Engaging Practicing Gynecologists in the Management of Infertile Men

13 Pages·2015·0.63 MB·English

TheJournalofObstetricsandGynecologyofIndia(March–April2015)65(2):75–87
DOI10.1007/s13224-014-0623-3
INVITED REVIEW ARTICLE
Engaging Practicing Gynecologists in the Management
of Infertile Men
Agarwal Ashok • Hamada Alaa • Esteves Sandro C.
Received:22August2014/Accepted:16September2014/Publishedonline:5November2014
(cid:2)FederationofObstetric&GynecologicalSocietiesofIndia2014
About the Author
Dr.AshokAgarwalistheDirectoroftheAndrologyCenterHeadofResearchattheCenterforReproductiveMedicine.He
holdsthesepositionsatClevelandClinic,whereheisaProfessorattheLernerCollegeofMedicineofCaseWesternReserve
University;and,since1993,SeniorStaffintheGlickmanUrologicalandKidneyInstitute,Obstetrics-Gynecology;andinthe
Women’s Health Institute, Anatomic Pathology, and Immunology. Ashok is active in basic and clinical research, and his
laboratoryhastrainedmorethan500basicscientistsandclinicalresearchersfromtheUnitedStatesandover50countries.
His current research interests are identifying biological markers of oxidative stress, DNA damage, and apoptosis using
proteomicresearchtoolsandbioinformaticsanalysisaswellaspreservingfertilityinpatientswithcancer.
Abstract Inthemodernera,contemporarymanagementof oftenthefirstphysicianswhoencounteraninfertilecouple,it
maleinfertilityhasundergonegroundbreakingchangeswith is essential that these clinicians are continuously updated
the introduction of new concepts, advanced testing, and about the new pearls and pitfalls of male infertility man-
therapeutic interventions. As practicing gynecologists are agement. Semen analysis is commonly ordered by gyne-
cologists.In2010,theWHOreleasednewcutoffreference
values forthe semen parametersadoptingnovel methodol-
AgarwalA.(&),Professor,Director
ogy,whichhasincitedmuchdebate.Referencevalueshave
LernerCollegeofMedicine,AndrologyCenterandCenterfor
beenloweredincomparisonwithpreviousstandards,witha
ReproductiveMedicine,ClevelandClinic,MailCodeX-11,
10681CarnegieAvenue,Cleveland,OH44195,USA direct clinical implication in decision-making strategies.
e-mail:[email protected] Specialized sperm-function tests, such as sperm oxidative
stress and sperm chromatin integrity assessments, became
HamadaA.
clinically available, thus offering an opportunity to better
DepartmentofUrology,ColumbiaUniversity,NewYork,USA
e-mail:[email protected] understand sperm dysfunctions concealed during routine
semen analysis. Furthermore, the initial counseling of
EstevesS.C.,Director
azoospermic men by an andrologically well educated
AndrologyandHumanReproductionClinic,ANDROFERT,Av.Dr.
gynecologist may alleviate the misconception and distress
HeitorPenteado,1464,Campinas,SP13075-460,Brazil
e-mail:[email protected] surroundingthefalsebeliefofsterility,andwillclarifythe
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Agarwaletal. TheJournalofObstetricsandGynecologyofIndia(March–April2015)65(2):75–87
availableoptionsofpercutaneousandmicrosurgicalsperm- quality with no previous history of fertility problems, in
retrieval techniques and assisted conception outcome. associationwithnormalfindingsonphysicalexaminationand
Regarding varicocele, which is commonly seen in infertile endocrinelaboratorytesting[6].UnexplainedMFIisreserved
males, it is now clear that the best treatment option for forinfertilemenwithsemenprofileswithinnormalranges,and
infertile men with clinical varicocele is the microsurgical in whom female infertility factors have beenruled out. This
vein ligation. Natural conception is significantly improved category accounts for 6–27 % of male infertility, and it
after varicocelectomy, and recent data suggest that such strongly dependsonhowexhaustive is theevaluationofthe
treatment optimizes reproductive outcome of couples male patient [5]. Table 1 depicts the male infertility history
undergoing ICSI or micro-TESE sperm retrieval. Lastly, outline, and Table 2 shows the distribution of the causes of
new therapeutic interventions, including oral antioxidant MFIinatertiarycarecenter[8,9].
therapyandlifestylemodifications,havegainedincreasing
attention,astheyaidinalleviatingmaleinfertility.
Gynecologist’s Role in the Initial Male Workup
Keywords Gynecologist (cid:2) Male infertility (cid:2)
Semen analysis (cid:2) Azoospermia (cid:2) Varicocele (cid:2) AthoroughhistoryandapreliminarySAmustbeobtained
Assisted reproductive technique (cid:2) Sperm function beforereferringthemalepartnertoanurologist.Advanced
maleageandalongstandinghistoryofinfertilityarenegative
factorsforfecundity,similartofemaleinfertility.Secondary
Introduction male infertility is often associated with correctable causes
such as varicocele, infection, and ejaculatory problems. A
Male factor infertility (MFI), alone or combined with history of early miscarriages or fetal genetic abnormalities
female factor infertility, accounts for approximately 50 % maysuggestamalefactorcontribution[10,11].Otherhis-
of fertility problems [1]. MFI has undergone revolutionary tory components should include sexual, family, childhood,
changes in terms of diagnostic and treatment options, anddevelopmentalandsurgicalhistoryoftheinfertilecou-
particularly in the last two decades. The objective of this ple,aswellasthepresenceofsystemicmedicalconditions.
article is to provide a better understanding of the evolving Aspaternalageincreases,theconceptionratedecreases,
conceptsinthefieldofmaleinfertilitytogynecologistsand and the risk of genetic defects in offspring rises. Sperm
all health professionals involved in reproductive medicine. chromosomal aneuploidy increases with paternal age as
well. By around age 35, both sperm DNA fragmentation
and germ cell apoptosis start to rise [12–14], while semen
Definitions volume, sperm morphology, and motility decline [15–17].
The risk of having a child with autosomal dominant dis-
The World Health Organization (WHO) defines male fac- ordersforoldermenisequaltothatofhavingachildwith
torinfertilityasthepresenceofabnormalitiesinthesemen Down syndrome for women aged[45 years [18].
analysis (SA), or the presence of sexual or ejaculatory A detailed history about current use of medication is
dysfunction [2]. However, a male infertility factor may be also important. Antihypertensive drugs such as alpha- and
present even when the semen analysis is normal. The beta-blockers, thiazide diuretics, and spironolactone may
results of SA within normal ranges, as conventionally cause erectile and ejaculatory dysfunction. Calcium-chan-
assessed for sperm count, motility, and morphology, have nel blockers may negatively impact sperm-fertilizing
low predictive power of only 60 % to forecast the occur- abilitybyblockingtheacrosomereaction.Antibioticssuch
rence of a natural pregnancy [3]. as gentamicin, erythromycin, and nitrofurantoin are go-
Normal daily sperm production is about 40 million and nadotoxic [19]. Cimetidine, spironolactone, certain hor-
declineswithaging.Thedurationofspermatogenesishasbeen monal preparations, and anabolic steroids may alter the
recentlyfoundtobeabout60 daysinsteadof70 ± 4 daysas hypothalamic–pituitary gonadal axis, thus affecting sper-
hadpreviouslybeendescribedforpastmanyyears[4].Sperm matogenesis [20]. Cancer treatments such as radiotherapy
productionessentiallycorrespondstotheinteractiveoutcome and chemotherapy also decrease sperm production.
ofbiological,physical,andoccupationalfactors,actingwithin Obesity has been also linked with male subfertility [21,
thepreceding2 monthsfromejaculation.Knownmaleinfer- 22]. Obesity is associated with altered semen parameters
tility etiologies include reversible and correctable causes to [23–25]. Furthermore, reduced sperm DNA integrity is
uncorrectable ones. These etiologies may be inherited or common in infertile obese men [26]. These changes are
acquired.In37–58 %ofthecases,MFIhasanunknownorigin, attributedtohighestrogenproductionfromfatstoresand/or
whichcanbeidiopathicandunexplained[5–7].IdiopathicMFI high accumulation of fertility-jeopardizing environmental
is characterized by an unexplained impairment in semen toxinsinfattytissue.Occupationalexposuretotoxicantsand
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Table1 Clinicalmaleinfertilityhistoryoutline Table2 Distribution of diagnostic categories of couples seeking
infertilityevaluationinamaleinfertilityclinic*
1.Infertilityhistory
Ageofpartners,timeattemptingtoconceive Category N %
Contraceptivemethods/duration
Varicocele 629 21.9
Previouspregnancy(actualpartner/otherpartner)
Infectious 72 2.5
Previoustreatments
Hormonal 54 1.9
Treatments/evaluationoffemalepartner
Ejaculatorydysfunction 28 1.0
2.Sexualhistory
Systemicdiseases 11 0.4
Potency,libido,lubricantuse
Idiopathic 289 10.0
Ejaculation,timedintercourse,frequencyofmasturbation
Normal/femalefactor 492 17.1
3.Childhoodanddevelopment
Immunologic 54 1.9
Cryptorchidism,hernia,testiculartrauma
Obstruction 359 12.5
Testiculartorsion,infection(e.g.,mumps)
Cancer 11 0.4
Sexualdevelopment,pubertyonset
Cryptorchidism 342 11.9
4.Personalhistory
Genetic 189 6.6
Systemicdiseases(diabetes,cirrhosis,hypertension)
Testicularfailure 345 11.9
Sexuallytransmitteddiseases,tuberculosis,viralinfections
Total 2,875
5.Previoussurgeries
*Androfert,Brazil
Orchidopexy,herniorraphy,orchiectomy(testicularcancer,
torsion)
Retroperitonealandpelvicsurgery
seminiferous tubules, epididymis, and accessory sex
Otheringuinal,scrotal,andperinealsurgery
glands. Physical properties of semen such as viscosity,
Bariatricsurgery,bladdernecksurgery,transurethralresectionof
color, and pH are assessed as well as semen volume and
theprostate
several microscopic parameters including sperm concen-
6.Gonadotoxinexposure
tration, motility(percentage ofmotile sperm),morphology
Pesticides,alcohol,cocaine,marijuanaabuse
(percentage of normally shaped sperm), viability (per-
Medication(chemotherapyagents,cimetidine,sulfasalazine,
centage of living sperm), and number of leukocytes [28].
nitrofurantoin,allopurinol,colchicine,thiazide,b-anda-
blockers,calciumblockers,finasteride) Thesemenparametersfromsameindividualsarehighly
Organicsolvents,heavymetals variable due to factors such as duration of ejaculatory
abstinence, activity of the accessory sex glands, analytic
Anabolicsteroids,tobaccouse
errors, and inherent biological variability [29–31]. Clini-
Hightemperatures,electromagneticenergy
ciansshouldrequestatleasttwoSAsfollowing2–5 daysof
Radiation(therapeutic,nuclearpowerplantworkers),etc.
ejaculatoryabstinencetoassessthebaselinesemen-quality
7.Familyhistory
status [32, 33].
Cysticfibrosis,endocrinediseases
Guidelines for evaluation, such as those issued by the
Infertilityinthefamily
American Urological Association and European Associa-
8.Currenthealthstatus
tion of Urology, rely to a large extent upon the concept of
Respiratoryinfection,anosmia
abnormal SA for management [6, 34]. These recommen-
Galactorrhea,visualdisturbances
dations understate the limitations of the SA results and do
Obesity
not discuss the paradigm shift that is likely to occur in
referralsandmanagementinthelightoftherecentchanges
exposuretoexcessiveheatfromsaunaandhottubsaredet- intheWHOreferencethresholds[35,36].Muchdebatehas
rimental to sperm production [20]. The use of pesticides, taken place thereafter, and a series of reports have ques-
radiationexposurefromX-ray,excessiveuseofcellphones, tioned the validity of the newly released reference values
and heavy metal intoxication may also potentially affect [36–38]. Table 3 highlights the cutoff values for SA as
spermproductionandquality[27]. published in consecutive WHO guidelines [35, 36]
Recommendation for treatment has been also based on
the results of SAs. Current guidelines for varicocele indi-
Semen Analysis cate that treatment should be offered to men with clinical
varicocele in the presence of abnormal semen parameters
Semen analysis is the corner stone of infertility evaluation [39, 40]. Application of the new WHO reference values
as it provides information on the functional status of the might lead to patients, earlier deemed to be candidates for
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Agarwaletal. TheJournalofObstetricsandGynecologyofIndia(March–April2015)65(2):75–87
varicocele repair, now being considered ineligible for defects in the DNA structure including single or double
treatmentiftheirsemenparametersareabovecutofflimits. DNA strand breaks, base deletion or modification, inter-
Of note, the most recent report on varicocele by the strand or intrastrand DNA crosslinkage, and protamine
American Society for Reproductive Medicine acknowl- mispackage via defective DNA–protein crosslinking [60].
edged the limitations of the routine SA and included the Sperm with damaged DNA although defective may still
presence of an abnormal sperm-function test as an indica- retain the ability to fertilize the ova. However, such DNA
tion for treatment [40]. damage has been associated with several infertility phe-
Yetanotherexampleisspermmorphologythresholdsof notypes, such as unexplained and idiopathic infertility,
which were lowered to 4 % in the 2010 WHO guidelines repeated IUI and IVF failures, and recurrent miscarriage
compared with 14 % prescribed in the previous 1999 [61–67]. Furthermore, the increased risks of imprinting
standards [41–43]. Infertility specialists recommend intra- defects and cancer in the offspring have been linked with
cytoplasmicsperminjection(ICSI)insteadofconventional sperm DNA damage [68, 69].
IVF or intrauterine insemination (IUI) in situations when Several assays used to measure sperm DNA damage are
the morphology results are below 4 %, owing to the basedondifferentprinciplesandthereforedifferintheirability
markedly lower pregnancy outcomes of these two treat- todetectDNAdamage[59,70].InTable 4,wesummarizethe
ment methods when using semen with low percentage of principles and interpretations of the most commonly used
normal sperm [44, 45]. Interestingly, the results of distri- assays.Acomprehensivereviewaboutthemethodstomeasure
bution of SA of fertile men in centiles, as shown by the spermDNAdamagecanbefoundelsewhere[51].
new WHO standards, clearly show that, although 5 % of
the studied men had morphology values below the 4 % Reactive Oxygen Species Testing
cutoff point, they still initiated an unassisted pregnancy
within 12 months of unprotected intercourse [35, 36]. Spermreactiveoxygenspecies(ROS)arethebyproductsof
Physicians treating infertile couples should exercise cir- oxygenmetabolism,whichinsmallconcentrationsregulate
cumspection when interpreting the results of routine SA physiological cellular functions such as capacitation,
because it is only a tool among several others for deter- acrosomal reaction, hyperactivation, and the fusion with
mining clinical care. The male infertility evaluation has to theoocyte[71].Insemen,leukocytesandspermatozoaare
be complemented with a proper physical examination, a the two main sources for ROS. In sperm, ROS are gener-
comprehensive history taking, and relevant endocrine, ated by both the NADPH oxidase and NADH-dependent
genetic, and other investigations [46, 47]. oxido-reductase systems at the plasma membrane and
mitochondrial levels, respectively [72]. When ROS levels
increase disproportionately, mainly due to the presence of
Current Sperm Function Tests superoxide, hydroxyl radicals or nitric derivatives, com-
pared with the neutralizing capacities of intracellular and
Before the advent of ICSI, tests which assessed antisperm extracellular antioxidants; or when a reduction in the
antibodies [48], sperm hyperactivation and acrosome antioxidant capacity occurs, OS is sustained.
reaction,spermbinding,andpenetrationtothehumanzona ROS can modify lipids, proteins, and DNA through a
pellucida were widely used both to investigate males with variety of oxidative mechanisms [71, 73] causing lipid
unexplained infertility and to predict the fertilizing poten- peroxidation, protein carbomoylation, and oxidized DNA,
tial of sperm in conventional IVF. respectively. Oxidative DNA modifications can sustain
Our improved understanding of the molecular mecha- serious damages to DNA, such as point mutations, poly-
nisms controllingspermfunctionenabledthe development morphisms,deletions,chromosomalrearrangements,frame
of new diagnostic tests, particularly oxidative stress (OS), shifts, and single-stranded or double-stranded breaks [74].
and nuclear DNA integrity testing [49–51]. These markers The assays to measure ROS, their principle, methodol-
cannot be detected by routine SA but seems to better cor- ogy, clinical utility, and drawbacks are summarized in
relate with the male fertility status than the latter [52–58]. Table 5 [75–77].
Sperm Chromatin Integrity Testing
Genetic Conditions Associated with Male Infertility
Sperm DNA damage is the loss of DNA integrity, and it
may occur at any level in vivo during spermatogenesis, Approximately 6 % of infertile men have chromosomal
spermiogenesis, epididymis transit, or in vitro when sper- abnormalities;therateisevenhigher(*16 %)inmenwith
matozoa are prepared for assisted conception [59]. Sperm azoospermia [78]. Sex chromosomal aneuploidy (Kline-
DNA damage is a broad term that accounts for many felter syndrome [KS]; 47, XXY) is the most common
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Table3 CutoffreferencevaluesforsemencharacteristicsaspublishedinconsecutiveWHOmanuals
Semen WHO1980 WHO1987 WHO1992 WHO1999 WHO2010a
characteristics
Volume(mL) ND C2 C2 C2 1.5
Spermcount(106/mL) 20–200 C20 C20 C20 15
Totalspermcount(106) ND C40 C40 C40 39
Totalmotility(%motile) C60 C50 C50 C50 40
Progressivemotilityb C2c C25% C25%(gradea) C25%(gradea) 32%(a?b)
Vitality(%alive) ND C50 C75 C75 58
Morphology(%normalforms) 80.5 C50 C30d (14) 4f
Leukocytecount(106/mL) \4.7 \1.0 \1.0 \1.0 \1.0
ND not defined, ART assisted reproductive techniques, G-band karyotype Giemsa band karyotype, CFTR cystic fibrosis transmembrane con-
ductanceregulator
a Lowerreferencelimitobtainedfromthelowerfifthcentilevalue
b Grade a=rapid progressive motility ([25lm/s); grade b=slow/sluggish progressive motility (5–25lm/s); Normal=50% motility
(gradesa?b)or25%progressivemotility(gradea)within60minofejaculation
c Forwardprogression(scale0–3)
d Arbitraryvalue
e Valuenotdefinedbutstrictcriterionissuggested
f Strict(Tygerberg)criterion
chromosomal disorder in infertile men and is generally orAZFbmicrodeletionsnormallyprecludeasperm-retrieval
associated with hypotrophic or atrophic testicles, elevated attemptasthereisnoevidencethattesticularspermcanbe
serum FSH levels and azoospermia or severe oligozoo- foundirrespectiveoftheretrievalmethod.However,incases
spermia. In men with KS presenting with azoospermia, with AZFc microdeletion, sperm can be retrieved in 50–
sperm are present in approximately 20–50 % of cases on 71 %ofpatients[84].Clinicalpregnancyratesarevirtually
testicular exploration, and pregnancy rates associated with the same as those of idiopathic azoospermic patients [87].
ICSI range from 30 to 50 % [79]. Men with KS can have However,theoffspringofafatherwithYCMDwillinherit
biologicaloffspringwithanormalkaryotypebecausegerm the same genetic trait. The main indications for genetic
cells are usually euploid (46, XY) and thus can form nor- testing in male infertility and the tests used to assess such
mal, haploid gametes [80]. conditionsarehighlightedinTable 6.
The long arm (q) of Y-chromosome contains genes
regulating spermatogenesis [81]. The Y-chromosome Themostcommongeneticsperm-transportdisorderisthe
region related to infertility is called azoospermia factor congenitalbilateralabsenceofthevasdeferens(CBAVD).
locus (AZF). This locus can harbor complete or partial Approximately80 %ofmenpresentingwithCBAVDhave
microscopic deletions, isolated or in combination, in sub- mutation inthe cystic fibrosis transmembrane conductance
regions called AZFa, AZFb, and AZFc (Fig. 1). regulator (CFTR) gene, located on the long arm of chro-
Yq chromosome microdeletions (YCMDs) are found in mosome 7. Depending on the extension of the mutation,
15 %ofmenwithazoospermiaandin6 %ofmenpresenting cysticfibrosiscanmanifestinafullclinicalpresentation(an
withsevereoligozoospermia(\1million/mL)[78,82,83]. autosomic recessive potentially fatal disease) or in a mild
Forspermcountsbetween1and5 million/mL,thedetection form, i.e., CBAVD, which affects approximately 1.3 % of
rate drops down to1.7 %[84].YCMD affectingtheAZFc infertilemen[88].Thefemalepartnershouldalsobetested
region usually results in severe oligozoospermia or azoo- fortheCFTRmutation;shemaybeacarrier(approximately
spermia. Patients with AZFa microdeletions generally 4 % risk). Such testing should be done before the man’s
presentwithgermcellaplasiaontesticularhistopathology, sperm is used for assisted conception because the cystic
whilemostpatientswithAZFbmicrodeletionspresentwith fibrosisgenecanbetransmittedtooffspring[87].
maturation arrest [85, 86]. To test for YCMD, peripheral
bloodisobtained,andpolymerasechainreactionisusedto
amplify the long arm of the Y-chromosome, which will Varicocele
identifydeletionsoftheAZFregions.YCMDscreeningmay
alsopredictthechanceofspermretrieval(SR)forcandidates Varicocele is an elongated, dilated, and tortuous testicular
ofassistedconception.ThefindingsofcompleteAZFaand/ veininthespermaticcord.Itisidentifiedin7and10–25 %of
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Agarwaletal. TheJournalofObstetricsandGynecologyofIndia(March–April2015)65(2):75–87
prepubertal and postpubertal males, respectively [89, 90]. After varicocelectomy, the chances of natural conception
Higher prevalence in elderly males and in men with sec- increase 2.8-fold [104], and varicocele repair is more cost
ondaryMFIsuggestsittobeaprogressivedisease[91,92]. effective than ART [105].
Recent data suggest that varicocele causes infertility by In azoospermic men with favorable testicular histopa-
inducing ultrastructural testicular changes and OS, with thology, clinical varicocele repair may lead to sperm
implicationsfortheseminalantioxidantcapacityandsperm appearance in the ejaculate [106]. As such, IVF/ICSI can
chromatinintegrity[93–95].Abnormalitiesofsemenparam- beperformedwithouttheneedtosurgicallyretrievesperm.
eters in patients with varicocele are variable and involve Sperm-retrieval success rates seems to be increased in
sperm count, motility, and morphology [96, 97]. Men with azoospermic men with treated varicocele compared with
varicocelewerealsoshowntohavelowertestosteronelevels, untreatedones[107].Livebirthrateswerealsoshowntobe
aswellasreducedtesticularsizeonthesamesideofvaricose significantly higher in men who had the varicocele treated
vesselscomparedtothosewithoutvaricocele[98,99]. before ICSI (46.2 %) compared to those undergoing ICSI
Physical examination with the patient standing in a in the presence of a clinical varicocele (31.4 %) [108].
warmroomiscurrentlythepreferredmethodforvaricocele
diagnosis and has a sensitivity and specificity of around
70 %comparedwithotherdiagnostictools[100,101].The Azoospermia
most widely used classification is as follows:
Azoospermiaisdefinedbythecompleteabsenceofspermcells
• Grade 3: visible and palpable at rest (Fig. 2)
in the ejaculate after centrifugation without implying an
• Grade 2: palpable at rest
underlying cause [109]. It affects approximately 1 % of the
• Grade 1: palpable during Valsalva maneuver
malepopulation.Mendiagnosedwithazoospermiaarebroadly
• Subclinical: not palpable or visible at rest or under
categorized as having a mechanical obstruction along the
Valsalva maneuver but detectable by Doppler
seminaltract(obstructive)oranintrinsictesticularimpairment
ultrasound
ofspermproduction(nonobstructiveazoospermia).
Whenever physical examination is inconclusive or dif- In obstructive azoospermia (OA), the blockage is loca-
ficulttoperform,imagingstudiesarerecommended.Color ted between the epididymis and the ejaculatory duct.
Doppler ultrasound (CDU) has been shown to be the best Causes of OA include CBAVD, infection, and vasectomy.
diagnostic tool. Using a cutoff value of 3 mm for vein Surgical reconstructive procedures are available for select
diameter, CDU has a sensitivity of about 50 % and speci- patients with OA (e.g., vasectomy reversal), and surgical
ficity of 90 % compared with physical examination [102]. SRisusuallysuccessfulinnoncorrectablecases[110,111].
Current recommendations propose varicocele treatment Nonobstructive azoospermia (NOA) is caused by
for couples with documented infertility, whose male part- genetic factors, prior testicular toxic exposures such as
ner has a clinical varicocele and at least one abnormal radiation or chemotherapy, trauma, infection, and idio-
semen parameter. Men not attempting to achieve concep- pathic reasons. While about 50 % of NOA patients have
tion but who fit into this description and have a desire for maturespermatozoaintheirtesticles,noreliablepredictive
future fertility are also candidates for treatment [6, 103]. factors exist to prospectively distinguish which patients
Table4 ExamplesofthecommonlyusedmethodsforassessmentofspermDNAdamage
Assay Principle Howresultsareexpressed Normallimits
Terminaldeoxynucleotide MeasureDNAdamageby PercentageofspermwithDNAdamage, \19%forTUNELwhenusedto
transferase-mediated incorporatingDNAprobesor representedbythosewiththeprobes discriminatefertilefrom
dUTPnickendlabeling modifiednucleotidesatthe incorporatedtoDNAbreaks unselectedinfertilemenwith
(TUNEL)assay siteofdamage 70%accuracy
Spermchromatinstructure Measurethesusceptibilityof PercentageofspermwithfragmentedDNA \30%
assay(SCSA) DNAtodenaturation
Spermchromatindispersion Measurethesusceptibilityof PercentageofspermwithfragmentedDNA \30%
test(SCD) DNAtodenaturation
Cometassay Measurethesusceptibilityof DegreeofDNAfragmentationinasingle Notdefined
DNAtodenaturation spermatozoonasassessedbythepercentage
ofDNAinthetailofthecomet,taillength
andintensityofstaining(Comet)
Anilinebluestaining(AB) Measurethelevelofchromatin Percentageofspermwithloosechromatin Notdefined
compaction packing
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TheJournalofObstetricsandGynecologyofIndia(March–April2015)65(2):75–87 PracticingGynecologistsintheManagementofInfertileMen
may have sperm that can be surgically retrieved except in Chemical gonadotoxins, including pesticides found in
cases of YCMD as indicated above [112]. vegetablesandindustrialwaste,canincreasetheformation
Given its untreatable nature, men with NOA seeking of free radicals due to the unstable chemical compounds
fertilityshouldrelyonSRandICSIforachievingbiological found in these products. Radiation exposures from cell
offspring.AmongtheSRmethods,microsurgicaltesticular phonesandlaptopcomputers,canproduceOSbyinducing
spermextraction(micro-TESE)isconsideredtobethebest cellular chemical changes through the electromagnetic
option for SR in men with NOA (retrieval rates ranging waves emitted from the devices, and decrease semen
from 40 to 60 %). Micro-TESE also provides the opportu- quality [117].
nity for both preserving testicular vasculature and mini- Antioxidant therapy, including vitamins E and C,
mizing the amountof extracted parenchyma[112, 113]. carotenoids,zinc,andselenium,enhancestotalantioxidant
ICSI is associated with lower fertilization rates per capacity of body fluids including semen resulting in scav-
injected oocyte as well as clinical pregnancy and delivery engingofexcessfreeradicals[118–129].Improvementsin
rateswhentesticularspermatozoafrommenwithNOAare sperm motility, sperm DNA fragmentation, fertilization
used in comparison to epididymal/testicular sperm from capacity,andoddsofnormalspermcountwereobservedin
men with OA [113–115]. Once a live birth is achieved, most studies [120–123], albeit, in a few of them, no
newborn parameters of infants conceived were not signif- advantage was documented [124, 130]. A Cochrane meta-
icantly different among the groups, and no major differ- analysis on the use of oral antioxidants in male infertility
ences arenotedintheoffspring’s neonatal profile[113].If found that these agents significantly improved pregnancy
there is no worthy sperm for fertilization, then the couple rates and live births and decreased sperm DNA damage
must consider adoption or donor insemination. [131]. Nevertheless, improvements in semen parameters
are not well evident [131] (Table 7). These observations
support the concept that antioxidants can improve sperm
Prescription of Antioxidants functionbyimprovingspermDNAintegrityandfertilizing
capabilities.
Fair evidence suggests that antioxidant therapy has a ben-
eficial role in MFI. However, it is also essential to
encourage lifestyle modifications, which helps in reducing Counseling of Male Infertile Patients
the generation of free radicals. For example, increased
intakeofvegetables andfruits,reductioninexcessweight, Infertile men are often anxious, and feel guilty regarding
smokingcessation,andmoderationinalcoholconsumption their inability to induce a pregnancy [132]. Proper coun-
are advised [116]. Exposures to various environmental selingofbothpartnersshouldbeoneofthetopprioritiesof
pollutants and/or radiation should be avoided or reduced. the treating physician, and in this sense, the gynecologist
Table5 Examplesofthemethodscommonlyusedforassessingoxidativestress
Assay Principle Specimen Howresultsareexpressed Normallimits
ROSby Intra-andextracellularROSlevels(mainly Semen 9106countedphotonsper \0.01859106cpm/
chemiluminescence H O ,O2-,andOH-)reactwithprobes minute(cpm)per209106 209106sperm
2 2
andemitphotonsthataremeasuredusinga sperm/mL
luminometer.Thefinalchemiluminescent
signalistheintegratedsumofthepartial
signalsgeneratedbyeveryspermatozoon
Thiobarbituricacid Malondialdehyde(MDA),abyproductof Semen nmoLMDA/109107sperm, 0.0287±0.0162nmol/
reactivesubstances lipidperoxidation,condenseswithtwo and nmolMDAmL-1seminal 108spermand
(TBARS) equivalentsthiobarbituricacidandgivea seminal plasma,ornmoLMDA/total 0.65±0.17nmol/mL-
fluorescentredderivativethatcanbe plasma seminalplasma 1seminalplasma
assayedspectrophotometrically.
Absorbanceat532nmisrecorded
Seminaltotal Capacityoftheantioxidantsinagiven Seminal MolarTroloxequivalents [2,000micromolesof
antioxidantcapacity sampletopreventABTSoxidationis plasma Trolox
(TAC)byenhanced proportionaltotheirConcentration.
chemiluminescence Suppressionofabsorbanceat750nmis
measuredandcomparedwiththatof
standardTrolox,awater-solubletocopherol
analog
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81
Agarwaletal. TheJournalofObstetricsandGynecologyofIndia(March–April2015)65(2):75–87
Fig.1 ImageofY
chromosome.Reprintedwith
permissionfrom:O’Flynn
O’BrienKLVargheseAC,
AgarwalA.Thegeneticcauses
ofmalefactorinfertility:a
review.FertilSteril.2010
Jan;93[1]:1–12
Table6 Mainindicationsforgenetictestinginmaleinfertility
Indications Recommendedtests
Menwithinfertilityofunknown Y-chromosome
etiologyandspermconcentration microdeletionandG-band
\10million/mLwhoarecandidates karyotype
forART
Nonobstructiveazoospermiainamale Y-chromosome
consideringtesticularsperm microdeletionandG-band
retrievalforART karyotype
Azoospermicoroligozoospermicmen CFTRgenemutation
withabsenceofatleastonevas
deferensatphysicalexamination
Azoospermicmenwithsignsof CFTRgenemutation
normalspermatogenesis(e.g.,
obstructiveazoospermiaofunknown
origin)
Historyofrecurrentmiscarriageor G-bandkaryotype
personal/familiarhistoryofgenetic
syndromes
ARTassistedreproductivetechniques
G-bandkaryotypegiemsabandkaryotype Fig.2 ImageofgradeIIIvaricocele.Reprintedwithpermissionfrom
CFTRcysticfibrosistransmembraneconductanceregulator Clinics(Sa˜oPaulo)2011,Esteves,Miyaoka,Agarwal.Anupdateon
the clinical assessment of the infertile male, vol. 66, issue 4, pages
plays a crucial role. The following list contains practical 691–700
recommendations for couples with male factor infertility,
who are attempting to conceive:
1. All commercially available lubricants decrease sperm relatively less detrimental to sperm than other sub-
motility and increase sperm DNA damage. Hydro- stances [133]. Saliva and vegetable oil also decrease
xylethylcellulose-based lubricant was shown to be sperm motility [134, 135].
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82
TheJournalofObstetricsandGynecologyofIndia(March–April2015)65(2):75–87 PracticingGynecologistsintheManagementofInfertileMen
Table7 ResultsofCochranereview2011[131]
Semenparameter No.ofstudies Averagedurationoftreatment Meandifference(MD) Pooledcumulative
No.ofpatients ±SD,95%CI gradeofresponse
Totalmotilesperm 10trials 3monthsorless MD11.72,95%CI ?
514patients 6.94to16.49; Verylow
P\0.00001
7trials 6months MD4.19,95%CI ?
963patients 3.81to4.56; Verylow
P\0.00001
3trials 9months MD1.38,95%CI ?
332patients 0.81to1.95; Verylow
P\0.00001
SpermCount 7trials 3monthsorless MD6.04,95%CI Noeffect
320patients -5.42to17.50;
P=0.30
6trials 6months MD5.25,95%CI ?
825patients 4.43to6.08; Verylow
P\0.00001
3trials 9months MD1.61,95%CI ?
332patients 0.61to2.61; Verylow
T181,C151 P=0.002
SpermDNAfragmentationindex(DFI) 1trial 2months MD-13.80,95%CI Decrease
64patients -17.50to-10.10; DFI
T32,C32 P\0.00001
Pregnancyrate 15trials 4.5months OR4.18,95%CI ????
964couples 2.65to6.59; High
P\0.00001
Livebirthpercouple 3trials 4months OR3.94,95%CI ???
214couples 1.14to13.55; Moderate
P=0.03
2. Male partners should stop smoking, and limit alcohol discouraged and should be informed that treatment
useto3–4units/week,andabstainfromillicitdruguse modalities are available.
[136, 137]. 6. If a palpable varicocele is present, then advise that
3. Prescribe exercise and weight loss for overweight or surgical repair may be an option to improve fertility.
obesemen.AhealthyBMIrangesfrom20to27[137– 7. Be aware that elderly infertile men usually have
139]. chronic medical diseases, which should be identified
4. Advise the male partner to avoid any situations that andtreatedbecausetheycannegativelyaffectfertility.
canincreasescrotaltemperaturesuchassittinginahot
tubs/sauna,andplacingportablecomputersdirectlyon
Compliance with ethical requirements and Conflict of interest
the lap. If occupational exposure to a hot work This article complies with the ethical standards as per the Journal’s
environment is unavoidable, the patient can take policies. Each author indicates that there is no financial interest or
proper precautionary measures to minimize testicular conflict of any kind to disclose. In addition, this article does not
containanystudieswithanimalsperformedbyanyoftheauthors.
heat exposure [93].
5. Abnormal findings in SA require thorough physical
examination and further laboratory investigation. This
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