and Methods

We searched PubMed with keywords, including combina-tions of search terms such as “male infertility” and “antiox-idants.” We searched for reviews, controlled and random-ized controlled clinical studies. From the numerous searchresults for the period between 1st January 2000 and 31stDecember 2013, 32 primary studies on idiopathic oligoas-thenoteratozoospermia (OAT) were chosen and their datawere gathered in order to provide a complete overview ofthe literature. Given the different antioxidants used (bothalone and in combination), the different dosages, differentduration of treatment, and various number of participants(from very small groups to large researches), we looked up forstatistical significance of changes in basic sperm parametersand pregnancy rates.

3. Results and Discussion

The review of the studies on antioxidants in clinical studies isillustrated in Table 1.

3.1. SpermConcentration. Low sperm concentration or oligo-zoospermia is defined as concentration less than 15 ×106 spermatozoa/mL according to WHO reference value

from 2010 [51] and less than 20 × 106 spermatozoa/mLaccording to WHO reference values from 1999 [52], whichwere considered in most of researches in this review. Manyresearches showed significant improvements in sperm con-centration after oral intake of different antioxidants [19–31].Most of these researches investigated combination of differentantioxidants, like L-carnitine, coenzyme Q10 (CoQ10), vita-min C, vitamin E, zinc (Zn), selenium (Se), and so forth. Butthere are also some studies that investigated only one type ofantioxidant. Safarinejad et al. showed that intake of 200mgCoQ10 daily for 26 weeks improved sperm concentration instudy group (28.7±4.6×106 spermatozoa/mL) versus placebogroup (16.8 ± 4.4 × 106 spermatozoa/mL) (𝑃 = 0.005) [23].After 6months of intake of combination of 25mg clomiphenecitrate and 400mg vitamin E per day sperm concentrationimproved from 10.2×106±4.14 spermatozoa/mL to 18×106±15 spermatozoa/mL (𝑃 = 0.0025) [26]. There was also signif-icant improvement in sperm concentration from 14.3±7.38×106 spermatozoa/mL to 32.8 ± 10.3 × 106 spermatozoa/mL

(𝑃 < 0.001) after consumption of 1 g of vitamin C twice dailytaken for 2 months as proved by Akmal et al. [28].

3.2. Sperm Motility. Asthenozoospermia is defined as lessthan 40% of motile spermatozoa [51] and according toWHO reference value from 1999 less than 50% of motilespermatozoa [52]. 20 out of 32 studies in our review provedsignificant improvement in sperm motility after the use ofantioxidants [19, 20, 22–39]. Improvement in sperm motilityhas been shown mostly in researches considering mixtureof more antioxidants such as selenium and vitamin E [38,39]. Most of studies with just one type of antioxidantwere about CoQ10 but in different dosages and in differentduration of consuming [22–24, 37]. Kumar et al. showed

that consumption of herbal-mineral supplement Addyzoafor 3 months improved total and progressive sperm motilityin study group. Total motility improved from 23.2 ± 17.3%before the treatment to 33.4 ± 23.2% after the treatment(𝑃 = 0.008). Progressivemotility improved from 15.7±12.6%before treatment to 22.6±18.0%after treatmentwithAddyzoa(𝑃 = 0.024) [33]. Wang et al. showed that L-carnitine incombination with vitamin E taken for 3 months significantlyimproved forward sperm motility from 28.6% ± 9.2% to45.4% ± 11.1% (𝑃 < 0.01), compared with just vitamin E[35]. After treatment with 200mg CoQ10 twice daily for 6months spermmotility improved from 9.13%± 2.50% beforethe therapy to 16.34% ± 3.43% after the therapy (𝑃 < 0.05)[37].

3.3. Sperm Morphology. WHO reference values from 1999[52] defined teratozoospermia as less than 14% of normalshape and form spermatozoa according to strict Krugercriteria. Although WHO reference values from 2010 defineteratozoospermia as less than 4% of normal shape andform spermatozoa [51] strict Kruger criteria are still used asreference value for assessing sperm morphology. L-carnitinein combinationwithCoQ10, vitamins E andC, zinc, selenium[20, 40], CoQ10 alone [23, 24], pentoxifylline [25], N-acetyl-cysteine with Se [27], vitamin C alone [28], combinationof papaya, beta-glucan, lactoferrin, vitamins C and E [36],Se, and vitamin E [38], and pycnogenol [41] significantlyimproved sperm morphology. Therapy with 200mg CoQ10daily for 26 weeks improved spermmorphology in 114 partic-ipants in study group to 17.6%± 4.4% versus 14.8%± 4.1% in114 participants in placebo group (𝑃 = 0.01) [23]. Safarinejadalso showed that intake of 400mg of pentoxifylline twicedaily for 24 weeks of treatment phase significantly improvedpercentage of sperm with normal morphology to 25.4 ± 4.3%in study group versus 17.4 ± 4.2% in placebo group (𝑃 =0.001) [25]. Combination of 20mg beta-glucan, 50mg fer-mented papaya, 97mg lactoferrin, 30mg vitamin C, and 5mgvitamin E, twice per day for 3 months, improved percentageof morphologically normal sperm in 36 participants from17.0 ± 5.2% to 29.8 ± 6.5% (𝑃 < 0.01) [36].

3.4. Sperm DNA Fragmentation and Chromatin Integrity.ROS can cause sperm DNA damage and integrity of spermDNAcan bemeasuredwithDNA fragmentation.The levels ofsperm-derived ROS (measured in sperm preparations havingminimal leukocyte contamination) have been associated withsperm DNA damage [53]. High level of denatured DNA inspermatozoa with large nuclear vacuole could arise fromprecocious decondensation and disaggregation of spermchromatin fibers [54]. Dietary antioxidants may be benefi-cial in reducing sperm DNA damage, particularly, in menwith high levels of DNA fragmentation [5]. Five out of 32studies confirmed that the usage of different antioxidants hadimportant influence on DNA fragmentation and chromatinintegrity [20, 42–46]. Song et al. showed that combination ofChinese medicine Compound Xuanju Capsule with vitaminE taken for 3months decreased degree ofDNA fragmentationindex (DFI) after therapy to 29.57 ± 12.19 compared just to

BioMed Research International 3

Table1:Stud

ycharacteris

ticsa

ndthee

ffectof

oralantio

xidantso

nbasic

andothersem

enparameters.

Stud

y/author

Year

Patients/test

Num

bero

fpatients

Antioxidant/durationof

th.

Sign

ificant

improvem

ent

Non

significant

improvem

ent

Negativee

ffect

Wirleitner

etal.[19]

2012

OAT

versus

non-OAT

,MSO

ME

147

Fertilo

vitM

plus/2–12

mon

ths

↑concentrationandmotilityof

sperm

Morph

olog

y

Abad

etal.[20]

2013

AT/D

FI,basicsperm

parameters

20

L-Ca

rnitine

1500

mg;

vitamin

C60

mg;CoQ

1020

mg;vitamin

E10mg;

Zn10mg;vitamin

B9200𝜇

g;Se

50𝜇g;vitamin

B121𝜇g/3mon

ths

DNAintegrity

(𝑃<0.01),the

prop

ortio

nof

DDS↓(𝑃<0.05).↑in

concentration,

motility,vita

lity,and

morph

olog

yparameters.

Safarin

ejad

[21]

2011

iOAT

238(analysis

on211)

SG:106

PG:105

SG:eicosapentaenoic

(EPA

)and

docosahexaenoica

cids

(DHA),1.8

4gperd

ayversus

PG/32weeks

SG:↑

ofsperm

celltotalcou

nt(fr

om38.7±8.7×106to61.7±11.2×106,

𝑃=0.001)a

ndsperm

cell

concentration(fr

om15.6±4.1×106/m

Lto

28.7±4.4×106/m

L,𝑃=0.001).

SeminalplasmaE

PAandDHAconc.

werep

ositivelycorrelated

with

seminalplasmaS

OD-like

and

catalase-like

activ

ity(both

𝑃=0.001).

Inseminalplasma,bo

thSO

D-like

andcatalase-like

activ

itywerep

ositively

correlated

with

sperm

coun

t,sperm

motility,and

sperm

morph

ology.

Safarin

ejad

[22]

2009

iOAT

/sem

enanalyses,

AR,

immun

obeadtestfor

antisperm

antib

ody,and

determ

inationof

resting

levelsof

LH,FSH

,prolactin

,testoste

rone,

andinhibinB

212

(SG:106,versusP

G:

106)

CoQ

10300m

g/26

weeks

follo

wed

bya3

0-week

treatment-freep

hase

SG:↑

insperm

density

andmotility

(each𝑃=0.01).↓FSHandLH

atthe

26-w

eektre

atmentp

hase

(each

𝑃=0.03).By

thee

ndof

the

treatmentp

hase

them

eanARhad

increasedfro

m14%±8%

and

15%±8%

to31%±11%

and

16%±10%

intheC

oQ10

andplacebo

grou

ps,respectively

(𝑃=0.01).

Safarin

ejad

etal.[23]

2012

iOAT

/sem

enparameters,

seminalplasmaT

AC,

FSH,and

inhibinB

228

SG:114

PG:114

CoQ

10200m

g/day/26

weeks

SG:↑

insperm

density

(28.7±4.6×106/m

Lversus

16.8±4.4×106/m

L(𝑃=0.005)),

sperm

motility(35.8%±2.7%

versus

25.4%±2.1%

(𝑃=0.008)),and

sperm

morph

ology(17.6%±4.4%

versus14.8%±4.1%

(𝑃=0.01)).

FSH↓(𝑃=0.02),inhibinB↑

(𝑃=0.01)


Table1:Con

tinued.

Stud

y/author

Year

Patients/test

Num

bero

fpatients


th.

Sign

ificant

improvem

ent

Non

significant

improvem

ent

Negativee

ffect

Safarin

ejad

[24]

2012

iOAT

/sem

enparameters

andpregnancyrates

287

CoQ

10300m

gorally

twiced

aily/12

mon

ths

Meansperm

conc.,s

perm

progressive

motility,and

sperm

with

norm

almorph

olog

yim

proved

by113.7,104.8,

and78.9%,respectively

(all𝑃<0.05).

Theo

verallspon

taneou

spregnancyratewas

34.1%

with

inam

eanof

8.4±4.7

mon

ths.

Safarin

ejad

[25]

2011

iOAT

/sem

enparameters,

testo

sterone,LH,FSH

,andinhibinB,

seminal

plasmaS

OD-like

activ

ity,

andacrosomer

eaction

254

(SG:127,

PG:127)

SG:P

TX(pentoxifylline)

400m

gtwiced

aily/4-w

eek

screeningph

ase,a

24-w

eektre

atmentp

hase,

anda1

2-week

treatment-freep

eriod

SGaft

erPT

X:↑sperm

conc.(mean

value,fro

m26.4±4.6×106/m

Lto

16.2±3.4×106/m

L),sperm

motility

(meanvalue,fro

m35.8±4.2%

to26.4±2.4%),andsperm

with

norm

almorph

olog

y(m

eanvalue,fro

m25.4±4.3%

to17.4±4.2%)

(all𝑃=0.001);meanSO

D-like

and

catalase-like

activ

ity↑than

inthe

semen

ofPG

(46.4±2.4versus

36.3±1.3U/m

Land371±44versus

301±14U/m

L,respectiv

ely,both

𝑃=0.003).Th

eARwas

observed

tobe↑in

PTXgrou

p(𝑃=0.01).

Ghanem

etal.[26]

2010

iOA/basicsemen

parameters,pregnancy

incidence

SG:30

PG:30

Clom

iphene

citrate

25mg/day+vit.E

400m

g/day/6mon

ths

SG:sperm

conc.:10.2×106±4.14→

18×106±15(𝑃=0.0025);

progressivem

otility:

4%±6→7%±10(𝑃=0.0286).

Spon

taneou

spregn

ancy

incidence,

SG:36.7%

,versusP

G:13.3%

(𝑃=0.037)

M.R

.Safarinejad

and

S.Safarin

ejad

[27]

2009

iOAT

/serum

Testradiol,

FSH,LH,prolactin,

inhibinB,

Se,and

N-acetyl-c

ysteine.Semen

analysis,

seminalplasma

Se,and

N-acetyl-c

ysteine.

468

SG1:116

SG2:118

SG3:116

PG:118

SG1:Se

200𝜇

g/day

SG2:N-acetyl-c

ysteine

600m

g/day

SG3:Se

200𝜇

g+

N-acet-c

ys60

0mg/day/26

weeks

+30-w

eek

treatment-freep

eriod

Astr

ongcorrelationwas

observed

betweenthes

umof

theS

eand

N-acetyl-c

ysteinec

oncentratio

ns,

andmeansperm

concentration

(𝑟=0.67,𝑃=0.01),sperm

motility

(𝑟=0.64,𝑃=0.01),andpercent

norm

almorph

olog

y(𝑟=0.66,

𝑃=0.01).

Se+N-ac-cy.:↓FSH,↑

T,inhibinB


Table1:Con

tinued.

Stud

y/author

Year

Patients/test

Num

bero

fpatients


th.

Sign

ificant

improvem

ent

Non

significant

improvem

ent

Negativee

ffect

Akm

aletal.[28]

2006

O/sem

enparameters

13vitamin

C1g

twiced

aily/2

mon

ths

Meansperm

coun

t:14.3±7.38×106

sperms/mLto32.8±10.3×106

sperms/mL(𝑃<0.001),meansperm

motility:31.2±9.61%

to60.1±8.47%

(𝑃<0.001),andmean

spermsw

ithno

rmalmorph

ology:

43±7.87%

to66.7±4.77%

(𝑃<0.001).

Shietal.[29]

2004

OA/sem

inalroutine

analysis

34

Xinx

ibao

(ZnandSe

tablets)threetim

esa

day/90

days

+fivetablets

atatim

efor

90days

insuccessio

n

Thes

perm

quality

was

improved

60days

and90

days

after

treatment.5

cases(14.7%)sho

wed

remarkable

effect,25

(73.5%

)improved.

4cases(11.8%

)did

not

respon

d.

Suzukietal.[30]

2003

OandAversus

norm

ozoo

spermia/sperm

parameters,serum

horm

ones,and

SOD

activ

ityin

thes

erum

and

thes

eminalplasma+

the

testiculara

rtery

SG:47

CG:16

Saire

i-to9g

/day/3

mon

ths

SG:totalsperm

conc.(17.1±20.0to

28.7±35.5×106/m

L,𝑃=0.02)a

ndsperm

motility(30.1%±21.6to

45.8%±24.4,𝑃<0.0001)a

ndthe

pulsa

tility

indexof

thetestic

ular

artery↓(2.03±0.84to1.64±0.48,

𝑃=0.04)

Afterth.serum

horm

ones

andSO

Dactiv

itydidno

tchange

significantly

ineither

grou

p.CG

:nosig

nificantchange

insperm

cond

ition

sor

testiculara

rteryflo

w.

Gup

taandKu

mar

[31]

2002

Idiopathicno

nobstructiv

eO/A

/Tspermia/sem

enanalysis

30Lycopene

2000

mcg,twice

aday/3

mon

ths

20patie

nts(66

%):↑sperm

conc.,16

(53%

)↑motility.Th

emedianchange

inconcentrationwas

22million/mL,

motility25%.H

igherb

aseline

concentra

tions

(morethan5

million/mL)

werea

ssociatedwith

significantimprovem

entand

resulted

insix

spon

taneou

spregn

ancies

in26

patie

nts(23%).

14patie

nts(46

%)↑

insperm

morph

ology

(medianchange

10%).

Baselin

esperm

concentra

tionlessthan

5million/mLwas

associated

with

nosig

nificant

improvem

ent.

Busetto

etal.[32]

2012

IdiopathicAT

/basicsperm

parameters

114(96fin

ished)

L-Ca

rnitine

145m

g,acetyl-L-carnitin

e64m

g,fructose

250m

g,citric

acid

50mg,Se

50𝜇g,

CoQ

1020

mg,Zn

10mg,

ascorbicacid

90mg,

cyanocob

alam

in1.5𝜇g,

andfolic

acid

200m

cgon

cead

ay/4

mon

ths

↑Meansperm

progressivem

otility:

18.3±3.8to42.1±5.5,

16patientsa

chievedpregnancy

durin

gthes

tudy.

Con

centratio

nand

morph

olog

y


Table1:Con

tinued.

Stud

y/author

Year

Patients/test

Num

bero

fpatients


th.

Sign

ificant

improvem

ent

Non

significant

improvem

ent

Negativee

ffect

Kumar

etal.[33]

2011

Atleasto

neparameter

ofOAT

/basicsemen

parameters,RO

S,TA

C,andDFI

(SCS

A)

SG:21

PG:23

herbal-m

ineral

supp

lementA

ddyzoa/3

mon

ths

SG:totalmotility:

23.2±17.3%→33.4±23.2%

(𝑃=0.008)

Progressivem

otility:

15.7±12.6%→22.6±18.0%

(𝑃=0.024)

Chen

etal.[34]

2012

O,A

/sperm

concentration

and%of

progressively

motile

sperm,the

rateof

clinicalpregn

ancy

Oligosp:

64(SG:33+CG

:31)

Asth

eno:42

(SG:22+CG

:20)

Oligosperm

ia:

CG:tam

oxifen10mgbid

SG:tam

oxifen10mgbid+

vit.E100m

gtid

Asth

enosperm

ia:

CG:levocarnitin

eoral

solutio

n1b

ottle

bid

SG:levocarnitin

eoral

solutio

n1b

ottle

bid+vit.

E100m

gtid

/3mon

ths

Oligosperm

ia:

then

umbero

fspo

ntaneous

pregnanciesa

fterth.wereC

G:0,and

SG:6

(𝑃<0.01).

Asth

enosperm

ia:

after

th.the

numbersof

cases

evaluatedas

with

noor

slight

improvem

entinthe%

ofprogressively

motile

sperm

were7

and2(𝑃<0.01),4and8(𝑃<0.01),

andthen

umbero

fspo

ntaneous

pregnanciesC

G:5,and

SG:9

(𝑃<0.01).

Asth

enosperm

:afte

rth,

then

umbero

fcases

evaluatedas

with

mod

erateo

rmarked

improvem

entinthe

percentage

ofprogressively

motile

sperm

was

3and2

(𝑃>0.05)a

nd1and

1(𝑃>0.05)

Wangetal.[35]

2010

A/basicsperm

parameters

135

Group

A(𝑛=68)

andB(𝑛=67)

Group

A:L-carnitin

e2g

/day

+vitamin

EGroup

B:vitamin

E/3

mon

ths

Group

A:↑

%of

forw

ardmotile

sperm

(28.6%±9.2%

to45.4%±11.1%,𝑃<0.01),ther

ateo

fspon

taneou

spregn

ancy↑(31.1%)

than

ingrou

pB(3.8%)a

fterthe

treatment(𝑃<0.01).

Group

A:sperm

density

andthe%

ofthes

perm

ofno

rmalmorph

olog

y(𝑃>0.05).

Piom

boni

etal.[36]

2008

AT+leuk

ocytosis/sperm

parameters,DNAdamage

(acridineo

range)

51(SG:36+CG

:15)

SG:beta-glucan

20mg,

ferm

entedpapaya

50mg,

lactoferrin

97mg,vit.C

30mg,andvit.E5m

g,twicep

erday/3mon

ths

SG:%

ofmorph

ologicallyno

rmal

sperm

(17.0±5.2to29.8±6.5)a

ndtotalprogressiv

emotility(19.0±7.8

to34.8±6.8),↓in

leuk

ocytec

onc.

(2.2±0.9to0.9±0.2),all𝑃<0.01

Structuralsperm

characteris

ticsa

swellas

chromatin

integrity

were

also

improved

after

treatment.

Balerciaetal.[37]

2004

iA(W

HO1999)/basic

sperm

parameters,

seminalplasmaa

ndsperm

CoQ

10,and

phosph

atidylcholine(PC

)

22CoQ

10200m

g2x/day/6

mon

ths

CoQ

10sem.plasm

a(ng

/mL:

42.0±5.1to127.1±1.9(𝑃<0.005))

CoQ

10sperm

cells

(ng/10

6cells):

3.1±0.4to6.5±0.3(𝑃<0.05)

PCsem.plasm

a(𝜇M):1.49±0.50to

5.84±1.15(𝑃<0.05)

PCsperm

cells

(nmol/10

6cells):

6.83±0.98to9.67±1.23(𝑃<0.05)

Sperm

cellmotility9.13±2.50%

to16.34±3.43%

after

th.(𝑃<0.05)

Sperm

conc.and

sperm

morph

olog

y


Table1:Con

tinued.

Stud

y/author

Year

Patients/test

Num

bero

fpatients


th.

Sign

ificant

improvem

ent

Non

significant

improvem

ent

Negativee

ffect

Moslemiand

Tavanb

akhsh[38]

2011

iAT/semen

parameters

andpregnancyrates

690(analysis

on525)

Se200𝜇

g+vitamin

E40

0units/

min.100

days

52.6%(362

cases)totalimprovem

ent

insperm

motility,m

orph

ology,or

both

and10.8%(75cases)

spon

taneou

spregn

ancy

versus

notre

atment(95%confi

denceinterval):

3.08

to5.52;𝑃≤0.001

Norespon

seto

treatment

occurred

in253cases

(36.6%

)

Keskes-Ammar

etal.

[39]

2003

Infertile

men/basicsperm

parameters,MDA,and

serum

vitamin

Elevel.

54:

SG:28(20analyzed)

CG:26

SG:vitamin

E40

0mg+Se

225𝜇

g/day

CG:vitamin

B4.5g

/day/3

mon

ths

SG:↓

inMDAconcentrations

andan

↑of

sperm

motility

Cavallini

etal.[40

]2012

IdiopathicOAT

/basic

sperm

parametersa

ndaneuploidy

(FISH)

55(analysis

on33:

22respon

der—

grou

p1

+11

nonrespo

nder—

grou

p2)

L-carnitine

1ggiventwice

perd

ay+

acetyl-L-carnitin

e500

mg

giventwicep

erday+on

e30

mgcinn

oxicam

tablet

every4days/3

mon

ths

Group

1versusg

roup

2:im

provem

ent

inmorph

ologyandnu

mbero

faneuploidspermatozoa

(𝑃<0.01);↑

%of

biochemicalpregnancyaft

erICSI

(54.4%

versus

9.1%,𝑃<0.01),

clinicalpregn

ancy

after

ICSI

(50%

versus

9.1%,𝑃<0.01),andliveb

irths

(45.4%

versus

9.1%,𝑃<0.01)

Num

bersof

oocytes

fertilizedandem

bryos

transfe

rred

Roseff[41]

2002

Subfertile/basic

sperm

parametersb

eforea

ndaft

ercapacitatio

nand

manno

sereceptor

bind

ing

19Py

cnogenol200m

gdaily

orally/90days

Them

eansperm

morph

olog

yfollo

wingHam

’sF-10

capacitatio

n↑

by38%follo

wingth.(𝑃<0.001)a

ndthem

anno

sereceptor

bind

ingassay

scores

improved

by19%(𝑃<0.005)

Baselin

emorph

olog

y↑

after

th.by33%

Them

ean%change

from

baselin

esperm

coun

tafter

th↓no

nsignificantly

by10%

Song

etal.[42]

2012

IdiopathicOA/basic

sperm

parameters,DFI

(SCS

A)

SG:24

CG:26

SG:vit.

E+xu

anju

caps

CG:vit.

E/3mon

ths

SGversus

CG:↓

DFI

after

th.:

29.57±12.19versus34.09±10.32,

𝑃<0.05

Menezoetal.[43]

2007

AtleastT

WOpervious

failu

resIVFor

ICSI,D

FI>15%/D

FIandthed

egree

ofsperm

decond

ensatio

n(SCS

A)

58

VitaminsC

andE40

0mg

each,𝛽

-carotene18m

g,Zn

500𝜇

mol,and

Se1𝜇

mol/90days

↓DNAfragmentatio

n:−9.1

%,

𝑃<0.0004

↑in

sperm

decond

ensatio

n(+22.8%,𝑃<0.0009).

Greco

etal.[44

]2005

TUNEL>15%/basicsperm

parameters,TU

NEL

38(26OAT

+6OT

+6no

rmal)

Vit.C1g

+vit.E1g/2

mon

ths

TUNEL

positives

perm

:24.0±7.9to

8.2±4.3(𝑃<0.001)

Clinicalpregnancyaft

erICSI:from

6.9%

to48.2%(𝑃<0.05)

Implantatio

nrateaft

erICSI:from

2.2%

to19.6%(𝑃<0.01)

Sperm

conc:17.9±16.3to

18.3±17.9

Sperm

motil.:40.6±24.8

to39.9±19.0

Normalsperm

morph

.:10.5±8.3to

9.6±0.4,all

𝑃>0.05


Table1:Con

tinued.

Stud

y/author

Year

Patients/test

Num

bero

fpatients


th.

Sign

ificant

improvem

ent

Non

significant

improvem

ent

Negativee

ffect

Greco

etal.[45]

2005

TUNEL>15%/basicsperm

parameters,TU

NEL

SG:32

PG:32

Vit.C1g

+vit.E1g/2

mon

ths

SG:↓

fragm.D

NA:

22.1±7.7→9.1±7.2(𝑃<0.001)

PG:T

UNEL

:22.4±7.8

→22.9±7.9

Raiganietal.[46]

2013

OAT

/sperm

quality,

sperm

mito

chon

drial

functio

n,sperm

chromatin

status,semen

andbloo

dfolate,zinc,B12,

TAC,

andMDAconcentr.

83Fo

licacid

5mg/day±Zn

sulphate220m

g/day

versus

placebo/16

weeks

Sperm

chromatin

integrity

(%)↑

ingrou

preceivingon

lyZn

sulphate

treatment(𝑃=0.048)

Sperm

conc.↑

ingrou

preceivingthec

ombinedth.

offolic

acid

andZn

sulphateandalso

inthe

grou

preceivingon

lyfolic

acid

th.;(𝑃=0.056and

𝑃=0.05,respectively

).

Trem

ellenetal.[47]

2007

Malefactorinfertility,

TUNEL>25%/embryo

quality,pregn

ancy

and

fertilizatio

nrateaft

erIV

F-ICSI

SG:36

PG:16

Menevit(likopen,

vit.C,

vit.E,

Zn,Se,folate,and

garlic)/3

mon

ths

Pregnancyrateaft

erICSI

inSG

:38.5%,versusP

G:16%

(𝑃=0.046)

Safarin

ejad

etal.[48]

2011

iOAT

/sem

enparameters

andTA

Cof

seminal

plasma

260

(SG:130,

PG:130)

Saffron

60mg/day/26

weeks

Nosta

tistic

allysig

nificant

improvem

entsin

either

grou

pin

anyof

the

studied

semen

parameters

Nadjarzadeh

etal.[49]

2011

iOAT

/basicsperm

parameters,TA

C47

CoQ

10200m

g/day/12

weeks

versus

placebo

SG:↑

TAC(𝑃<0.05)

Semen

parameterso

fCoQ

10grou

p

Com

haire

etal.[50]

2000

Infertile

men/sperm

characteris

tics,RO

S,fatty

acidso

fsperm

mem

brane

phosph

olipids,sperm

oxidized

DNA

(8-O

H-dG),andindu

ced

AR

27N-acetyl-c

ysteineo

rvitaminsA

+Eand

essentialfattyacids

↓RO

S,↑AR

Noim

provem

entinsperm

motilityandmorph

olog

yor↓of

roun

dcells

and

whitebloo

dcells

insemen.Sperm

concentration↑in

oligozoo

sp.m

en(7.4±1.3

to12.5±1.9

million/mL).

Legend

:Add

yzoa:G

okshura(Trib

ulus

terrestris)200m

g,Ashtavarga200m

g,Gud

uchi

(Tinospora

cordifolia)150

mg,

Ashwagandh

a(W

ithania

Somnifer

a)150m

g,Amalaki(Em

blica

officin

alis)

75mg,

Balamoo

l(Sidacordifolia)7

5mg,

Vridhadh

aru(Argyreia

speciosa)7

5mg,

Shatavari(Asparagusracem

osus)7

5mg,

Shwet

musli(Chlorophytum

arun

dina

ceum

)150

mg,

Shud

dhakapikachchhu

(Purified

Mucun

aprurien

s)150m

g,Va

rahikand

(Tacca

aspera)30

mg,

Chop

chin

(Smila

xchina)

30mg,

Vidarik

and(Ip

omoeadigitata)30

mg,

Mun

jatak(Eulophiacampestris)

15mg,

Purnachand

rodaya

rasa

45mg,

Suvarnavang30

mg,

Muk

tashuk

tibh

asma30

mg,

Suvarnam

akshik

bhasma30

mg,

Shilajit

shud

dha30

mg,

Abhrak

bhasma15mg,

Makardh

wajrasa

15mg,

Rasa

sindu

r5mg;AR:

acrosomereactio

n;CG

:con

trolg

roup

;DDS:DNA

degraded

sperm;D

FI:D

NAfragmentatio

nindex;Fertilo

vitM

plus:L-citrullin

e(20.2%),L-carnitine-L-ta

rtrate,D

-alpha-to

coph

erylacetate,hydroxypropylm

ethylcellulose

(capsulecoating),acidifiertartaric

acid,

L-ascorbicacid

(6.7%),partingcompo

undsilicon

dioxide,calcium

carbon

ate,lycopene,N

-acetyl-L

-cysteine,glutathion

e(redu

ced),cornsta

rch,zinc

oxide,coenzymeQ

10,vegetableoil,shellacc

oatin

g,pteroyl-L

-glutam

ate,sodium

selenite,coloringagenttitanium

dioxide(

capsule),coloringagento

rangey

ellow

S(capsule);CoQ

10:coencym

eQ10,FISH:fluo

rescentinsituhybridization;

FSH:follicle-stim

ulatingho

rmon

e;ICSI:intracytoplasmicsperm

injection;

iOAT

:idiop

athicOAT

;IVF:

invitro

fertilizatio

n;LH

:luteinizing

horm

one;MDA:m

alon

dialdehyde;M

SOME:

motile

sperm

organelle

morph

olog

yexam

ination;

OAT

:oligoastheno

teratozoosperm

ia;PG:placebo

grou

p;RO

S:reactiv

eoxygenspecies;Saire

i-to:aC

hinese

herbaldrug;SCS

A:sperm

chromatin

structureassay;Se:sele

nium

;SG:study

grou

p;T:

testo

sterone;TAC

:total

antio

xidant

capacity;T

UNEL

:TdT

(term

inaldeoxyribon

ucleotidyltransfe

rase)—

mediateddU

TPnick-end

labelin

g;Xu

anju:Formica

fusca,Herba

epim

edii,Fructusc

nidii,andFructuslycii;Zn

:zinc.


vitamin E with degree of DFI of 34.09±10.32 (𝑃 < 0.05) [42].Greco et al. [44, 45] had proved that 1 g of vitamin C and 1 g ofvitamin E together taken for 2months significantly decreasedthe degree of DNA fragmentation from 22.1 ± 7.7 to 9.1 ± 7.2(𝑃 < 0.001) [45]. Raigani et al. showed that zinc sulphatesignificantly improved sperm chromatin integrity [46].

3.5. Pregnancy Rate. CoQ10 [24], clomiphene citrate withvitamin E [26], lycopene [31], L-carnitine with vitamin E [34,35], and selenium with vitamin E [38] significantly improvedspontaneous pregnancy rates during duration of treatment,while L-carnitine with cinnoxicam [40] and vitamins C andE together [44] significantly improved pregnancy rates percycle after assisted reproductive technology with intracyto-plasmic sperm injection (ICSI). Ghanem et al. proved higherspontaneous pregnancy rate in 30 participants after the intakeof combination of 25mg clomiphene citrate and 400mgvitamin E per day for 6months (36.7%) than in placebo group(13.3%) with 𝑃 = 0.037 [26]. L-Carnitine, 2 g, with vitamin Etaken for 3 months improved spontaneous pregnancy rate to31.1% compared to vitamin E group with pregnancy rate of3.8% (𝑃 < 0.01) [35]. Another example in study by Greco etal. confirmed higher pregnancy rate after 2 months therapywith 1 g of vitamin C and 1 g of vitamin E daily. After ICSIclinical pregnancy rate was 48.2% after therapy versus 6.9%before therapy (𝑃 < 0.05) [44].

3.6. Negative or No Effect on Sperm Parameters. In this reviewwe find out also rare negative effects of antioxidants on spermparameters or no effect. Pycnogenol caused nonsignificantfall in baseline sperm count by 10% [41]. Similarly, treatmentwith vitamins C and E, ß-carotene, zinc, and selenium signif-icantly increased sperm decondensation [43]. Large researchon saffron showed no statistically significant improvementsin any of the studied semen parameters [48].

3.7. Other Parameters. We looked at the basic sperm param-eters but there were also many other positive influences; forexample, CoQ10 and pentoxifylline caused improvements intotal antioxidant capacity and acrosome reaction [22, 25, 49,50]; FSH value [22, 23] decreased after CoQ10 treatment,semen leucocyte concentration decreased [36], and level ofROS [50] decreased after antioxidant mixtures. Antioxidantsprotect unsaturated fatty acids and so provide fluidity thatis necessary for membrane fusion events like the acrosomereaction. Although hormonal abnormalities are not alwaysevident, iOAT is sometimes associated with lower serumtestosterone and inhibin levels and higher serum estradiol,LH, and FSH levels [55, 56].The increased serumFSH level inmen with azoospermia or severe oligozoospermia indicatesdamaged seminiferous tubule [57] and is inversely associatedwith sperm concentration, motility, and morphology [58].ROS has been found in the seminiferous tubules and seminalplasma of most patients with iOAT [59]. Decreased levels ofROS due to antioxidant consumption can cause fall in serumFSH level. Leukocytes are potential source of ROS and due toprotective influence of antioxidants their concentration maydecrease [15]. In addition, studies have found an increase in

inhibin B value [23] and in superoxide-dismutase- (SOD-)like and catalase activity [21, 25], which among others rep-resent the total antioxidant capacity of seminal plasma [60].Inhibin B in positively correlated with sperm concentrationand is, like FSH, thought to be a marker of spermatogenesisand Sertoli cell function [61, 62].

4. Conclusions

Most of the published studies were randomized and placebocontrolled. The majority of studies confirmed beneficialeffect of different antioxidants on at least one of the semenparameters and the biggest effect was determined on spermmotility. In many of these trials combinations of moreantioxidants were assessed. The optimal dosages of one ormore antioxidants were not defined.

Most commonly antioxidants studied were vitamin E,vitamin C, selenium, CoQ10, N-acetyl-cysteine, L-carnitine,and zinc and their favorable effect was confirmed. Accordingto this review favorable effects on iOAT have been deter-mined with CoQ10, vitamin E, selenium, and also vitamin CandN-acetyl-cysteine treatments. In case of oligozoospermiavitamin E and CoQ10 were most often proved to be effective.Favorable effects on asthenozoospermia havemost often beendeterminedwith vitamin E, CoQ10, and selenium treatments.In teratozoospermia selenium and CoQ10 treatments weremost often proved to be effective. In addition, combination ofvitamin C and E showed the biggest favorable effect on DNAfragmentation; similar effects were determined with zinc andselenium treatments.

In conclusion, antioxidants play an important role inprotecting semen from ROS and can improve basic spermparameters in case of idiopathic oligoasthenoteratozoosper-mia.

Conflict of Interests

The authors declare that they have no conflict of interestsregarding the publication of this paper.

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