4. Male Infertility - A Critical Review

1. Introduction

2. Hormonal treatment

3. Anti-inflammatory therapy

4. Antibiotics

5. Anti-oxidants

6. a-Agonists

7. Parasympathomimetics

8. Mast-cell stabilizers/blockers

9. Phosphodiesterase-5

inhibitors (e.g., sildenafil,

tadalafil, vardenafil)

10. Non-specific

phosphodiesterase inhibitors

(e.g., pentoxifylline)

11. Conclusion

12. Expert opinion

Review

Male infertility: a critical reviewof pharmacologic managementAlaa J Hamada*, Brian Montgomery* & Ashok Agarwal††Glickman Urological and Kidney Institute, Center for Reproductive Medicine, Cleveland Clinic,

Cleveland, OH, USA

Introduction: Male factor infertility contributes partially and solely to the

problem of childlessness in around 50% of the cases. Unfortunately,

30 -- 50% of the etiologies of male infertility are unknown and therefore,

no specific therapy can be instituted. Evidence-based medical therapy for

male infertility is an attractive research area where a large number of clinical

trials, controlled and uncontrolled, using different types of medications have

been conducted yielding variable results and outcomes.

Areas covered: In this review, we summarize and evaluate the most important

and most recent information pertaining to the use of different medications in

male infertility and assign level of evidence to these medications. An exten-

sive literature search was performed using the search engines: Pubmed,

Science-direct, Ovid and Scopus.

Expert opinion: Male infertility represents a very challenging area of clinical

medicine. Many different types of medications have been tried and very few

have had satisfactory results. There is a huge need to advance and develop

andrologic diagnostic techniques, focusing on the metabolomics and proteo-

mics of the sperm, seminal plasma, and testicular tissue. Clarification of the

causes of idiopathic male infertility and the discovery of novel molecular

targets will help guide future innovative development of new pharmacologic

agents.

Keywords: male infertility, medical treatment, pregnancy outcome, semen analysis

Expert Opin. Pharmacother. [Early Online]

1. Introduction

The World Health Organization currently defines infertility as the inability of asexually active couple (at least three times per month), not using contraception, toachieve pregnancy within one year. About 15% of sexually active couples are infer-tile [1,2] and male factor infertility contributes to about 50% of the infertilitycases [2-4]. There are both known and unknown causes of male infertility, withidiopathic causes accounting for approximately 30 -- 50% of all the cases of maleinfertility [2,3,5]. Idiopathic male infertility is also known as idiopathic oligoastheno-teratozoospermia (iOAT), which indicates that the patient has unexplained abnor-malities in sperm parameters including low sperm concentration (£ 15 � 106 permL), reduced sperm motility (£ 40%), and abnormal sperm morphology (£ 4%normal forms) [6]. The list of known causes of male infertility is enormous andbroadly includes: varicocele, urogenital infections, immunologic factors (e.g., anti-sperm antibodies), sexual/ejaculatory inadequacy, congenital disorders (e.g.,Kallmann’s syndrome, Klinefelter’s syndrome, etc.), acquired urogenital abnormal-ities, and endocrine disorders [1-3,5]. Only a handful of the known causes of inferti-lity have a pharmacologic option as the first line of treatment. Known causes of maleinfertility tend to have targeted and effective treatment options, whereas idiopathiccases of infertility have non-specific or empirical treatment options withquestionable efficacy.

10.1517/14656566.2012.740011 © 2012 Informa UK, Ltd. ISSN 1465-6566 1All rights reserved: reproduction in whole or in part not permitted

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This review article will focus on the pharmacologic therapiescurrently available for treatment of male infertility and thelatest data on the efficacy of those therapies (data on efficacy,indications, and level of evidence is shown in Table 1).

2. Hormonal treatment

2.1 Pulsatile gonadotropin-releasing

hormone (GnRH)GnRH is a decapeptide that is produced within the hypotha-lamus and released in a pulsatile fashion to stimulate the releaseof follicle-stimulating hormone (FSH) and luteinizing hormone(LH) from the anterior pituitary. In men, FSH and LHare responsible for induction of spermatogenesis and steroido-genesis [7]. Pulsatile GnRH therapy attempts to simulate thenormal physiology of GnRH secretion and is used to replaceGnRH deficiency. Pulsatile GnRH, dosed at 5 -- 20 µg every120 min via a subcutaneous needle, has been unsuccessfullyused as an empirical therapy for idiopathic male infertility andas an effective specific treatment option for male infertility dueto hypogonadotropic hypogonadism (HH) (e.g., Kallmann’ssyndrome, isolated and idiopathic HH).In patients with HH, secondary sexual characteristics are

easily induced by exogenous testosterone administration, butfertility is mainly induced by either pulsatile GnRH or a com-bination of LH and FSH analogs. Multiple studies have shownthat pulsatile GnRH therapy is effective at increasing testicular

size and inducing spermatogenesis (requires approximately4 months of treatment) in patients with HH whose fertilitypotential is the main concern [8-13]. Pulsatile GnRH therapyinduces spermatogenesis in approximately 40% of patientswith HH [8] and small studies have found pregnancy rates inthe 50 -- 60% range [10,14]. Pulsatile GnRH therapy is verysimilar to gonadotropin therapy in terms of successful induc-tion of spermatogenesis [10], although pulsatile GnRH possiblyresults in a more rapid initiation of spermatogenesis [12]. Over-all, pulsatile GnRH is an effective and a generally well-toleratedtreatment option for those individuals with HH. PulsatileGnRH use is limited by its expensive cost, invasive delivery,and the need to regularly change subcutaneous needles. Inaddition, there are reported cases of anti-GnRH antibodiesdeveloping in a patient receiving pulsatile GnRH therapy [14].

Pulsatile GnRH has been considered as an empirical treat-ment option for idiopathic male infertility, but its invasivedelivery and cost has limited its use. One underpowered(n = 19), randomized, placebo-controlled study found nohormone or semen parameters improvements in men withidiopathic infertility treated for 12 weeks with a GnRH ana-log or saline [15]. The European Association of Urology doesnot recommend empirical use of pulsatile GnRH based onthe lack of controlled trials [5].

2.2 Gonadotropin therapyAs stated before, the anterior pituitary is responsible for pro-ducing and releasing the gonadotropins FSH and LH inresponse to GnRH. FSH and LH are responsible for inducingspermatogenesis and sex steroid production in the testes [7].The gonadotropin hCG is of placental origin and hashormonal effects that are similar to those of LH because itcontains subunits in its structure closely related to LH [16].Purified urinary extractions of hCG, FSH, and hMG (similarto FSH activity), along with recombinant forms of FSH andLH are available to treat patients with pituitary lesions orGnRH deficiencies and have been also tried as an empiricaltherapy in idiopathic male infertility.

Multiple well-designed studies have shown that gonadotro-pins are an effective treatment option for HH [10,17-19]. Typi-cal treatment is self-administered subcutaneous injections of75 -- 150 IU FSH or hMG thrice weekly plus1500 -- 2500 IU hCG twice weekly. Treatment is typicallycontinued until sperm appear in the ejaculate and/or a preg-nancy is induced. Studies have shown that gonadotropinsinduce spermatogenesis in 80 -- 96% of patients withHH [10,18,19]. Median treatment time to first sperm has beenshown to be approximately 5 -- 7 months [18,19]. The mediantreatment time to achieve conception is about 28 months andthe pregnancy rate is approximately 38 -- 51% [10,18]. Gona-dotropins have also been shown to increase testosterone levelsand average testicular volume with relatively few side-effects(e.g., gynecomastia) [10,19].

There are really no appreciable differences in pregnancy rateand spermatogenesis induction when comparing gonadotropin

Article highlights.

. About 15% of sexually active couples are infertile andmale factor infertility contributes to about 50% ofinfertility cases.

. Idiopathic male infertility constitutes at least 30% of allcases of male infertility.

. Medical therapy in male factor infertility is divided intospecific (etiology is known) and non-specific or empiric(etiology is unknown).

. Specific medical therapy is successful in 20% of malefactor infertility cases, particularly for certain etiologiesof male infertility such as urogenital infections,hypogonadotropic hypogonadism, hyperprolactinemia,and erectile dysfunction.

. Idiopathic male infertility represents a challengingsituation for clinicians, because many availablemedications have little or no beneficial effect.

. Hormonal therapy, anti-oxidants, anti-inflammatory agents, phosphodiesterase inhibitors,anti-estrogens and aromatase inhibitors often haveambiguous benefits in men with idiopathic infertilityand lack reproducibility in studies.

. Testosterone is strictly contraindicated as a treatmentoption for men with idiopathic infertility.

. Anti-oxidant use in idiopathic male infertility modestlyimproves pregnancy rates and live birth rates, withoutserious side-effects.

This box summarizes key points contained in the article.

A. J. Hamada et al.

2 Expert Opin. Pharmacother. [Early Online]

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Table

1.Overview

ofpharm

aco

logic

agents

usedformale

infertility.

Medication

Indication

Pregnancy

rate

Other

effects

Relative

cost

Delivery

Levelof

evidence

Reco

mmendation

level

Pulsatile

GnRH

HH

50--60%

htesticularsize

hsperm

atogenesis

$$$

subQ

II-1

B

iOAT

--------

$$$

subQ

IIII

Gonadotropin

(FSH,hCG,hMG)

HH

38--51%

htesticularsize

hsperm

atogenesis

$$$

subQ

orIM

II-1

B

iOAT

13.4%

*----

$$$

subQ

orIM

II

DopamineAgonist

HPRL

-----Norm

alizePRL

-Improve

sperm

parameters

hsexualfunction

$$

Oral

IA

iOAT

0--5%

-Noneseen

$$

Oral

ID

Anti-estrogen

iOAT

13--19%

-Improve

sperm

parameters

$$

Oral

II

Aromatase

Inhibitor

iOAT

0%

-Improve

sperm

parameters

htestosterone

$$

Oral

II-1

I

Corticosteroid

ASA

18--31%

*-Improve

sperm

parameters

$Oral

IC

NSAIDs

Leuko-cytosperm

ia----

ileukocytes

-Improve

sperm

parameters

$oral

IB

Antibiotic

Leuko-cytosperm

ia47%

*ileukocytes

$oral

IB

Anti-oxidant

iOAT

17%

*-Improve

sperm

parameters

$oral

II

a-Agonists

RE

34%

-Antegradeejaculation

$$

oral

IA

AE

2%


-Retrogradeejaculation

$$

Oral

II-1

D

Parasympathomim

etics

AE

2%


-Retrogradeejaculation

$$

Oral

II-1

D

Mast

cellblocker

iOAT

29%

*-Improve

sperm

parameters

$$

oral

II

PDE5i

iOAT

-----Improve

sperm

parameters

$$

oral

II

PTX

iOAT

0%

-Improve

sperm

parameters

$$

Oral

II

Levelofevidence

basedonU.S.Preventive

ServicesTask

Force(USPSTF)

system:LevelI:Evidence

obtainedfrom

atleast

oneproperlydesignedrandomizedcontrolledtrial;LevelII-1:Evidence

obtainedfrom

well-

designedcontrolledtrialswithoutrandomization;LevelII-2:Evidence

obtainedfrom

well-designedcohort

orcase-controlanalyticstudies,

preferably

from

more

thanonecenterorresearchgroup;LevelII-3:Evidence

obtainedfrom

multiple

timeserieswithorwithouttheintervention.Dramaticresultsin

uncontrolledtrialsmightalsoberegardedasthistypeofevidence;LevelIII:Opinionsofrespectedauthorities,

basedonclinical

experience,descriptive

studies,

orreportsofexpert

committees.

RecommendationsbasedonU.S.Preventive

ServicesTask

Force(USPSTF)

guidelines:

LevelA:Goodscientificevidence

suggeststhatthebenefits

oftheclinicalservicesubstantially

outw

eighthepotentialrisks.

Clinicians

should

discuss

theservicewitheligible

patients;LevelB:Atleast

fairscientificevidence

suggeststhatthebenefits

oftheclinicalserviceoutw

eighthepotentialrisks.

Cliniciansshould

discuss

theservicewitheligible

patients;LevelC:Atleast


suggeststhatthere

are

benefits

providedbytheclinicalservice,butthebalance

betw

eenbenefits

andrisksare

tooclose

formakinggeneralrecommendations.

Cliniciansneednotofferitunless

there

are

individualconsiderations;

LevelD:Atleast


suggeststhattherisksoftheclinicalserviceoutw

eighpotentialbenefits.Cliniciansshould

notroutinely

offer

theserviceto

asymptomaticpatients;LevelI:Scientificevidence

islacking,ofpoorquality,

orconflicting,such

thattherisk

versusbenefitbalance

cannotbeassessed.Cliniciansshould

help

patients

understandthe

uncertainty

surroundingtheclinicalservice.

*Statistically

significantcomparedto

placebo/notreatm

ent.

$:Low;$$:Moderate;$$$:High;AE:Anejaculation;ASA:Anti-sperm

antibodies;

HH:Hypogonadotropic

hypogonadism;HPRL:

Hyperprolactinemia;IM

:Intramuscular;iOAT:Idiopathic

oligoasthenoteratozo

osperm

ia;

PTX:Pentoxifylline;PDE5i:Phosphodiesterase-5

inhibitor;RE:Retrogradeejaculation;subQ:Subcutaneous;

USPSTF:

U.S.Preventive

ServicesTask

Force.

Male infertility: a critical review of pharmacologic management

Expert Opin. Pharmacother. [Early Online] 3

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therapy to pulsatile GnRH [10]. Gonadotropin therapy is aneffective, well-tolerated treatment option for HH that is typi-cally used as a first-line therapy over pulsatile GnRH therapydue to an easier route of administration. Patients are able toself-administer subcutaneous injections of FSH and hCG,whereas pulsatile GnRH requires a subcutaneous butterfly nee-dle placed by a healthcare professional approximately every2 days. Recombinant forms of FSH and LH are appealingwhen compared to urinary preparations because of theirsteady supply, dependable composition, purity, and specificactivity [20].Gonadotropins have been used to empirically treat men

with idiopathic infertility. A large meta-analysis (n = 278)including four randomized controlled trials [21-24] showedthat in comparison to placebo or no treatment, 3 months ofgonadotropins therapy significantly increased pregnancy ratein men with idiopathic infertility (13.4 vs. 4.4%, OR 3.03,95% CI 1.30 – 7.90) [25]. The number needed to treat toachieve one pregnancy was 12. Of note, two older meta-analyses found no significant improvement in pregnancyrate with gonadotropins treatment, but the inclusion criteriawere not as strict and some patients included utilized assistedreproductive technologies (ART) [26,27]. One study includedin the two meta-analyses mentioned in the previous sectionshowed no statistically significant improvement in pregnancyrate with intrauterine insemination (IUI) [28]. However, natu-ral pregnancy rate outside of the IUI cycle was 14.7% in theFSH treatment group versus 2.5% in the controlgroup [23,24,28]. Gonadotropins show marginal improvementsin pregnancy rates, but the high cost and invasive route ofdelivery limit the use. The European Association of Urologydoes not recommend the use of gonadotropins for idiopathicmale infertility due to a lack of unambiguous efficacy, whichmandates further conduction of additional well-designedrandomized, controlled trials to show their advantages [5].

2.3 Dopamine agonistsHyperprolactinemia is a known cause of male infertility and isclinically manifested with hypogonadism, impotence, andgalactorrhea [29]. Causes of pathologic hyperprolactinemia inmales include pituitary adenoma (prolactinomas, macro andmicroadenomas), idiopathic hyperprolactinemia, and emptysella syndrome [30]. Dopamine released from the hypothala-mus is largely responsible for the tonic inhibition of prolactinsecretion from the anterior pituitary [31]. Dopamine agonistshave successfully been used to treat male infertility due tohyperprolactinemia, but have shown little promise as anempirical therapy for idiopathic male infertility [27,32].Two dopamine agonists have been used and thoroughly

studied for pathologic hyperprolactinemia, i.e., bromocriptineand cabergoline. Cabergoline (0.5 -- 1 mg twice weekly) hasbeen shown to normalize prolactin levels in 83 -- 86% ofpatients with pathologic hyperprolactinemia compared to59% of patients treated with bromocriptine (2.5 -- 5.0 mgtwice weekly) [30,33]. Cabergoline has been shown to

normalize prolactin levels in 70% of bromocriptine-resistantpatients and only about 4% of patients had to stop themedication due to side-effects (e.g., headache, postural hypo-tension, nausea, and sleepiness) [30]. Cabergoline has beenshown to improve gonadal and sexual function in maleswith prolactinoma earlier than bromocriptine [34]. After6 months of treatment, prolactin levels were 7.9 ± 2.2 µg/lin the cabergoline treatment group, whereas prolactin levelsin the bromocriptine group were 16.7 ± 1.8 µg/l. In addition,at 6 months, the sperm concentration and motility were sig-nificantly higher in the cabergoline treatment group com-pared to the bromocriptine treatment group [34]. Similarly,Walia et al. reported a significant rise in seminal volume,sperm concentration, and motility following a 6-monthcourse of cabergoline in patients with macroprolactinoma [35].Interestingly, both De Rosa et al. and Colao et al. reportedthat cabergoline treatment for a longer period (24 months)leads to significant increases in sperm concentration andmotility, whereas, short-term administration (6 months) canlead to a reduction in serum prolactin and increase in testos-terone, LH, and FSH [36,37]. Pregnancies have been reportedin very few studies [38]. Although normalizing prolactin levelsin males improves gonadal and sexual function, there is a needfor studies with live pregnancy rate as a primary outcome.

Bromocriptine is not effective as an empirical therapyfor idiopathic male infertility and three studies showed nodifference between bromocriptine and placebo in terms ofpregnancy rate and sperm parameters [39-41]. Bromocriptineshould not be used to treat idiopathic male infertility, butstudies have not looked at newer dopamine agonists such ascabergoline in idiopathic oligozoospermia.

2.4 Estrogen receptor antagonist and aromatase

inhibitorsTestosterone is aromatized peripherally by a P450 cyto-chrome enzyme into estradiol, which in turn providesnegative feedback to the hypothalamus and pituitary. Thisfeedback decreases GnRH pulse frequency and decreasespituitary responsiveness to GnRH, which ultimately decreasesgonadotropin production [42]. Estrogen receptor antagonistand aromatase inhibitors both interfere with estrogen’snegative feedback, and therefore, may increase gonadotropinsecretion (FSH and LH enhancers), which in turn wouldstimulate spermatogenesis and steroidogenesis. Anotherspecific potential indication for estrogen receptor antagonistis direct interference with xenoestrogens which were foundto be higher in semen of infertile men [43,44]. These twotherapies have been explored as potential empirical therapiesfor idiopathic male infertility.

Estrogen receptor antagonists, also known as anti-estrogens, such as clomiphene and tamoxifen, act on bothendogenous and exogenous estrogens. Tamoxifen is a pureanti-estrogen, whereas clomiphene citrate is a non-steroidalsubstance with a strong intrinsic estrogenic effect and anti-estrogenic properties. This difference is important because

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there is concern that the estrogenic effect of clomiphene canpotentially have deleterious effects on spermatogenesis. How-ever, Katz et al. and Whitten et al. showed that clomiphenecan have substantial effects on serum testosterone levels inhypogonadal men [45,46]. Furthermore, Whitten et al. showedin small series that two of four hypogonadal men were able toinduce pregnancy [46].

The role of clomiphene citrate in normogonadal idiopathicmale infertility is controversial and the medication is consid-ered as off-label use. World health organization conducted arandomized, double-blind study on 1308 couples whenmale partners received 25 mg of clomiphene citrate dailyfor 6 months and found no significant effects on pregnancyrates or semen quality [47]. Several authors, however, com-bined clomiphene with anti-oxidants and showed modestbenefits. However, whether such improvement was attributedto clomiphene citrate or to the anti-oxidant is still unclear.Hussein et al. titrated doses of clomiphene in 42 menwith idiopathic non-obstructive azoospermia to achievetestosterone levels of 600 ng/dL to 800 ng/dL. Only 36%of the participants remained azoospermic, but they hadadequate sperm for intracytoplasmic sperm injection(ICSI) [48]. Adamopoulos et al. found that men with idio-pathic infertility treated with tamoxifen (10 mg twice daily)for 3 -- 6 months had a significant increase in sperm concen-tration, functional fraction, and testicular volume comparedto placebo [49].

Studies looking at aromatase inhibitors to treat idiopathicinfertility are limited and those that are available are small.Two types of aromatase inhibitors are available, steroidal(e.g., testolactone) and non-steroidal (letrozole and anastro-zole). The latter is more effective at increasing the testosteroneto estrogen ratio (T/E) and is less likely to cause interruptionof the adrenal axis beyond aromatase inhibition. Anastrozoleis the third most common medication used by Americanandrologists [50]. Aromatase inhibitors must be used with cau-tion because they increase the risk of developing osteoporosis(11%) and joint disorders (17%). Indications for clinical useinclude infertile men with hyperestrogenemia or low T/Eratio (< 10). Elevated estrogen level or estrogen/testosteroneratio is obviously observed in men with significant obesityand is associated with idiopathic HH and Klinefeltersyndrome.

A small study showed serum testosterone levels, sperm con-centration, sperm motility, and ejaculate volume significantlyincrease in men with idiopathic infertility treated withletrozole (2.5 mg for 6 months) [51]. Another small studywas unable to show any differences in testosterone, spermconcentration, semen quality, or pregnancy rate betweenmen with idiopathic infertility treated with testolactone (2 gdaily) or placebo [52].

Several studies have examined the role of aromatase inhi-bitors in infertile men with hyperestrogenemia (low T/Eratio) Raman et al. reported that therapy with testolactone(100 -- 200 mg/day) and/or anastrozole (1 mg/day) resulted

in a rise in T/E ratio and increase in semen parameters [53].Gregoriou et al. treated two groups (n = 29) of infertile menwith low T/E ratio with two different non-steroidal aromataseinhibitors (2.5 mg/day letrozole or 1 mg/day anastrozole) for6 months [54]. Both forms of treatment resulted in a signifi-cant improvement in serum testosterone, T/E ratio, semenvolume, sperm concentration, sperm motility, and reducedserum estradiol [54].

Interestingly, Ramasamy et al. demonstrated that medi-cations that lead to endogenous testosterone secretion (e.g.,aromatase inhibitors, clomiphene, or human chorionicgonadotropin) resulted in a better chance of sperm retrievalin men with Klinefelter’s syndrome with either normal orlow baseline testosterone compared to men with Klinefelter’ssyndrome who received exogenous testosterone to inducesecondary sexual characteristics (77 vs. 55%) [55]. This obser-vation can be attributed to the fact that exogenous testo-sterone suppresses the production of FSH and LH and,therefore, suppress spermatogenesis [55].

Due to a paucity of studies looking at pregnancy rateas a primary outcome, there is little evidence that anti-estrogens or aromatase inhibitors are effective empiricaltherapies for idiopathic infertility. Studies have indicatedthat these treatments may show more potential in infertilemen with low T/E ratios.

2.5 AndrogensTestosterone is fundamentally important for maintenance ofspermatogenesis and male sexual function. It was thoughtthat raising serum testosterone could improve epididymal func-tion and sperm maturation, whereas sudden withdrawal of tes-tosterone would result in a transient rise in gonadotropins andsperm concentration, which has been termed the “reboundeffect.” Testosterone, however, has contraceptive properties inmen due to its negative feedback on hypothalamic--pituitaryaxis and thus inhibition of LH, FSH, and spermatogenesis.Various meta-analyses have demonstrated that androgentherapy does not improve pregnancy rates in men with idio-pathic male infertility [26,27]. Based on the published literature,testosterone is contraindicated as a treatment option for maleinfertility. Surprisingly, a recent survey of 387 urologistsbelonging to the American Urologic Association reported that25% of the responders are still prescribing androgens forinfertile patients [50].

2.6 Combination therapyCombinations of different hormonal therapies and hormonaltherapies plus anti-oxidants have been studied as potentialempirical treatments for idiopathic male infertility. A largestudy (n = 212) showed tamoxifen (20 mg daily) (estrogenantagonist and FSH and LH enhancer in adult men) plustestosterone undecanoate (120 mg daily) for 6 months signi-ficantly increases sperm concentration and spontaneouspregnancy rate (33.9 vs. 10.3%, RR 3.195, 95% CI2.615 -- 3.765) compared to placebo [56]. Another study found



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that tamoxifen (20 mg daily) plus testosterone undecanoate(120 mg daily) resulted in a significant increase in sperm con-centration, motility, normal morphology, functional fraction,and testicular volume when compared to placebo. The samestudy found tamoxifen plus testosterone improved sperm func-tional fraction when compared to tamoxifen or testosteronealone [49]. Clinicians frequently recognize harmful effects of tes-tosterone administration on testicular function as it suppressespituitary secretion of LH and FSH. However, the above twostudies conducted by the same group of researchers demon-strated that testosterone undecanoate has minimal pituitarysuppressive influence and it mainly promotes epididymaldihydrotestosterone (DHT) secretion [57]. Furthermore, FSH-enhancing effects of tamoxifen might explain the beneficialeffects of the combination on the semen parameters.A randomized, controlled trial (n = 30) found clomiphene

citrate (25 mg) plus vitamin E (400 mg) daily resulted in asignificant increase in pregnancy rate (36.7 vs. 13.3%, OR3.76, 95% CI 1.03 -- 13.64) and sperm concentration whencompared to placebo [58].A few combination therapies have been proven to be mode-

rately effective in the treatment of idiopathic infertility, butthere are still many potential combinations that have yet tobe explored.

3. Anti-inflammatory therapy

3.1 CorticosteroidsAnti-sperm antibodies (ASA) interfere with sperm motility andsperm function, thereby reducing the chance of spontaneouspregnancy [59,60]. Corticosteroids have been tried as a specifictherapy for male infertility associated with ASA. One random-ized, double-blind crossover study (n = 43) compared prednis-olone treatment to placebo. The men were treated with 20 mgof prednisolone twice daily for the first 10 days of their part-ner’s menstrual cycle and then received 5 mg daily for days11 and 12. The treatment period was 9 months before cross-over and alcohol use was forbidden. Pregnancy rate was 31%(9/29) in the prednisolone group versus 10% (2/20) in placebogroup. There were no serious complications, but 60% of thepatients experienced mild side-effects (acne, weight gain,dyspepsia, and irritability) [61]. Another randomized, controlledtrial (n = 40) found 5 mg of prednisolone for 3 -- 6 monthssignificantly reduced the anti-sperm antibody titer, improvedsperm motility, and increased pregnancy rate when comparedto placebo (20 vs. 5%). No side-effects were reported in thisstudy [62]. Six randomized, controlled trials, including theabove two, were included in a meta-analysis with prednisolonedoses ranging from 5 to 96 mg daily. The two studies men-tioned above were the only studies to find a significant increasein pregnancy rate, but they were also the only studieswhere treatment lasted more than 3 months. Combining allthe studies resulted in an 18.3% (30/164) pregnancy rate inthe treatment group and 10.7% (16/150) pregnancy ratein the placebo group (OR 1.82, 95% CI 0.96 -- 3.42) [27].

The benefits of prednisolone therapy are at most modest andonly when used for greater than 3 months. Although rare, thepotential risk for serious side- effects such as weight gain, gen-eralized infections and avascular necrosis (AVN) of the femoralhead makes prednisolone less preferrable treatment option forinfertile men with ASA [26].

3.2 Non-steroidal anti-inflammatories (NSAIDs)Leukocytes are a common finding in seminal plasma of infer-tile males and have been shown to negatively affect spermfunction [63], but the link between abacterial leukocytosper-mia and male infertility is not completely clear [64,65]. NSAIDshave been tried as an empirical therapy for infertile males withabacterial leukocytospermia. Two studies found that 25 mg ofCOX-2 inhibitors (rofecoxib) daily for 30 days significantlyreduced leukocytospermia and improved sperm parameters(increased sperm concentration, motility, and normal mor-phology) [66,67]. Randomized, controlled trials with live birthrates as a primary outcome are needed to assess whether theimprovement in sperm parameters with COX-2 inhibitorsleads to increased fertility.

4. Antibiotics

Genitourinary (GU) infections are a potential cause of maleinfertility. Gallegos et al. found that GU infections increasesperm DNA fragmentation and decrease sperm concentra-tion, morphology, and motility [68]. Appropriate antibiotictreatment of GU infections has been shown to significantlyreduce sperm DNA fragmentation and improve sperm con-centration and motility [68]. There are notable differences inthe ability of different groups of antibiotics to penetrate thevarious areas of the male GU tract, and therefore, carefulselection is critical.

Antibiotics have been tried as an empirical therapy in infer-tile men with low-level leukocytospermia (0.2 -- 1.0 � 106

WBC/mL). One study administered doxycycline to34 patients with low-level leukocytospermia and comparedthem to 27 historical controls. No significant changes insemen parameters were seen in either group, but leuko-cytospermia resolved in 56% of the treatment group versusspontaneous resolution in 25% of the historical controls.The natural pregnancy rate in the treatment group was signi-ficantly greater than the pregnancy rate in the historicalcontrols (47 vs. 20%, OR 3.7, 95% CI 1.1 -- 11.7,p = 0.04) [69]. Another study (n = 53) found that leukocyto-spermia resolved in 68% of infertile men treated with antibi-otics and 53% of these men were able to induce pregnancycompared to only 6% of the men whose leukocytospermiawas unresponsive to antibiotic and were able to achievepregnancy [70]. Doxycycline, besides its broad anti-bacterialspectrum, has specific inhibitory effects on the generation ofreactive oxygen species by leukocytes. The use of antibioticsin patients with low-level leukocytospermia appears to be aneffective option.

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5. Anti-oxidants

Increased rates of infertility have been found in men withseminal fluid containing high levels of reactive oxygen species(ROS) [71,72]. Seminal fluid from men with idiopathic infertil-ity has been shown to be significantly associated with low totalanti-oxidant capacity and high oxidative stress [73]. Spermato-zoa membranes are largely composed of polyunsaturated fattyacids (PUFA), which makes them highly susceptible to free-radical lipid peroxidation [74]. ROS have been shown toreduce sperm motility [75-77], increase sperm DNA damage,and induce apoptosis of spermatozoa [78,79]. Anti-oxidanttherapy has been utilized as an empirical therapy for idio-pathic male infertility in an effort to reduce free radicals andin turn improve sperm function and fertility (see Table 2).Anti-oxidants are a broad medication category and are bestclassified as reducing agents which able to donate an electronto the free radical and become oxidized, e.g., ascorbic acid andlycopene, and catalytic agents which have no intrinsic electrondonation property but it enhances the natural anti-oxidantsystem in the body, e.g., carnitine and N-acetyl cysteine.

Showell et al. recently analyzed 34 randomized, controlledtrials with a total of 2876 couples dealing with idiopathicmale infertility [80]. Table 3 provides a summary of the resultsfrom this meta-analysis. Interventions used in studies withinthis meta-analysis included: combinations of anti-oxidants,carnitines, Coenzyme Q10, docosahexaenoic acid (DHA),magnesium, N-acetyl cysteine (NAC), pentoxifylline (PTX),selenium, vitamin C, vitamin E, and Zinc. Three of the stud-ies reported a total of 20 live births out of 214 couples, whichwas significantly greater than the controls (OR 4.85, 95% CI1.92 to 12.24; p = 0.0008). Fifteen of the studies looked atpregnancy rate (96 pregnancies out of 964 couples) and foundanti-oxidants had a significantly higher pregnancy rate whencompared to controls (OR 4.18, 95% CI 2.65 to 6.59;p < 0.00001). Sperm motility significantly increased with3 -- 6 months of anti-oxidant therapy, but not with 9 months.Sperm concentration significantly increased with 6 monthsof therapy, but not with 3 or 9 months. These spermparameter findings may diminishing sample size at 9 monthsor it may be a coincidence. Head-to-head comparisons ofdifferent types of anti-oxidants did not reveal any superioranti-oxidant in terms of pregnancy rate or sperm parameters,but this is likely due to low statistical power as there were onlya limited number of studies for each specific anti-oxidant. Noserious side-effects were noted and the most common anti-oxidant side-effect was GI upset, but it was statistically nodifferent than the rate seen in the control group. Overall,the included studies were very low quality due to inadequatemethodology descriptions, lack of head-to-head comparisons,wide confidence intervals, and high heterogeneity. Coupleswith idiopathic male infertility should be advised that currentevidence on the effectiveness of anti-oxidants is inconclusiveand that further randomized, placebo-controlled trials withpregnancy rates as an outcome are needed [80]. Two other

meta-analyses had similar results, reporting that both spermparameters and pregnancy rate improve with anti-oxidanttherapy [81,82].

Comhaire and Decleer pooled data (1013 couples) thatspecifically looked at pregnancy rates from the two largestmeta-analyses [80,81]. The pregnancy rate in the anti-oxidantgroup was 17.2% (88/512) versus 4.4% (22/501) in the con-trol group (RR 3.91, 95% CI 2.49 -- 6.14, p < 0.0001). Theauthors concluded that oral anti-oxidants quadrupledthe probability of spontaneous pregnancy within 3 monthsand also reduced the cost per pregnancy by 60% [83].

In addition to the need for additional studies with preg-nancy rate as an outcome, there is a need to further elucidatethe physiologic mechanisms and actions of anti-oxidants.Before discussing the anti-oxidants in the following section,it is important to note that unless stated specifically, few ofthese studies measured levels (plasma, serum, seminal orsperm) of anti-oxidants in patients before or after treatment.If a specific deficiency was not demonstrated, it is possiblethe effects were merely coincidental. We have tried to discuss,where available, large randomized, placebo-controlled trials inan effort to minimize this issue.

5.1 Vitamin CVitamin C (ascorbic acid) is a water-soluble, natural anti-oxidant that is capable of scavenging reactive oxygen species(ROS). Ascorbic acid is found in seminal plasma at concen-trations 10 -- 60 times the concentration in serum, whichemphasizes the importance of ascorbic acid in seminalplasma [84]. Low levels of seminal ascorbic acid are associatedwith significant increases in sperm-DNA damage [85]. Lowlevels of seminal ascorbic acid have also been found to be arisk factor for abnormal spermatozoa and idiopathic maleinfertility [86,87]. Ascorbic acid supplementation improvessperm parameters in healthy men [88] and protects spermDNA from oxidative damage [89]. Akmal et al. found thatmen with idiopathic infertility receiving 1000 mg vitamin Ctwice daily had significant increases in sperm concentration,sperm motility, and normal sperm morphology [90], but ran-domized, controlled trials with pregnancy rate as an outcomeare still needed.

5.2 Vitamin EVitamin E denotes a group of eight naturally occurring lipid-soluble compounds that contain chromanol rings (i.e., toco-pherols a, b, d, g and tocotrienols a, b, d, g). However,only a-tocopherol (the natural dietary form RRR-a-tocoph-erol and the synthetic form 2R-stereoisomeric all racemic-a-tocopherol) is maintained in human plasma and retained inbody tissues. Vitamin E forms are not interconvertible andonly a & g tocopherols are absorbed through the intestineand carried to the liver through chylomicrons. In the liver,the a-tocopherol transfer protein is responsible for preferen-tial secretion of a-tocopherol in human plasma with verylow-density, low-density, and high-density lipoproteins.



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Table

2.List

ofanti-oxidants

andtheir

effectsonmale

infertility.

Compound

Positiveeffect

onsp

erm

*Negative/noeffect

onsp

erm

Positiveeffect

on

pregnancy

rate*

Negative/noeffect

on

pregnancy

rate

Carnitines

Moradietal.,2010

[100]

Balercia

etal.,2005

[105]

Lenzi

etal.,2004

[101]

Cavallinietal.2004

[108]

Costaetal.,1994

[106]

Vitalietal.,1995

[103]

Moncadaetal.,1992

[104]

Sigmanetal.,2006

[107]

Lenzi

etal.,2004

[101]

Cavallinietal.2004

[108]

Sigmanetal.,2006

[107]

Balercia

etal.,2005

[105]

Carotenoids

Comhaireetal.,2005

[133]

Gupta

&Kumar,2002

[138]

----Comhaireetal.,2005

[133]

----

CoenzymeQ10

Balercia

etal.,2009

[112]

Safarinejad,2009

[113]

--------

Balercia

etal.,2009

[112]

Safarinejad,2009

[113]

Folate

----Wongetal.,2002

[139]

--------

Magnesium

----Zavaczkietal.,2003

[121]

----Zavaczkietal.,2003

[121]

NAC

Ciftcietal.,2009

[132]

Safarinejad,2009

[117]

Erkkila,etal.,1998

[131]

Oedaetal.,1997

[130]

--------

----

Omega-3

FASafarinejad,2011

[142]

--------

----Selenium

Safarinejad,2009

[117]

Scott

etal.,1998

[118]

----Scott

etal.,1998

[118]

----

Selenium

+NAC

Safarinejad,2009

[117]

--------

----

Vitamin

C(‡

1000mgdaily)

Colagar&Marzony,

2009

[86]

Pateletal.,2009

[87]

Akmaletal.,2006

[90]

Songetal.,2006

[85]

Fragaetal.,1991

[89]

Dawsonetal.,1990

[88]

Scottetal.,1998

[118]

--------

Vitamin

ESuleim

anetal.,1996

[94]

Kessopoulouetal.,1995

[95]

Scottetal.,1998

[118]

Suleim

anetal.,1996

[94]

Kessopoulouetal.,1995

[95]

Vitamin

E+C

Greco

etal.,2005

[143]

Rolfetal.,1999

[96]

----Rolfetal.,1999

[96]

Vitamin

E+Selenium

Keskes-Ammaretal.,2003

[146]

Vezinaetal.,1996

[145]

--------

----

Zinc

Colagaretal.,2009

[124]

Omuetal.,2008

[73]

Omuetal.,1998

[127]

Tikkiwaletal.,1987

[126]

Hartomaetal.,1977

[125]

Wongetal.,2002

[139]

Omuetal.,1998

[127]

----

*=statistically

significanteffect

(p<0.05).

A. J. Hamada et al.


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Table

2.List

ofanti-oxidants

andtheir

effectsonmale

infertility(continued).

Compound

Positiveeffect

onsp

erm

*Negative/noeffect

onsp

erm

Positiveeffect

on

pregnancy

rate*

Negative/noeffect

on

pregnancy

rate

Zinc+

Folate

Wongetal.,2002

[139]

--------

----Menevit

--------

Tremellenetal.,2007

[147]

----PTX

Safarinejad,2010

[179]

Okadaetal.,1997

[175]

Tesariketal.,1992

[171]

Micic

etal.,1988

[176]

Marramaetal.,1985

[177]

Wangetal.,1983

[178]

----Wangetal.,1983

[178]

PDE5i

Dim

itriadisetal.,2010

[165]

Pomara

etal.,2007

[166]

Glennetal.,2007

[168]

--------

----

*=statistically

significanteffect

(p<0.05).



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Table

3.Resu

ltsfrom

Coch

ranereview

onanti-oxidantuse

inmale

subfertility

[80].

Outcome

No.ofstudies

No.ofpatients

or

couples(T,C)

Anti-oxidants

usedin

trials

Durationof

treatm

ent

MD

(95%

CI)orOR(95%

CI)

pValue

Totalsperm

motility

10

514(302,212)

Combinations,

Carnitines,

CoQ10,DHA,

Magnesium,NAC,PTX,

Selenium,Vitamin

C,

Vitamin

E,Zinc

£3months

MD

11.72(6.94to

16.49)

<0.00001

7963(625,338)

Carnitines,

CoQ10,NAC,

Selenium,Vitamin

E6months

MD

4.19(3.81to

4.56)

<0.00001

3332(181,151)

Carnitines,

CoQ10

9months

MD

1.38(0.81to

1.95)

<0.00001

Sperm

concentration

7320(162,158)

Carnitines,

DHA,

Magnesium,NAC,PTX,

Vitamin

C,Vitamin

E

£3months

MD

6.04(-5.42to

17.50)

0.30

6825(536,289)

Carnitines,

CoQ10,NAC,

PTX,Selenium

6months

MD

5.25(4.43to

6.08)

<0.00001

3332(181,151)

Carnitines,

CoQ10

9months

MD

1.61(0.61to

2.61)

0.002

Sperm

DNA

fragmentation

164(32,32)

Vitamin

C,Vitamin

E2months

MD

-13.80(-17.50to

-10.10)

<0.00001

Pregnancy

rate

percouple

15(2

trials

includedcou-

plesusingART)

964(515,449)

Combinations,

Carnitines,

CoQ10,Magnesium,PTX,

Vitamin

C,Vitamin

E,

Zinc

2--9months

OR4.18(2.65to

6.59)

<0.00001

Live

birth

rate

percouple

3(1

trial

includedcou-

plesusingIVF

orICSI)

214(116,98)

Vitamin

E,Zinc

3--6months

OR4.85(1.92to

12.24)

0.0008

ART:Assistedreproductivetechnology;

C:Numberofpatients/couplesin

controlgroup;CI:Confidence

interval;CoQ10:CoenzymeQ10;DHA:Docosahexaenoic

acid;ICSI:Intracytoplasm

icsperm

injection;IVF:

Invitro

fertilization;MD:Meandifference;NAC:N-acetylcysteine;OR:Oddsratio;PTX:Pentoxifylline;T:numberofpatients/couplesin

treatm

ent(anti-oxidant)group.

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Vitamin E is described as a chain-breaking anti-oxidant thatprevents the propagation of free-radical reactions [91]. Naturalforms of vitamin E are sensitive to light and oxidation, andtherefore, esterification of the labile hydroxyl group on thechromanol ring can extend its half-life. Natural forms ofa-tocopherol (d-forms) are twice as active as synthetic formsand synthetic forms (dl-forms) are capable of inhibiting thenatural forms from entering cell membranes [92,93].

A meta-analysis of two randomized, controlled trials [94,95]

found men with idiopathic male infertility treated vitamin Ehad a live birth rate of 15% (10/67) compared to 0% (0/50)in the control groups (OR 6.44, 95% CI 1.72 -- 24.04) [80].However, different doses of synthetic forms were used in thesestudies (300 mg vs. 600 mg), which undermines drawingspecific conclusions about the best form or dose of vitaminE that should be used to treat infertile men. Furthermore,contradictory results were reported by Rolf et al. in theirrandomized, placebo-controlled trial exploring the protectiverole of vitamin E in infertile men who were given 800 mgof vitamin E for 56 days [96].

These controversies point out the importance of measuringsemen ROS levels before instituting vitamin E anti-oxidanttherapy, due to the fact that anti-oxidant therapy may notbe useful in infertile men without oxidative stress in theirsemen. In addition, high doses of vitamin E, especially syn-thetic forms, can act as pro-oxidants [97]. Due to these issues,studies are needed to assess the efficacy of natural forms ofa-tocopherol and optimum doses required for the treatmentof infertility in men suffering from oxidative stress.

5.3 Carnitines (L-acetyl carnitine and L-carnitine)Carnitines play an important role in generating cellular energyvia b-oxidation by transporting fatty acyl groups across theinner mitochondrial membrane. In mammals, the concentra-tion of free L-carnitine is highest in epididymal plasma andspermatozoa where it accumulates in both the free and acety-lated forms [98]. The increase in L-carnitine in the epididymallumen corresponds with the initiation of sperm motility [98].The mechanism of the anti-oxidant abilities of carnitineshas not fully been elucidated, but carnitines have been shownto scavenge ROS and inhibit lipid peroxidation [99]. Multipleplacebo-controlled studies have found that carnitines (2 -- 3 gdaily of LC plus LAC or LC alone for 3 -- 6 months) signi-ficantly improves sperm straight progressive velocity, totaloxyradical scavenging capacity, sperm motility, sperm concen-tration, and semen volume [100-106]. Sigman et al. found nosignificant improvement in semen parameters in men withidiopathic infertility taking LC plus LAC (2 -- 3 g daily for6 months), but the sample size was small (n = 12) [107].Meta-analysis of four randomized, controlled trials [101,107,108]

found LC plus LAC resulted in a pregnancy rate of 20%(19/96) in males with idiopathic infertility compared to3.4% (3/87) in the placebo group (OR 4.48, 95% CI1.77 -- 11.36) [80]. Although these studies did not reportthat oral carnitine therapy could raise semen carnitine level,

there is good evidence to suggest carnitines are mildly effec-tive at improving the fertility rates of men with idiopathicinfertility.

5.4 Coenzyme Q10It is well known that coenzyme Q10 (ubiquinone) is a funda-mental component of the electron transport chain, participa-ting in aerobic respiration and the generation of energy inthe form of ATP [109,110]. Coenzyme Q10 is ubiquitous inmembranes throughout eukaryotic cells [111], which ideallyplaces it to scavenge free radicals and prevent lipid peroxida-tion [110]. In addition to direct anti-oxidant activity, coenzymeQ10 helps restore other anti-oxidants, such as Vitamin Eand C, to their reduced state [109,110]. Randomized, placebo-controlled trials have found coenzyme Q10 (200 -- 300 mgdaily for 6 months) can significantly improve sperm motilityin males with idiopathic infertility [112,113]. Although statisti-cal significance was not achieved, Balercia et al. found thattreatment with 200 mg of Coenzyme Q10 daily for 6 monthsresulted in a 20% (6/30) pregnancy rate compared to a 10%(3/30) pregnancy rate in the placebo group [112]. These preg-nancy rates are similar to those seen in other anti-oxidant studies. A lack of studies with live birth rate outcomesleaves efficacy questionable.

5.5 SeleniumSelenium is a non-metal element that is an essential compo-nent of important anti-oxidant enzymes such as glutathioneperoxidase [114]. High levels of glutathione peroxidase andreductase found in sperms indicate that the glutathione sys-tem is an important defense mechanism against ROS [115].Selenium also plays an important role in sperm matura-tion [116]. A randomized, placebo-controlled trial (n = 468)found selenium (200 µg daily for 6 months) significantlyincreases sperm motility, concentration, and normal mor-phology in men with idiopathic infertility when comparedto placebo [117]. Another randomized, placebo-controlledstudy treated subfertile men with low plasma selenium levels(n = 69) with selenium, which significantly improved spermmotility, but had no effect on sperm concentration. An 11%pregnancy rate was seen in the treatment group versus 0%in the placebo group [118].

5.6 MagnesiumMagnesium is a co-factor for hundreds of enzymes involved incritical processes like nucleic acid synthesis and energy meta-bolism [119]. Magnesium deficiency correlates with increasesin ROS and lipid peroxidation, but the exact mechanism ofmagnesium’s anti-oxidant activity remains unknown [120].One small, randomized, placebo-controlled pilot study(n = 20) found 3000 mg magnesium-orotate for 3 monthsresulted in no significant improvement in sperm parametersor pregnancy rates [121]. This study was too small to assessthe impact of magnesium on idiopathic male infertility.Larger studies are needed.



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5.7 ZincZinc acts as a cofactor for approximately 100 metalloenzymesis involved in important biologic processes such as DNA tran-scription and protein synthesis. Zinc has direct anti-oxidanteffects and synergistically helps other anti-oxidants [122]. It isthought that zinc can occupy copper- and iron-bindingsites, thereby preventing copper- or iron-initiated lipidperoxidation [122]. Zinc is also thought to have membrane-stabilizing effects and anti-apoptotic properties [123]. Lowlevels of zinc in seminal plasma are associated with male infer-tility [124]. Higher levels of zinc in seminal plasma correlatesignificantly with increased sperm concentration and normalsperm morphology [124]. Early studies revealed zinc supple-mentation could improve sperm concentration, motility,and morphology [125,126]. Zinc sulfate (500 mg daily for3 months) significantly improved sperm concentration,motility, and fertilizing capacity, while reducing anti-spermantibody (ASA) and tumor necrosis factor-alpha (TNF-a)(inflammatory reactant) in a sizable randomized, controlledtrial (n = 100), although such a therapy did not significantlyraise semen zinc level [127]. The same treatment group had abirth rate of 22.5% (11/49) which was significantly higherthan the 4.3% (2/48) birth rate in the no-therapy group. Inaddition, there were eight live births (8/49) in the treatmentgroup which was significantly higher than the two livebirths (2/48) that occurred in the group receiving no therapy(p < 0.03) [127]. Of note, zinc was found to improvesperm parameters, reduce oxidative stress, decrease spermapoptosis, and decrease sperm DNA fragmentation, alone orin combination with vitamin E and C [73]. Zinc therapy hasmultiple effects on sperm physiology, but has not been shownto raise semen zinc levels. The complete activity spectrumand specific indications of zinc therapy for male infertilityare unclear.

5.8 N-acetyl cysteine (NAC)NAC is a precursor for reduced glutathione (GSH), andtherefore, can replenish this important anti-oxidant mecha-nism [128]. NAC can also directly scavenge ROS [128-130].NAC has been tried as a potential therapeutic option inmen with idiopathic infertility, because NAC has been shownto improve germ cell survival in seminiferous tubules [131],increase sperm motility, and reduce semen ROS [130]. Tworandomized, placebo-controlled trials looked at the effect ofNAC (600 mg daily for 6 months) on men with idiopathicinfertility and found NAC significantly improved spermparameters and semen oxidative status [117,132]. Once againdata on pregnancy rates are absent, but needed to fully assessthe impact of NAC on idiopathic male infertility.

5.9 Carotenoids (e.g., astaxanthin and lycopene)Carotenoids are considered to be powerful anti-oxidants thatcan scavenge ROS and inhibit lipid peroxidation [133-137].Comhaire et al. conducted a small, randomized, placebo-controlled trial that included 30 men with idiopathic

infertility [133]. Treatment consisted of 16 mg of astaxanthindaily for 3 months. Astaxanthin therapy only resulted in a sig-nificant decrease in ROS and Inhibin B and a significantincrease in sperm linear velocity. No significant changeswere seen in other semen parameters, zona-free hamsteroocyte test, testosterone levels, LH levels, or FSH levels. Thepregnancy rate in the treatment group was 54.5% (6/11) ver-sus 10.5% (2/19) in the placebo group [133]. The pregnancyrate in the treatment group seems excessively high whichmay be due to small sample size and emphasizes the needfor larger studies.

Another study included 30 men with idiopathic male infer-tility that were all treated with 2000 µg of lycopene twice dailyfor 3 months [138]. Semen analysis at the end of the studyrevealed that 66% of the patients had an improvement insperm concentration (p < 0.05), 53% had improved spermmotility (p <0.05), and 46% had improved sperm morphol-ogy. Of note, no changes were seen in patients with baselinesperm concentrations less than 5 million/mL, which mayprove to be an important cut-off point for future studies.Six pregnancies (20%) were reported in this study, whichis a comparable rate to that with other anti-oxidantsdiscussed [138]. Larger, randomized, placebo-controlled trialsare needed to truly assess the impact of carotenoids onidiopathic male infertility.

5.10 FolateFolate is essential to DNA synthesis, which in turn is a vitalcomponent of spermatogenesis. Wong et al. conducted a ran-domized, placebo-controlled study (n = 103) in which menwith idiopathic male infertility were treated with 5 mg offolate daily for 6 months [139]. There were no changes insperm parameters and pregnancy rate was not included asan outcome [139]. This large study demonstrates that folateshows little promise as a treatment option for idiopathicmale infertility.

5.11 Omega-3 fatty acidsDietary omega-3 polyunsatured fatty acids are thought tohave anti-inflammatory and anti-oxidant properties [140,141].Safarinejad conducted a double-blind, placebo-controlled,randomized study on 238 males with idiopathic infertilityto look at the effects of omega-3 fatty acids on semen para-meters [142]. Men in the treatment group received 1.84 g ofeicosapentaenoic (EPA) and docosahexaenoic acids (DHA)daily for 32 weeks. Statistically significant improvement insperm concentration, motility, and morphology was seenin the treatment group. In addition, concentrations of EPAand DHA were significantly greater in seminal plasma,RBCs, and sperm of the treatment group. Superoxide dis-mutase (SOD) and catalase-like activity were significantlygreater in the treatment group after the treatment period.Seminal plasma levels of EPA and DHA positively correlatedwith semen parameters and seminal plasma SOD-like andcatalase-like activity [142]. The inclusion of seminal and

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sperm EPA and DHA levels made this an excellent model forfuture studies of other anti-oxidants, but the lack ofpregnancy rate as a primary outcome leaves something tobe desired.

5.12 Anti-oxidant combinationsNumerous studies have looked at combinations of anti-oxidants for the treatment of idiopathic male infertility. Inaddition, pharmaceutical companies are producing andmarketing specific combinations of anti-oxidants for maleswith idiopathic male infertility. Greco et al. demonstrated ina randomized, controlled trial that 1 g of vitamin C plus 1 gvitamin E daily for 2 months significantly reduced(p < 0.001) the DNA fragmentation in spermatozoa whencompared to placebo, but had no effect on semen parame-ters [143]. Rolf et al. conducted a similar study (1 g vitaminC plus 800 mg vitamin E daily for 56 days) and found noimprovement in semen parameters or pregnancy rate [96].Scott et al. found vitamin A, C, and E together had no effecton semen parameters in men with idiopathic infertility [118].Another randomized, controlled trial (n = 42) treated patientsfor 3 months with vitamins A, C, and E plus NAC and zinc.This anti-oxidant combination significantly increased theodds of having a normal sperm concentration, but had noimpact on pregnancy rate after 12 months of follow-up [144].Vitamin E (400 mg daily) plus selenium (225 µg daily) sup-plementation for at least 3 months in men with idiopathicinfertility has been shown to significantly improve spermmorphology and motility [145,146] and to decrease MDA (lipidperoxidation marker) concentrations [146]. Safarinejad foundthat men with idiopathic infertility taking 6 months of sele-nium (200 µg daily) plus NAC (600 mg daily) had signifi-cantly increased sperm motility, concentration, normalmorphology, and ejaculate volume when compared toplacebo [117]. One randomized, placebo-controlled studyinvolving 60 men with idiopathic infertility looked at theuse of a commercial combination of anti-oxidants as an adju-vant to IVF-ICSI treatment. The specific combination capsulecontains 6 mg lycopene, 400 IU vitamin E, 100 mgvitamin C, 25 mg zinc, 26 mg selenium, 0.5 mg folate, and1000 mg garlic. The study found a pregnancy rate of 64%(23/36) in the treatment group compared to 38% (6/16) inthe placebo group (p = 0.077). There was also a significantimprovement (p = 0.046) in viable pregnancies at 13 weeksin the treatment group (38%, 20/52) compared to placebogroup (16%, 4/25) [147]. Of note, the pharmaceutical com-pany provided the capsules for the study. The anti-oxidantcombinations that have been studied thus far show no addedbenefit of certain anti-oxidants alone.

6. a-Agonists

Retrograde ejaculation is a rare cause of male infertility, butcan arise secondary to surgical damage to the hypogastricplexus during retroperitoneal lymph-node dissection or pelvic

operations [148] or can be due to neuropathy associated withmedical diseases such as diabetes mellitus [149]. Drugs witha-agonist properties include chlorpheniramine, phenylpropa-nolamine, midodrine, and imipramine. a-Agonist therapyincreases sympathetic tone at the bladder, thereby increasingpressures in the posterior urethra, which increases the likeli-hood of achieving antegrade ejaculation in a patient withretrograde ejaculation [148,150]. A recent review looked at sixsmall studies involving pharmacologic management of retro-grade ejaculation, including surgical causes, and found that11 out of 40 patients (28%) treated with a sympathomimeticachieved antegrade ejaculation [151]. The use of anti-cholinergics resulted in 22% (11/50) achieving antegradeejaculation [151]. Combinations of sympathomimetics andanti-cholinergics resulted in 39% (5/13) of patients achievingantegrade ejaculation [151]. The number of patients in thestudies was too small for a valid statistical comparison [151].

A larger meta-analysis (44 studies) by Kamischke and Nies-chlag found that the overall success rate of pharmacologicmanagement in treating retrograde ejaculation is 50% andconcluded that pharmacologic management should be consid-ered a first-line treatment for retrograde ejaculation [152]. Thehighest success rate (79%) was seen with 50 mg chlorphenir-amine plus phenylpropanalamine daily [152]. A 64% successrate was found with 25 -- 75 mg of imipramine daily and a56% success rate was found with 5 -- 40 mg of midodrinedaily [152]. A natural pregnancy rate of 34% (30/87) wasseen with a-agonist therapy (19 studies) [152]. The most com-mon side-effects of a-agonist therapy included dizziness,weakness, nausea, and sweating [152]. A newer meta-analysis(36 studies) found that imipramine and chlorpheniramineplus phenylpropanalamine have significantly higher reversalrates when compared to ephedrine [153].

a-Agonist therapy has also been used with less success totreat male infertility due to anejaculation. Causes of anejacu-lation in order of most to least common include spinal cordinjury, retroperitoneal lymph node dissection, idiopathic, dia-betes mellitus, multiple sclerosis, colorectal surgery, trauma,and myelitis [152]. A meta-analysis (29 studies) found thatonly 19% of patients with anejaculation (excluding spinalcord injury) achieved ejaculation [152]. Midodrine dosed at5 -- 30 mg daily had the greatest success rate at 54% [152].Only two natural pregnancies were reported out of127 patients [152]. A newer meta-analysis (40 studies) founda-agonistic treatment of anejaculation was significantly infe-rior to parasympathomimetic treatment of anejaculation [153].Of the a-agonist medications, midodrine was found to be sig-nificantly better at treating anejaculation than imipramine,pseudoephedrine, and ephedrine. a-Agonists are not recom-mended as a first-line treatment for anejaculation becauseelectrovibration stimulation and electroejaculation havemuch higher success rates [153].

A large, randomized, controlled trial (n = 128) found that7.5 -- 15 mg of midodrine daily in a stepwise approachreversed anejaculation in 57.4% (29.5% achieved antegrade



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ejaculation, 13.1% achieved retrograde ejaculation, and14.8% achieved antegrade plus retrograde ejaculation) ofpatients with anejaculation, excluding patients with anejacula-tion secondary to spinal cord injury [154]. No patients (0/64)in the placebo group achieved antegrade or retrograde ejacula-tion. The most favorable responses were seen among patientswith multiple sclerosis and least favorable responses were seenamong patients with bilateral sympathectomy [154]. Strongevidence reveals a-agonists are an excellent therapeutic optionfor patients with retrograde ejaculation, but better therapiesexist for patients with anejaculation.

7. Parasympathomimetics

To occur, antegrade ejaculation requires both sympatheticand parasympathetic stimulation [155]. Parasympathomimeticssuch as neostigmine and physostigmine have been used totreat anejaculation. Meta-analysis of 13 studies found a 51%overall success rate of parasympathomimetics in the treatmentof anejaculation [152]. Only six natural pregnancies out of396 patients were reported [152]. An updated meta-analysis found that parasympathetic drugs are significantlymore successful than a-agonistic drugs in the treatment ofanejaculation [153]. Neostigmine has been abandoned due toinvasive intrathecal delivery and severe side-effects includingautonomic dysreflexia and cerebral hemorrhage [156,157].Physostigmine can be administered subcutaneously andhas less severe side-effects (e.g., GI upset and orthostatichypotension) [152].

8. Mast-cell stabilizers/blockers

Increased numbers of mast cells in seminal fluid havebeen associated with idiopathic male infertility [158,159].Yamamoto et al. conducted a placebo-controlled, single-blind study in which 50 men with idiopathic infertilitywere randomly assigned to treatment with 300 mg of trani-last (mast cell blocker) daily or placebo for 3 months [160].The mast cell blocker group had a significantly higher preg-nancy rate than the placebo group (28.6 vs. 0%). Themast cell blocker group also had significantly improvedsperm concentration and motility compared to placebo [160].In an uncontrolled study, 55 men with leukocytospermiawere treated with 2 mg of ketotifen daily for 3 months [161].Sperm motility (p = 0.002) and sperm morphology(p = 0.002) significantly improved and semen WBC countsignificantly diminished to normal levels (p < 0.0001)after 12 weeks of treatment [161]. Ketotifen (2 mg for3 months) was recently tried as a post varicocelectomyadjunct therapy in a randomized, controlled trial including103 infertile men [162]. By 9 months post treatment, themast cell blocker group had a significantly greater pregnancyrate compared to placebo (41.17 vs. 21.15%, p < 0.05). Inaddition, the mast cell blocker group had a significantimprovement in sperm concentration, sperm motility, sperm

morphology, and sperm protamine content, plus a signifi-cant reduction in the mean value of seminal white bloodcells [162]. There is convincing evidence suggesting mast cellblockers are a good treatment option, but more studiesare needed.

9. Phosphodiesterase-5 inhibitors (e.g.,sildenafil, tadalafil, vardenafil)

Phosphodiesterase-5 inhibitors (PDE5-i) are well-known fortheir use in the treatment of erectile dysfunction, but theyhave also been considered as a possible treatment option foridiopathic male infertility. PDE5-i prevents the hydrolysis ofcGMP, thereby increasing intracellular levels of cGMP [163].It is thought that cGMP may play a role in sperm motilityand function, especially the acrosome reaction [164]. One ran-domized trial (n = 70) treated men with idiopathic infertilitywith 10 mg of vardenafil daily or 50 mg of sildenafil daily orplacebo for 3 months [165]. Sperm concentration, spermmotility, and normal sperm morphology significantlyincreased after treatment with PDE5-i [165]. PDE5-i alsoenhanced Leydig cell secretion of insulin-like-3 peptide [165].Another prospective, randomized, double-blind, crossoverstudy looked at the effects of sildenafil or tadalafil on18 patients with idiopathic male infertility [166]. Patientsreceived a single dose of sildenafil (50 mg) or tadalafil(20 mg) and semen samples were collected 1 or 2 h aftereach treatment. A significant increase in sperm motility wasseen after sildenafil treatment when compared to baseline,but a significant decrease in sperm motility was seen aftertreatment with tadalafil. The difference is thought to be dueto the fact that tadalafil also inhibits phosphodiesterase-11(PDE11) [166]. PDE11 has been shown to play an importantrole in spermatogenesis, sperm motility, and capacitance [167].Another study (n = 57) found that 100 mg of sildenafil signi-ficantly increases sperm motility at 1 and 2 h after treat-ment [168]. The study also found a statistically significantincrease in the proportion of acrosome-reacted sperm aftertreatment, which may be detrimental to fertility [168]. Thisemphasizes the importance of including pregnancy rate as aprimary outcome when investigating treatment options formale infertility.

10. Non-specific phosphodiesterase inhibitors(e.g., pentoxifylline)

Pentoxifylline’s mechanism of action involves the inhibitionof phosphodiesterase, which subsequently leads to an increasein intracellular cyclic adenosine monophosphate (cAMP) [169].cAMP is important to sperm motility, sperm respiration, andthe acrosome reaction [170-173]. Pentoxifylline reduces supe-roxide anions in vitro [174,175] and significantly increases spermmotility and normal sperm morphology in men withidiopathic infertility [175-177]. A small, randomized, placebo-controlled trial (n = 46) showed that 1200 mg of

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pentoxifylline daily for 6 months had no effect on pregnancyrate or sperm concentration in men with idiopathic infertil-ity [178]. A larger, randomized, placebo-controlled trial(n = 254) utilizing a smaller dose of pentoxifylline (800 mgdaily for 6 months) [179], found that treatment resulted in astatistically significant increase in sperm concentration, spermmotility, normal sperm morphology, and seminal SOD-like and catalase-like activity, but found no differences inserum hormones (testosterone, LH, FSH, PRL, TSH, andInhibin B) [179]. Again, pregnancy rate as a primary outcomeis absolutely necessary in further studies.

11. Conclusion

Pharmacologic therapy is only effective in a handful of knowncauses of male infertility. The pathophysiology behind thesespecific causes of male infertility is relatively well-defined andunderstood, which allowed for the development of specific phar-macologic agents to correct the problem. More research isneeded to delineate the pathophysiology behind idiopathicmale infertility in order to develop specific therapies. Based oncurrent data, hormonal therapies in general are a poor choicefor idiopathic male infertility due to questionable efficacy andrestrictive cost. At present, anti-oxidants appear to be the bestpharmacologic choice for empirical treatment of idiopathicmale infertility due to their low cost, high availability, goodsafety profile, and modest efficacy.

Many studies on infertility tend to focus on semen parametersas a primary outcome, but this outcome doesn’t necessarily cor-relate well with fertility rates. Studying the treatment of maleinfertility is inherently difficult due to length of time to achievepregnancy, the long human gestational period, and complexitiesof sexual relationships. A greater number of adequately poweredrandomized, controlled trials using live birth rates as aprimary outcome are needed to determine the most effectiveanti-oxidant, dosing, and combination treatments.

12. Expert opinion

Medical treatment of male infertility is a fascinating field forurologists, reproductive biology researchers, scientists, andpatients, as it allows for, when absolutely effective, reversalin the decline of man’s fertility potential by simply prescribingmedications. Assisted reproductive techniques (ART) areexpensive and their success rates are 40 -- 60% in the bestcenters. Although further research is necessary, an importantand growing area of infertility management is the use ofadjunct medical therapies with ART. Some medical therapiesmay improve the success rates of ART and thus reduce thecost from repeated cycles.

Male infertility of unknown origin constitutes around 50%of male infertility cases and is very difficult to treat. Specificmedical therapy is applied to around 20% of known etiologiesof male infertility, where such therapy eventually culminatesin improvement in semen parameters and pregnancy rates.

HH, urogenital infections, erectile dysfunction, anejaculation,and retrograde ejaculation (due to medical causes) are theonly areas where medical therapy has proven successful inrestoration of male fertility.

Both pulsatile GnRH analogs and combined LH and FSHtreatment are effective in reversing the basic hormonal defectsin HH, resulting in successful manifestation of secondarysexual characteristics, testicular enlargement and inductionof spermatogenesis (Level B). However, their therapeutic rolesin idiopathic male infertility have not been reproducible.Furthermore, the devastating consequences of exogenoustestosterone on infertile men, in the form of testicular atrophyand further deterioration of spermatogenesis, make it criticalto avoid such practice.

Dopamine agonists are effective in mitigating the patho-logic consequences of hyperprolactinemia on semen para-meters, hormonal profile and erectile function (Level A);however, no studies on improvement of pregnancy rateswere conducted. Again, their role in idiopathic male infertilityis limited.

Anti-estrogens were tried in many studies on idiopathicmale infertility as single agents or in combination with otheragents and they generally have limited therapeutic benefits(Level I). To combat idiopathic and obesity-related hyperes-trogenemia, several aromatase inhibitors were tested resultingin modest improvement in hormonal profile without sub-stantial effects on pregnancy rates (Level I). In addition,long-term use of these medications may lead to developmentof osteoporosis and joint pain.

For immune infertility, intracytoplasmic microinjection ofspermatozoa into the oocyte constitutes the best treatmentoption due to the fact that long-term use of high-dose cortico-steroids can lead to development of serious side-effects withno clear advantages on pregnancy rates (Level C).

Although the recent Cochrane review on use of oral anti-oxidants highlighted the therapeutic role of anti-oxidantsin idiopathic male infertility, such a conclusion may be jeop-ardized by the fact that the selected controlled studies useddifferent therapeutic agents. Oral anti-oxidants are generallysafe drugs even in high doses; however, it is unknown whethersuch a safety profile is applied to redox cells such as sperm.Use of anti-oxidants should be evidence-based and goal-directed. Therefore, estimation of the oxidative burden andspecific anti-oxidant deficiency in semen can be a solid indica-tion to select specific therapeutic anti-oxidant agents withgradual dose increase based on the observed improvement insemen parameters, semen anti-oxidant levels, oxidative stressparameters and pregnancy rates.

Idiopathic male infertility represents a challenging andfrustrating situation for clinicians, because many differentmedications have no outstanding benefits. Regimens such ashormonal therapies, anti-oxidants, anti-inflammatory agents,and phosphodiesterase inhibitors have been utilized as amonotherapy or in combinations, in both controlled anduncontrolled studies, but their beneficial influences seem to



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be ambiguous and lack reproducibility. There is a fundamen-tal need for advances in andrologic diagnostic techniques,focusing on metabolomics and proteomics of sperm, seminalplasma, and testicular tissue. This will allow for the elucida-tion and categorization of causes of idiopathic male infertility.In addition, the discovery of novel molecular targets isrequired to guide innovative research activity and thecreation of new pharmacologic agents directed at correctingspecific irregularities.The testes are immune-privileged organs, whose cells are pro-

tected by the blood--testis barrier. Many chemical compounds

are unable to penetrate inside the testes and therefore can’t exerttheir effects. Modern thinking is directed toward enhanceddelivery of these drugs to the testicular cells by non-toxic meanssuch as nanotechnology. When these advances come to fruition,we can expect more efficient therapies and more consistentresults.

Declaration of interest

The authors state no conflict of interest and have received nopayment in preparation of this manuscript.

BibliographyPapers of special note have been highlighted as

either of interest (�) or of considerable interest(��) to readers.

1. Rowe PJ, Comhaire FH. WHO manual

for the standardised investigation and

diagnosis of the infertile couple.

Cambridge University Press,

Cambridge; 2000

2. Irvine DS. Epidemiology and aetiology

of male infertility. Hum Reprod

1998;Apr13(Suppl 1):33-44

3. Nieschlag E, Behre HM, Nieschlag S.

Andrology: male reproductive health and

dysfunction. 3rd edition. Springer;

Heidelberg; New York: 2010

4. Farhi J, Ben-Haroush A. Distribution of

causes of infertility in patients attending

primary fertility clinics in Israel. Isr Med

Assoc J 2011;13(1):51-4

5. Dohle GR, et al. EAU guidelines on

male infertility. Eur Urol

2005;Nov48(5):703-11

6. Jungwirth A, Diemer T, Dohle GR,

et al. EAU guidelines on male infertility.

Epub. Uroweb, 2012. Available at:

http://www.uroweb.org/gls/pdf/

15_Male_Infertility_LR%20II.pdf

[Accessed June 1, 2012]

7. Conn PM, Crowley WF Jr.

Gonadotropin-releasing hormone and its

analogues. N Engl J Med

1991;Jan10324(2):93-103

8. Liu L, Banks SM, Barnes KM,

Sherins RJ. Two-year comparison of

testicular responses to pulsatile

gonadotropin-releasing hormone and

exogenous gonadotropins from the

inception of therapy in men with isolated

hypogonadotropic hypogonadism. J Clin

Endocrinol Metab

1988;Dec67(6):1140-5

9. Schopohl J. Pulsatile gonadotrophin

releasing hormone versus gonadotrophin

treatment of hypothalamic hypogonadism

in males. Hum Reprod

1993;Nov8(Suppl 2):175-9

10. Buchter D, Behre HM, Kliesch S,

Nieschlag E. Pulsatile GnRH or human

chorionic gonadotropin/human

menopausal gonadotropin as effective

treatment for men with

hypogonadotropic hypogonadism:

a review of 42 cases. Eur J Endocrinol

1998;Sep139(3):298-303

11. Raivio T, Falardeau J, Dwyer A, et al.

Reversal of idiopathic hypogonadotropic

hypogonadism. N Engl J Med

2007;Aug30357(9):863-73

12. Schopohl J, Mehltretter G,

von Zumbusch R, et al. Comparison of

gonadotropin-releasing hormone and

gonadotropin therapy in male patients

with idiopathic hypothalamic

hypogonadism. Fertil Steril

1991;Dec56(6):1143-50

13. Delemarre-Van de Waal HA. Induction

of testicular growth and spermatogenesis

by pulsatile, intravenous administration

of gonadotrophin-releasing hormone in

patients with hypogonadotrophic

hypogonadism. Clin Endocrinol (Oxf)

1993;May38(5):473-80

14. Blumenfeld Z, Frisch L, Conn PM.

Gonadotropin-releasing hormone

(GnRH) antibodies formation in

hypogonadotropic azoospermic men

treated with pulsatile GnRH--diagnosis

and possible alternative treatment.

Fertil Steril 1988;Oct50(4):622-9

15. Badenoch DF, Waxman J, Boorman L,

et al. Administration of a gonadotropin

releasing hormone analogue in

oligozoospermic infertile males.

Acta Endocrinol (Copenh)

1988;Feb117(2):265-7. Randomized controlled study.

16. Pierce JG, Parsons TF. Glycoprotein

hormones: structure and function.

Annu Rev Biochem 1981;50:465-95

17. Liu PY, Gebski VJ, Turner L, et al.

Predicting pregnancy and

spermatogenesis by survival analysis

during gonadotrophin treatment of

gonadotrophin-deficient infertile men.

Hum Reprod 2002;Mar17(3):625-33

18. Liu PY, Baker HW, Jayadev V, et al.

Induction of spermatogenesis and fertility

during gonadotropin treatment of

gonadotropin-deficient infertile men:

predictors of fertility outcome. J Clin

Endocrinol Metab 2009;Mar94(3):801-8

19. Burgues S, Calderon MD. Subcutaneous

self-administration of highly purified

follicle stimulating hormone and human

chorionic gonadotrophin for the

treatment of male hypogonadotrophic

hypogonadism. Spanish Collaborative

Group on Male Hypogonadotropic

Hypogonadism. Hum Reprod

1997;May12(5):980-6

20. Zitzmann M, Nieschlag E. Hormone

substitution in male hypogonadism.

Mol Cell Endocrinol

2000;Mar30161(1-2):73-88

21. Baccetti B, Piomboni P, Bruni E, et al.

Effect of follicle-stimulating hormone on

sperm quality and pregnancy rate.

Asian J Androl 2004;Jun6(2):133-7. Randomized controlled study.

22. Foresta C, Bettella A, Garolla A, et al.

Treatment of male idiopathic infertility

with recombinant human

follicle-stimulating hormone:

a prospective, controlled, randomized

clinical study. Fertil Steril

2005;Sep84(3):654-61. Randomized controlled study.

23. Kamischke A, Behre HM, Bergmann M,

et al. Recombinant human follicle

stimulating hormone for treatment of

A. J. Hamada et al.


Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y C

leve

land

Clin

ic o

n 11

/07/

12Fo

r pe

rson

al u

se o

nly.

http://www.uroweb.org/gls/pdf/15_Male_Infertility_LR%20II.pdf

http://www.uroweb.org/gls/pdf/15_Male_Infertility_LR%20II.pdf

male idiopathic infertility: a randomized,

double-blind, placebo-controlled, clinical

trial. Hum Reprod

1998;Mar13(3):596-603. Randomized controlled study.

24. Knuth UA, Honigl W, Bals-Pratsch M,

et al. Treatment of severe oligospermia

with human chorionic gonadotropin/

human menopausal gonadotropin:

a placebo-controlled, double blind trial.

J Clin Endocrinol Metab

1987;Dec65(6):1081-7

25. Attia AM, Al-Inany HG, Farquhar C,

Proctor M. Gonadotrophins for

idiopathic male factor subfertility.

Cochrane Database Syst Rev

2007(4):CD005071.. Meta-analysis.

26. Kamischke A, Nieschlag E. Analysis of

medical treatment of male infertility.

Hum Reprod 1999;Sep14(Suppl 1):1-23.. Meta-analysis.

27. Liu PY, Handelsman DJ. The present

and future state of hormonal treatment

for male infertility. Hum Reprod Update

2003;Jan-Feb9(1):9-23.. Meta-analysis.

28. Matorras R, Perez C, Corcostegui B,

et al. Treatment of the male with

follicle-stimulating hormone in

intrauterine insemination with husband’s

spermatozoa: a randomized study.

Hum Reprod 1997;Jan12(1):24-8

29. Segal S, Yaffe H, Laufer N,

Ben-David M. Male hyperprolactinemia:

effects on fertility. Fertil Steril

1979;Nov32(5):556-61

30. Verhelst J, Abs R, Maiter D, et al.

Cabergoline in the treatment of

hyperprolactinemia: a study in

455 patients. J Clin Endocrinol Metab

1999;Jul84(7):2518-22

31. Freeman ME, Kanyicska B, Lerant A,

Nagy G. Prolactin: structure, function,

and regulation of secretion. Physiol Rev

2000;Oct80(4):1523-631

32. De Rosa M, Zarrilli S, Di Sarno A, et al.

Hyperprolactinemia in men: clinical and

biochemical features and response to

treatment. Endocrine

2003;Feb-Mar20(1-2):75-82

33. Webster J, Piscitelli G, Polli A, et al.

A comparison of cabergoline and

bromocriptine in the treatment of

hyperprolactinemic amenorrhea.

Cabergoline Comparative Study Group.

N Engl J Med 1994;Oct6331(14):904-9

34. De Rosa M, Colao A, Di Sarno A, et al.

Cabergoline treatment rapidly improves

gonadal function in hyperprolactinemic

males: a comparison with bromocriptine.

Eur J Endocrinol

1998;Mar138(3):286-93

35. Walia R, Bhansali A, Dutta P, et al.

Recovery pattern of

hypothalamo-pituitary-testicular axis in

patients with macroprolactinomas after

treatment with cabergoline. Indian J

Med Res 2011;Sep134:314-19

36. De Rosa M, Ciccarelli A, Zarrilli S, et al.

The treatment with cabergoline for

24 month normalizes the quality of

seminal fluid in hyperprolactinaemic

males. Clin Endocrinol (Oxf)

2006;Mar64(3):307-13

37. Colao A, Vitale G, Cappabianca P, et al.

Outcome of cabergoline treatment in

men with prolactinoma: effects of a

24-month treatment on prolactin levels,

tumor mass, recovery of pituitary

function, and semen analysis. J Clin

Endocrinol Metab

2004;Apr89(4):1704-11

38. Laufer N, Yaffe H, Margalioth EJ, et al.

Effect of bromocriptine treatment on

male infertility associated with

hyperprolactinemia. Arch Androl

1981;Jun6(4):343-6

39. AinMelk Y, Belisle S, Kandalaft N, et al.

Bromocriptine therapy in

oligozoospermic infertile men.

Arch Androl 1982;Mar8(2):135-41

40. Hovatta O, Koskimies AI, Ranta T, et al.

Bromocriptine treatment of oligospermia:

a double blind study.

Clin Endocrinol (Oxf)

1979;Oct11(4):377-82

41. Lunglmayr G, Maier U, Spona J.

Therapy of idiopathic oligozoospermia

with bromicriptine. Results of a

prospective controlled study. Andrologia

1983;15(Spec No):548-53

42. Hayes FJ, Seminara SB, Decruz S, et al.

Aromatase inhibition in the human male

reveals a hypothalamic site of estrogen

feedback. J Clin Endocrinol Metab

2000;Sep85(9):3027-35

43. Richthoff J, Rylander L, Jonsson BA,

et al. Serum levels of

2,2’,4,4’,5,5’-hexachlorobiphenyl

(CB-153) in relation to markers of

reproductive function in young males

from the general Swedish population.

Environ Health Perspect

2003;Apr111(4):409-13

44. Rozati R, Reddy PP, Reddanna P,

Mujtaba R. Role of environmental

estrogens in the deterioration of male

factor fertility. Fertil Steril

2002;Dec78(6):1187-94

45. Katz DJ, Nabulsi O, Tal R, Mulhall JP.

Outcomes of clomiphene citrate

treatment in young hypogonadal men.

BJU Int 2012;Aug110(4):573-8

46. Whitten SJ, Nangia AK, Kolettis PN.

Select patients with hypogonadotropic

hypogonadism may respond to treatment

with clomiphene citrate. Fertil Steril

2006;Dec86(6):1664-8

47. World Health Organization.

A double-blind trial of clomiphene

citrate for the treatment of idiopathic

male infertility. Int J Androl

1992;15(4):299-307.. Meta-analysis.

48. Hussein A, Ozgok Y, Ross L,

Niederberger C. Clomiphene

administration for cases of nonobstructive

azoospermia: a multicenter study.

J Androl 2005;Nov-Dec26(6):787-91;

discussion 92-3

49. Adamopoulos DA, Nicopoulou S,

Kapolla N, et al. The combination of

testosterone undecanoate with tamoxifen

citrate enhances the effects of each agent

given independently on seminal

parameters in men with idiopathic

oligozoospermia. Fertil Steril

1997;Apr67(4):756-62

50. Ko EY, Siddiqi K, Brannigan RE,

Sabanegh ES Jr. Empirical medical

therapy for idiopathic male infertility:

a survey of the American Urological

Association. J Urol

2012;Mar187(3):973-8

51. Saylam B, Efesoy O, Cayan S. The effect

of aromatase inhibitor letrozole on body

mass index, serum hormones, and sperm

parameters in infertile men. Fertil Steril

2011;Feb95(2):809-11

52. Clark RV, Sherins RJ. Treatment of men

with idiopathic oligozoospermic

infertility using the aromatase inhibitor,

testolactone. Results of a double-blinded,

randomized, placebo-controlled trial with

crossover. J Androl

1989;May-Jun10(3):240-7

53. Raman JD, Schlegel PN. Aromatase

inhibitors for male infertility. J Urol

2002;Feb167(2 Pt 1):624-9

54. Gregoriou O, Bakas P, Grigoriadis C,

et al. Changes in hormonal profile and



Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y C

leve

land

Clin

ic o

n 11

/07/

12Fo

r pe

rson

al u

se o

nly.

seminal parameters with use of aromatase

inhibitors in management of infertile

men with low testosterone to estradiol

ratios. Fertil Steril 2012;98:48-51

55. Ramasamy R, Ricci JA, Palermo GD,

et al. Successful fertility treatment for

Klinefelter’s syndrome. J Urol

2009;Sep182(3):1108-13

56. Adamopoulos DA, Pappa A, Billa E,

et al. Effectiveness of combined

tamoxifen citrate and testosterone

undecanoate treatment in men with

idiopathic oligozoospermia. Fertil Steril

2003;Oct80(4):914-20

57. Koukkou E, Billa E, Kapolla N, et al. An

empiric treatment for idiopathic

oligozoospermia revisited: a 20-year

investigative saga. Andrologia

2012;Oct44(5):337-42

58. Ghanem H, Shaeer O, El-Segini A.

Combination clomiphene citrate and

antioxidant therapy for idiopathic male

infertility: a randomized controlled trial.

Fertil Steril 2010;May193(7):2232-5

59. Marshburn PB, Kutteh WH. The role of

antisperm antibodies in infertility.


60. Abshagen K, Behre HM, Cooper TG,

Nieschlag E. Influence of sperm surface

antibodies on spontaneous pregnancy

rates. Fertil Steril 1998;Aug70(2):355-6

61. Hendry WF, Hughes L, Scammell G,

et al. Comparison of prednisolone and

placebo in subfertile men with antibodies

to spermatozoa. Lancet

1990;Jan13335(8681):85-8

62. Omu AE, al-Qattan F,

Abdul Hamada B. Effect of low dose

continuous corticosteroid therapy in men

with antisperm antibodies on

spermatozoal quality and conception rate.

Eur J Obstet Gynecol Reprod Biol

1996;Nov69(2):129-34

63. Wolff H. The biologic significance of

white blood cells in semen. Fertil Steril

1995;Jun63(6):1143-57

64. Fedder J, Askjaer SA, Hjort T.

Nonspermatozoal cells in semen:

relationship to other semen parameters

and fertility status of the couple.

Arch Androl 1993;Sep-Oct31(2):95-103

65. Curi SM, Ariagno JI, Chenlo PH, et al.

Asthenozoospermia: analysis of a large

population. Arch Androl

2003;Sep-Oct49(5):343-9

66. Lackner JE, Herwig R, Schmidbauer J,

et al. Correlation of leukocytospermia

with clinical infection and the positive

effect of antiinflammatory treatment on

semen quality. Fertil Steril

2006;Sep86(3):601-5

67. Gambera L, Serafini F, Morgante G,

et al. Sperm quality and pregnancy rate

after COX-2 inhibitor therapy of infertile

males with abacterial leukocytospermia.

Hum Reprod 2007;Apr22(4):1047-51

68. Gallegos G, Ramos B, Santiso R, et al.

Sperm DNA fragmentation in infertile

men with genitourinary infection by

Chlamydia trachomatis and Mycoplasma.

Fertil Steril 2008;Aug90(2):328-34

69. Hamada A, Agarwal A, Sharma R, et al.

Empirical treatment of low-level

leukocytospermia with doxycycline in

male infertility patients. Urology

2011;Dec78(6):1320-5

70. Branigan EF, Spadoni LR, Muller CH.

Identification and treatment of

leukocytospermia in couples with

unexplained infertility. J Reprod Med

1995;Sep40(9):625-9

71. Sharma RK, Agarwal A. Role of reactive

oxygen species in male infertility.

Urology 1996;Dec48(6):835-50

72. Chen H, Zhao HX, Huang XF, et al.

Does high load of oxidants in human

semen contribute to male factor

infertility? Antioxid Redox Signal

2012;Apr1516(8):754-9

73. Omu AE, Al-Azemi MK, Kehinde EO,

et al. Indications of the mechanisms

involved in improved sperm parameters

by zinc therapy. Med Princ Pract

2008;17(2):108-16

74. Aitken RJ, Clarkson JS, Fishel S.

Generation of reactive oxygen species,

lipid peroxidation, and human sperm

function. Biol Reprod

1989;Jul41(1):183-97

75. de Lamirande E, Gagnon C. Reactive

oxygen species and human spermatozoa.

I. Effects on the motility of intact

spermatozoa and on sperm axonemes.

J Androl 1992;Sep-Oct13(5):368-78

76. de Lamirande E, Gagnon C. Reactive

oxygen species and human spermatozoa.

II. Depletion of adenosine triphosphate

plays an important role in the inhibition

of sperm motility. J Androl

1992;Sep-Oct13(5):379-86

77. Kovalski NN, de Lamirande E,

Gagnon C. Reactive oxygen species

generated by human neutrophils inhibit

sperm motility: protective effect of

seminal plasma and scavengers.

Fertil Steril 1992;Oct58(4):809-16

78. Lopes S, Jurisicova A, Sun JG,

Casper RF. Reactive oxygen species:

potential cause for DNA fragmentation

in human spermatozoa. Hum Reprod

1998;Apr13(4):896-900

79. Kothari S, Thompson A, Agarwal A,

du Plessis SS. Free radicals: their

beneficial and detrimental effects on

sperm function. Indian J Exp Biol

2010;May48(5):425-35

80. Showell MG, Brown J, Yazdani A, et al.

Antioxidants for male subfertility.

Cochrane Database Syst Rev

2011(1):CD007411.. Meta-analysis.

81. Ross C, Morriss A, Khairy M, et al.

A systematic review of the effect of oral

antioxidants on male infertility.

Reprod Biomed Online

2010;Jun20(6):711-23.. Meta-analysis.

82. Gharagozloo P, Aitken RJ. The role of

sperm oxidative stress in male infertility

and the significance of oral antioxidant

therapy. Hum Reprod

2011;Jul26(7):1628-40.. Meta-analysis.

83. Comhaire F, Decleer W. Quantifying the

effectiveness and cost-efficiency of food

supplementation with antioxidants for

male infertility. Reprod Biomed Online

2011;Sep23(3):361-2

84. Dawson EB, Harris WA, Rankin WE,

et al. Effect of ascorbic acid on male

fertility. Ann NY Acad Sci

1987;498:312-23

85. Song GJ, Norkus EP, Lewis V.

Relationship between seminal ascorbic

acid and sperm DNA integrity in

infertile men. Int J Androl

2006;Dec29(6):569-75

86. Colagar AH, Marzony ET. Ascorbic Acid

in human seminal plasma: determination

and its relationship to sperm quality.

J Clin Biochem Nutr

2009;Sep45(2):144-9

87. Patel S, Panda S, Nanda R, et al.

Influence of oxidants and anti-oxidants

on semen parameters in infertile males.

J Indian Med Assoc

2009;Feb107(2):78-80; 2

88. Dawson EB, Harris WA, Powell LC.

Relationship between ascorbic acid and

male fertility. World Rev Nutr Diet

1990;62:1-26

A. J. Hamada et al.


Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y C

leve

land

Clin

ic o

n 11

/07/

12Fo

r pe

rson

al u

se o

nly.

89. Fraga CG, Motchnik PA, Shigenaga MK,

et al. Ascorbic acid protects against

endogenous oxidative DNA damage in

human sperm. Proc Natl Acad Sci USA

1991;88(24):11003-6

90. Akmal M, Qadri JQ, Al-Waili NS, et al.

Improvement in human semen quality

after oral supplementation of vitamin C.

J Med Food 2006;Fall9(3):440-2

91. Brigelius-Flohe R, Traber MG. Vitamin

E: function and metabolism. FASEB J

1999;13(10):1145-55

92. Burton GW, Traber MG. Vitamin E:

antioxidant activity, biokinetics, and

bioavailability. Annu Rev Nutr

1990;10:357-82

93. Traber MG, Ramakrishnan R,

Kayden HJ. Human plasma vitamin E

kinetics demonstrate rapid recycling of

plasma RRR-alpha-tocopherol. Proc Natl

Acad Sci USA 1994;91(21):10005-8

94. Suleiman SA, Ali ME, Zaki ZM, et al.

Lipid peroxidation and human sperm

motility: protective role of vitamin E.

J Androl 1996;Sep-Oct17(5):530-7.. Meta-analysis.

95. Kessopoulou E, Powers HJ, Sharma KK,

et al. A double-blind randomized placebo

cross-over controlled trial using the

antioxidant vitamin E to treat reactive

oxygen species associated male infertility.

Fertil Steril 1995;Oct64(4):825-31.. Meta-analysis.

96. Rolf C, Cooper TG, Yeung CH,

Nieschlag E. Antioxidant treatment of

patients with asthenozoospermia or

moderate oligoasthenozoospermia with

high-dose vitamin C and vitamin E:

a randomized, placebo-controlled,

double-blind study. Hum Reprod

1999;Apr14(4):1028-33.. Meta-analysis.

97. Bowry VW, Mohr D, Cleary J,

Stocker R. Prevention of

tocopherol-mediated peroxidation in

ubiquinol-10-free human low density

lipoprotein. J Biol Chem

1995;Mar17270(11):5756-63

98. Jeulin C, Lewin LM. Role of free

L-carnitine and acetyl-L-carnitine in

post-gonadal maturation of mammalian

spermatozoa. Hum Reprod Update

1996;Mar-Apr2(2):87-102

99. Gulcin I. Antioxidant and antiradical

activities of L-carnitine. Life Sci

2006;Jan1878(8):803-11

100. Moradi M, Moradi A, Alemi M, et al.

Safety and efficacy of clomiphene citrate

and L-carnitine in idiopathic male

infertility: a comparative study. Urol J

2010;7(3):188-93

101. Lenzi A, Sgro P, Salacone P, et al.

A placebo-controlled double-blind

randomized trial of the use of combined

l-carnitine and l-acetyl-carnitine

treatment in men with

asthenozoospermia. Fertil Steril

2004;Jun81(6):1578-84

102. Cavallini G, Ferraretti AP, Gianaroli L,

et al. Cinnoxicam and L-carnitine/acetyl-

L-carnitine treatment for idiopathic and

varicocele-associated oligoasthenospermia.

J Androl

2004;Sep-Oct25(5):761-70; discussion

71-2.. Meta-analysis.

103. Vitali G, Parente R, Melotti C. Carnitine

supplementation in human idiopathic

asthenospermia: clinical results.

Drugs Exp Clin Res 1995;21(4):157-9

104. Moncada ML, Vicari E, Cimino C, et al.

Effect of acetylcarnitine treatment in

oligoasthenospermic patients.

Acta Eur Fertil 1992;Sep-Oct23(5):221-4

105. Balercia G, Regoli F, Armeni T, et al.

Placebo-controlled double-blind

randomized trial on the use of

L-carnitine, L-acetylcarnitine, or

combined L-carnitine and

L-acetylcarnitine in men with idiopathic

asthenozoospermia. Fertil Steril

2005;Sep84(3):662-71

106. Costa M, Canale D, Filicori M, et al.

L-carnitine in idiopathic

asthenozoospermia: a multicenter study.

Italian Study Group on Carnitine and

Male Infertility. Andrologia

1994;May-Jun26(3):155-9.. Meta-analysis.

107. Sigman M, Glass S, Campagnone J,

Pryor JL. Carnitine for the treatment of

idiopathic asthenospermia: a randomized,

double-blind, placebo-controlled trial.


108. Cavallini G, Ferraretti AP, Gianaroli L,

et al. Cinnoxicam and L-carnitine/acetyl-

L-carnitine treatment for idiopathic and

varicocele-associated oligoasthenospermia.

J Androl 2004;Sep-Oct25(5):761-70;

discussion 71-2

109. Ernster L, Dallner G. Biochemical,

physiological and medical aspects of

ubiquinone function.

Biochim Biophys Acta

1995;May241271(1):195-204

110. Crane FL. Biochemical functions of

coenzyme Q10. J Am Coll Nutr

2001;Dec20(6):591-8

111. Kalen A, Norling B, Appelkvist EL,

Dallner G. Ubiquinone biosynthesis by

the microsomal fraction from rat liver.

Biochim Biophys Acta

1987;Oct8926(1):70-8.. Meta-analysis.

112. Balercia G, Buldreghini E, Vignini A,

et al. Coenzyme Q10 treatment in

infertile men with idiopathic

asthenozoospermia: a placebo-controlled,

double-blind randomized trial.


113. Safarinejad MR. Efficacy of coenzyme

Q10 on semen parameters, sperm

function and reproductive hormones in

infertile men. J Urol

2009;Jul182(1):237-48

114. Rayman MP. The importance of

selenium to human health. Lancet

2000;Jul15356(9225):233-41

115. Alvarez JG, Storey BT. Lipid

peroxidation and the reactions of

superoxide and hydrogen peroxide in

mouse spermatozoa. Biol Reprod

1984;May30(4):833-41

116. Ursini F, Heim S, Kiess M, et al. Dual

function of the selenoprotein PHGPx

during sperm maturation. Science

1999;Aug27285(5432):1393-6.. Meta-analysis.

117. Safarinejad MR, Safarinejad S. Efficacy

of selenium and/or N-acetyl-cysteine for

improving semen parameters in infertile

men: a double-blind, placebo controlled,

randomized study. J Urol

2009;Feb181(2):741-51

118. Scott R, MacPherson A, Yates RW, et al.

The effect of oral selenium

supplementation on human sperm

motility. Br J Urol 1998;Jul82(1):76-80

119. Fawcett WJ, Haxby EJ, Male DA.

Magnesium: physiology and

pharmacology. Br J Anaesth

1999;Aug83(2):302-20

120. Rayssiguier Y, Durlach J, Gueux E, et al.

Magnesium and ageing. I. Experimental

data: importance of oxidative damage.

Magnes Res 1993;6(4):369-78

121. Zavaczki Z, Szollosi J, Kiss SA, et al.

Magnesium-orotate supplementation for

idiopathic infertile male patients:

a randomized, placebo-controlled clinical



Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y C

leve

land

Clin

ic o

n 11

/07/

12Fo

r pe

rson

al u

se o

nly.

pilot study. Magnes Res

2003;16(2):131-6

122. Zago MP, Oteiza PI. The antioxidant

properties of zinc: interactions with iron

and antioxidants. Free Radic Biol Med

2001;Jul1531(2):266-74

123. Chimienti F, Aouffen M, Favier A,

Seve M. Zinc homeostasis-regulating

proteins: new drug targets for triggering

cell fate. Curr Drug Targets

2003;May4(4):323-38

124. Colagar AH, Marzony ET, Chaichi MJ.

Zinc levels in seminal plasma are

associated with sperm quality in fertile

and infertile men. Nutr Res

2009;Feb29(2):82-8

125. Hartoma TR, Nahoul K, Netter A. Zinc,

plasma androgens and male sterility.

Lancet 1977;Nov262(8048):1125-6

126. Tikkiwal M, Ajmera RL, Mathur NK.

Effect of zinc administration on seminal

zinc and fertility of oligospermic males.

Indian J Physiol Pharmacol

1987;Jan-Mar31(1):30-4

127. Omu AE, Dashti H, Al-Othman S.

Treatment of asthenozoospermia with

zinc sulphate: andrological,

immunological and obstetric outcome.

Eur J Obstet Gynecol Reprod Biol

1998;Aug79(2):179-84

128. De Flora S, Cesarone CF, Balansky RM,

et al. Chemopreventive properties and

mechanisms of N-Acetylcysteine.

The experimental background. J Cell

Biochem Suppl 1995;22:33-41

129. Gressier B, Cabanis A, Lebegue S, et al.

Decrease of hypochlorous acid and

hydroxyl radical generated by stimulated

human neutrophils: comparison in vitro

of some thiol-containing drugs.

Methods Find Exp Clin Pharmacol

1994;Jan-Feb16(1):9-13

130. Oeda T, Henkel R, Ohmori H,

Schill WB. Scavenging effect of N-acetyl-

L-cysteine against reactive oxygen species

in human semen: a possible therapeutic

modality for male factor infertility?

Andrologia 1997;May-Jun29(3):125-31

131. Erkkila K, Hirvonen V, Wuokko E,

et al. N-acetyl-L-cysteine inhibits

apoptosis in human male germ cells in

vitro. J Clin Endocrinol Metab

1998;Jul83(7):2523-31

132. Ciftci H, Verit A, Savas M, et al. Effects

of N-acetylcysteine on semen parameters

and oxidative/antioxidant status. Urology

2009;Jul74(1):73-6

133. Comhaire FH, El Garem Y,

Mahmoud A, et al. Combined

conventional/antioxidant “Astaxanthin”

treatment for male infertility: a double

blind, randomized trial. Asian J Androl

2005;Sep7(3):257-62

134. Krinsky NI. Antioxidant functions of

carotenoids. Free Radic Biol Med

1989;7(6):617-35

135. Palozza P, Krinsky NI. The inhibition of

radical-initiated peroxidation of

microsomal lipids by both

alpha-tocopherol and beta-carotene.

Free Radic Biol Med 1991;11(4):407-14

136. Krinsky NI. Effects of carotenoids on

cells. Mol Aspects Med 1993;14(3):241-6.. Meta-analysis.

137. Liebler DC, McClure TD. Antioxidant

reactions of beta-carotene: identification

of carotenoid-radical adducts.

Chem Res Toxicol

1996;Jan-Feb9(1):8-11

138. Gupta NP, Kumar R. Lycopene therapy

in idiopathic male infertility--a

preliminary report. Int Urol Nephrol

2002;34(3):369-72

139. Wong WY, Merkus HM, Thomas CM,

et al. Effects of folic acid and zinc sulfate

on male factor subfertility:

a double-blind, randomized,

placebo-controlled trial. Fertil Steril

2002;Mar77(3):491-8

140. James MJ, Gibson RA, Cleland LG.

Dietary polyunsaturated fatty acids and

inflammatory mediator production. Am J

Clin Nutr 2000;Jan71(1 Suppl):343S-8S

141. Hodge WG, Schachter HM, Barnes D,

et al. Efficacy of omega-3 fatty acids in

preventing age-related macular

degeneration: a systematic review.

Ophthalmology

2006;Jul113(7):1165-72; quiz 72-3, 78

142. Safarinejad MR. Effect of

omega-3 polyunsaturated fatty acid

supplementation on semen profile and

enzymatic anti-oxidant capacity of

seminal plasma in infertile men with

idiopathic oligoasthenoteratospermia:

a double-blind, placebo-controlled,

randomised study. Andrologia

2011;Feb43(1):38-47

143. Greco E, Iacobelli M, Rienzi L, et al.

Reduction of the incidence of sperm

DNA fragmentation by oral antioxidant

treatment. J Androl

2005;May-Jun26(3):349-53

144. Paradiso Galatioto G, Gravina GL,

Angelozzi G, et al. May antioxidant

therapy improve sperm parameters of

men with persistent oligospermia after

retrograde embolization for varicocele?

World J Urol 2008;Feb26(1):97-102

145. Vezina D, Mauffette F, Roberts KD,

Bleau G. Selenium-vitamin E

supplementation in infertile men. Effects

on semen parameters and micronutrient

levels and distribution. Biol Trace

Elem Res 1996;53(1-3):65-83

146. Keskes-Ammar L, Feki-Chakroun N,

Rebai T, et al. Sperm oxidative stress and

the effect of an oral vitamin E and

selenium supplement on semen quality in

infertile men. Arch Androl

2003;Mar-Apr49(2):83-94

147. Tremellen K, Miari G, Froiland D,

Thompson J. A randomised control trial

examining the effect of an antioxidant

(Menevit) on pregnancy outcome during

IVF-ICSI treatment. Aust N Z J

Obstet Gynaecol 2007;Jun47(3):216-21. Randomized controlled study.

148. Goldwasser B, Madgar I, Jonas P, et al.

Imipramine for the treatment of sterility

in patients following retroperitoneal

lymph node dissection. Andrologia

1983;15(Spec No):588-91

149. Wabrek AJ. Sexual dysfunction associated

with diabetes mellitus. J Fam Pract

1979;Apr8(4):735-40

150. Yavetz H, Yogev L, Hauser R, et al.

Retrograde ejaculation. Hum Reprod

1994;Mar9(3):381-6

151. Jefferys A, Siassakos D, Wardle P. The

management of retrograde ejaculation:

a systematic review and update.

Fertil Steril 2012;Feb97(2):306-12

152. Kamischke A, Nieschlag E. Treatment of

retrograde ejaculation and anejaculation.

Hum Reprod Update

1999;Sep-Oct5(5):448-74

153. Kamischke A, Nieschlag E. Update on

medical treatment of ejaculatory

disorders. Int J Androl

2002;Dec25(6):333-44

154. Safarinejad MR. Midodrine for the

treatment of organic anejaculation but

not spinal cord injury: a prospective

randomized placebo-controlled double-

blind clinical study. Int J Impot Res

2009;Jul-Aug21(4):213-20. Randomized controlled study.

A. J. Hamada et al.


Exp

ert O

pin.

Pha

rmac

othe

r. D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y C

leve

land

Clin

ic o

n 11

/07/

12Fo

r pe

rson

al u

se o

nly.

155. Hershlag A, Schiff SF, DeCherney AH.

Retrograde ejaculation. Hum Reprod

1991;Feb6(2):255-8

156. Linsenmeyer TA, Perkash I. Infertility in

men with spinal cord injury. Arch Phys

Med Rehabil 1991;Sep72(10):747-54

157. Guttmann L, Walsh JJ. Prostigmin

assessment test of fertility in spinal man.

Paraplegia 1971;May9(1):39-51

158. Yamanaka K, Fujisawa M, Tanaka H,

et al. Significance of human testicular

mast cells and their subtypes in male

infertility. Hum Reprod

2000;Jul15(7):1543-7

159. El-Karaksy A, Mostafa T, Shaeer OK,

et al. Seminal mast cells in infertile

asthenozoospermic males. Andrologia

2007;Dec39(6):244-7

160. Yamamoto M, Hibi H, Miyake K. New

treatment of idiopathic severe

oligozoospermia with mast cell blocker:

results of a single-blind study.

Fertil Steril 1995;Dec64(6):1221-3

161. Oliva A, Multigner L. Ketotifen

improves sperm motility and sperm

morphology in male patients with

leukocytospermia and unexplained

infertility. Fertil Steril

2006;Jan85(1):240-3

162. Azadi L, Abbasi H, Deemeh MR, et al.

Zaditen (Ketotifen), as mast cell blocker,

improves sperm quality, chromatin

integrity and pregnancy rate after

varicocelectomy. Int J Androl

2010;Oct34(5 Pt 1):446-52

163. Dimitriadis F, Giannakis D,

Pardalidis N, et al. Effects of

phosphodiesterase-5 inhibitors on sperm

parameters and fertilizing capacity.

Asian J Androl 2008;Jan10(1):115-33

164. Revelli A, Ghigo D, Moffa F, et al.

Guanylate cyclase activity and sperm

function. Endocr Rev

2002;Aug23(4):484-94

165. Dimitriadis F, Tsambalas S, Tsounapi P,

et al. Effects of

phosphodiesterase-5 inhibitors on Leydig

cell secretory function in

oligoasthenospermic infertile men:

a randomized trial. BJU Int

2010;Oct106(8):1181-5. Randomized controlled study.

166. Pomara G, Morelli G, Canale D, et al.

Alterations in sperm motility after acute

oral administration of sildenafil or

tadalafil in young, infertile men.

Fertil Steril 2007;Oct88(4):860-5. Randomized controlled study.

167. Wayman C, Phillips S, Lunny C, et al.

Phosphodiesterase 11 (PDE11) regulation

of spermatozoa physiology. Int J

Impot Res 2005;May-Jun17(3):216-23

168. Glenn DR, McVicar CM, McClure N,

Lewis SE. Sildenafil citrate improves

sperm motility but causes a premature

acrosome reaction in vitro. Fertil Steril

2007;May87(5):1064-70

169. Essayan DM. Cyclic nucleotide

phosphodiesterases. J Allergy

Clin Immunol 2001;Nov108(5):671-80

170. Tesarik J, Mendoza C, Carreras A.

Effects of phosphodiesterase inhibitors

caffeine and pentoxifylline on

spontaneous and stimulus-induced

acrosome reactions in human sperm.

Fertil Steril 1992;Dec58(6):1185-90

171. Tesarik J, Thebault A, Testart J. Effect

of pentoxifylline on sperm movement

characteristics in normozoospermic and

asthenozoospermic specimens.

Hum Reprod 1992;Oct7(9):1257-63

172. Garbers DL, First NL, Gorman SK,

Lardy HA. The effects of cyclic

nucleotide phosphodiesterase inhibitors

on ejaculated porcine spermatozoan

metabolism. Biol Reprod

1973;Jun8(5):599-606

173. Nassar A, Mahony M, Morshedi M,

et al. Modulation of sperm tail protein

tyrosine phosphorylation by

pentoxifylline and its correlation with

hyperactivated motility. Fertil Steril

1999;May71(5):919-23

174. Gavella M, Lipovac V.

Pentoxifylline-mediated reduction of

superoxide anion production by human

spermatozoa. Andrologia

1992;Jan-Feb24(1):37-9

175. Okada H, Tatsumi N, Kanzaki M, et al.

Formation of reactive oxygen species by

spermatozoa from asthenospermic

patients: response to treatment with

pentoxifylline. J Urol

1997;Jun157(6):2140-6

176. Micic S, Hadzi-Djokic J, Dotlic R,

Tulic C. Pentoxifyllin treatment of

oligoasthenospermic men. Acta Eur Fertil

1988;May-Jun19(3):135-7

177. Marrama P, Baraghini GF, Carani C,

et al. Further studies on the effects of

pentoxifylline on sperm count and sperm

motility in patients with idiopathic

oligo-asthenozoospermia. Andrologia

1985;Nov-Dec17(6):612-16

178. Wang C, Chan CW, Wong KK,

Yeung KK. Comparison of the

effectiveness of placebo, clomiphene

citrate, mesterolone, pentoxifylline, and

testosterone rebound therapy for the

treatment of idiopathic oligospermia.

Fertil Steril 1983;Sep40(3):358-65

179. Safarinejad MR. Effect of pentoxifylline

on semen parameters, reproductive

hormones, and seminal plasma

antioxidant capacity in men with

idiopathic infertility: a randomized

double-blind placebo-controlled study.

Int Urol Nephrol 2011;Jun43(2):315-28. Randomized controlled study.

AffiliationAlaa J Hamada*1 MD, Brian Montgomery*2 &

Ashok Agarwal†3 PhD HCLD†Author for correspondence

*Both authors are contributed equally1Research Fellow in Andrology/Male Infertility,

Glickman Urological and Kidney Institute,

Center of Reproductive Medicine, Cleveland

Clinic, 9500 Euclid Avenue,

Cleveland, OH 44195, USA2Research intern,

Glickman Urological and Kidney Institute,

Center of Reproductive Medicine,

Cleveland Clinic,

9500 Euclid Avenue, Cleveland, OH 44195,

USA3Professor, Lerner College of Medicine,

Director, Center for Reproductive Medicine,

Director, Andrology Laboratory,

Cleveland Clinic, Desk A19.1,

9500 Euclid Avenue, Cleveland,

OH 44195, USA

Tel: +1 216 444 9485;

Fax: +1 216 445 6049;

E-mail: [email protected]



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Documents

4. Male Infertility - A Critical Review