Surgical Treatment of Male Surgical Treatment of Male Infertility Infertility

Selahittin Selahittin ÇÇayan, ayan, M.D.M.D.Associate Professor of UrologyAssociate Professor of Urology

Department of UrologyDepartment of UrologyUniversity of Mersin School of University of Mersin School of

MedicineMedicine

Natural conception

IUI

DecreasingRisk and Cost

Upgrading Fertility Upgrading Fertility StatusStatus

IVF/ICSI

Ejaculated sperm

IncreasedDesirability

Surgical sperm retrievalfor IVF/ICSI

Donor sperm inseminationAdoption

Why Evaluate the Why Evaluate the Infertile Male in Era of Infertile Male in Era of ART?ART?

Pathophysiology-specific treatmentPathophysiology-specific treatment

Diagnose correctable pathologiesDiagnose correctable pathologies Varicocele Varicocele → → Progressive damageProgressive damage

Total loss of fertility possibleTotal loss of fertility possible ↓ ↓ TeTestosterone stosterone →→Erectile dysfunction, decreased lipidoErectile dysfunction, decreased lipido

Diagnose life threatened diseaseDiagnose life threatened disease 37 times higher incidence of testis cancer37 times higher incidence of testis cancer ProlactinomaProlactinoma

Detect genetic diseaseDetect genetic disease 30-100 times higher incidence of genetic 30-100 times higher incidence of genetic

abnormalitiesabnormalities

Positive effect of Positive effect of pathophysiologic specific pathophysiologic specific treatment of male infertility on treatment of male infertility on ARTART

To obviate the need for ARTTo obviate the need for ART

To downstage the level of ART needed to To downstage the level of ART needed to bypass male factor infertilitybypass male factor infertility

From IUI to spontaneous pregnancyFrom IUI to spontaneous pregnancy FF rom IVF/ICSI to IUIrom IVF/ICSI to IUI

To increase pregnancy rates with ART in To increase pregnancy rates with ART in cases who had improved sperm cases who had improved sperm morphology after the treatmentmorphology after the treatment

HistoryPhysical examinationSemen analysis (2x)

Hormonal evaluationRadiologic evaluation

TREATMENT

Evaluation of Infertile Evaluation of Infertile ManMan

Advanced fertility testsGenetic tests

Biopsy/Cytology

10

20

30

VaricoceleVaricocele

ObstructionObstructionNon-obstructionNon-obstruction

Total Motile Sperm Total Motile Sperm CountCount

Ejaculate volume x sperm density x Ejaculate volume x sperm density x motile fraction (a+b)motile fraction (a+b)

Volume: 3 ml.Volume: 3 ml. Density: 10 million/ml.Density: 10 million/ml. Motility: 30%Motility: 30%

9 million9 million

Total Motile Sperm Count*Total Motile Sperm Count*

SexSex >20 >20 million millionIUIIUI 5-20 5-20 million millionIVFIVF 1.5 -5 million1.5 -5 millionICSIICSI <1.5 million<1.5 million

* TMC: Ejaculate volume x sperm concentration x motile fraction* TMC: Ejaculate volume x sperm concentration x motile fraction

Reasonable Reasonable AlternativesAlternatives

Etiology of Male Factor Infertility

0102030405060708090

100

Varicocele Obstruction Testisfailure

Idiopathic Hormonal Others

%

Correctable Pathologies Correctable Pathologies of of Male InfertilityMale Infertility

VaricoceleVaricocele Obstructive azoospermiaObstructive azoospermia Ejaculatory duct obstructionEjaculatory duct obstruction Hormonal abnormalityHormonal abnormality InfectionInfection Ejaculatory Ejaculatory dysfuntiondysfuntion Gonadotoxin exposureGonadotoxin exposure

VVaricocelaricocelee

Semen Semen abnormalitiesabnormalities

Density Density Motility Motility

Morphology Morphology Testicular volume Testicular volume ↓ ↓ Leydig cell Leydig cell function ↓function ↓

WHO, Fertil Steril, 1992WHO, Fertil Steril, 1992

AApproach in infertile men pproach in infertile men with varicocelewith varicocele

Treatment of VaricoceleTreatment of Varicocele Surgery (Open, laparoscopic)Surgery (Open, laparoscopic)

Microsurgical Varicocelectomy Microsurgical Varicocelectomy Radiologic embolizationRadiologic embolization

Assisted Reproductive Assisted Reproductive TechnologiesTechnologies

IUI, IVF/ICSIIUI, IVF/ICSI

Guidelines on Treatment of Guidelines on Treatment of VaricoceleVaricocele

Varicocelectomy should not be offered to Varicocelectomy should not be offered to improve fertility, since pregnancy rates improve fertility, since pregnancy rates do not increase.do not increase.

National Collaborating Centre for Women’s and Children’s Health 2005National Collaborating Centre for Women’s and Children’s Health 2005

Treatment of varicocele should be offered Treatment of varicocele should be offered to infertile men with palpable varicocele to infertile men with palpable varicocele and abnormal semen analysis.and abnormal semen analysis.

Best Policies Practice Groups of the AUA Best Policies Practice Groups of the AUA 20022002

Best Policies Practice Groups of the ASRM Best Policies Practice Groups of the ASRM 20042004

Treatment of varicocele is still Treatment of varicocele is still controversial, although it improves controversial, although it improves spontaneous pregnancy rates.spontaneous pregnancy rates.

EAU Guideline on Male infertility 2004EAU Guideline on Male infertility 2004

Selected 7 studies or abstracts (1979-2002)Selected 7 studies or abstracts (1979-2002) Inclusion-exclusion criterias: ?Inclusion-exclusion criterias: ?

TreatmentTreatment ControlControl Pregnancy ratesPregnancy rates 21.7%21.7% 19.3%19.3%

Odds ratio: 1.01 (95% CI: 0.73-1.4)Odds ratio: 1.01 (95% CI: 0.73-1.4) Recommendation: Treatment of varicocele Recommendation: Treatment of varicocele

does not improve fertility in unexplained does not improve fertility in unexplained infertility.infertility.

Evers and Collin, Lancet, 2003Evers and Collin, Lancet, 2003

Treatment of Varicocele: Treatment of Varicocele: Systematic review-2003Systematic review-2003

Selected 8 randomized controlled study (1985-Selected 8 randomized controlled study (1985-2004)2004)

Inclusion criterias:Inclusion criterias: Subclinic varicocele (3 papers)Subclinic varicocele (3 papers) Clinical varicocele + normal semen analiysis (2 Clinical varicocele + normal semen analiysis (2

papers)papers) Varicocele ? + Abnormal semen parameters (3 Varicocele ? + Abnormal semen parameters (3

papers)papers) Comparison: Pregnancy ratesComparison: Pregnancy rates Peto Odds ratio: 1.1 (95% CI: 0.73-1.68)Peto Odds ratio: 1.1 (95% CI: 0.73-1.68)

Recommendation: Treatment of varicocele does Recommendation: Treatment of varicocele does not improve fertility in unexplained infertility.not improve fertility in unexplained infertility.Evers and Collin, Evers and Collin, Cochrane Database Syst Rev 2004Cochrane Database Syst Rev 2004

Varicocelectomy- Meta analiysis-Varicocelectomy- Meta analiysis-20042004

Turkish Society of Andrology: Turkish Society of Andrology: Guidelines on VaricoceleGuidelines on Varicocele

Varicocele: Diagnosis and Varicocele: Diagnosis and EvaluationEvaluation

Türk Androloji Derneği, Varikosel Kılavuzu, Türk Androloji Derneği, Varikosel Kılavuzu, 20052005

Physical examination:Physical examination:

Grade 1: Palpable with ValsalvaGrade 1: Palpable with Valsalva

Grade 2: Direct palpableGrade 2: Direct palpable

Grade 3: Visible with no Grade 3: Visible with no palpationpalpation

Endications for treatment of Endications for treatment of VaricoceleVaricocele

InfertilityInfertility Symptomatic varicoceleSymptomatic varicocele

Türk Androloji Derneği Varikosel Kılavuzu, 2005Türk Androloji Derneği Varikosel Kılavuzu, 2005

Varicocelectomy-Meta analysis-Varicocelectomy-Meta analysis-20062006

Selected 8 randomized clinical studiesSelected 8 randomized clinical studies Exclusion criterias from the meta-Exclusion criterias from the meta-

analysis:analysis: Subclinical varicoceleSubclinical varicocele Normal semen analysisNormal semen analysis

Inclusion criterias to the meta-Inclusion criterias to the meta-analysis:analysis: Clinical palpable varicoceleClinical palpable varicocele Abnormal semen parametersAbnormal semen parameters

3 randomized studies matching to the 3 randomized studies matching to the criteriascriterias Tedavi grubu (n: 120)Tedavi grubu (n: 120) Kontrol grubu (n: 117)Kontrol grubu (n: 117) Ficarra V et al, Eur Urol 2006Ficarra V et al, Eur Urol 2006

Treatment ControlTreatment Control P P valuevalue

Pregnancy ratesPregnancy rates 36.4% 20% 36.4% 20% 0.0090.009

Ficarra V et al, Eur Urol 2006Ficarra V et al, Eur Urol 2006

Varicocelectomy-Meta analysis-Varicocelectomy-Meta analysis-20062006

Inclusion criterias:Inclusion criterias: InfertilityInfertility Abnormal semen analysisAbnormal semen analysis Palpable varicocelePalpable varicocele Surgical techniques:Surgical techniques:

High ligation High ligation InguinalInguinal MicrosurgicalMicrosurgical

24 months of postop follow-up24 months of postop follow-up Spontaneous pregnancy ratesSpontaneous pregnancy rates

5 randomized clinical studies5 randomized clinical studies Treatment group (n: 396)Treatment group (n: 396) Control group (n: 174)Control group (n: 174)

TreatmentTreatment ControlControl Pregnancy ratesPregnancy rates 33% 15.5%33% 15.5%

Marmar J et al, Fertil Steril 2007Marmar J et al, Fertil Steril 2007

Varicocelectomy- Meta-analysis-Varicocelectomy- Meta-analysis-20072007

Best Candidates for Best Candidates for VaricocelectomyVaricocelectomy

Palpable, large varicocelePalpable, large varicocele Normal testicular volume Normal testicular volume Normal FSH/testosterone, inhibin Normal FSH/testosterone, inhibin

BB↓↓ Total Motile Sperm> 5 millionTotal Motile Sperm> 5 million No genetic abnormalityNo genetic abnormality Short infertility durationShort infertility duration

Fretz PC Fretz PC && Sandlow JI, Urol Clin North Am, 2002 Sandlow JI, Urol Clin North Am, 2002Türk Androloji Derneği, Varikosel Kılavuzu, 2005Türk Androloji Derneği, Varikosel Kılavuzu, 2005

Improvement after Improvement after VaricocelectomyVaricocelectomy

Sperm concentrationSperm concentration 66%66% Sperm motilitySperm motility 70% 70%

Pryor and Howards, 1987Pryor and Howards, 1987

50% increase in TMC 50% increase in TMC 34 - 54%34 - 54% Spontaneous pregnancySpontaneous pregnancy 31 - 43%31 - 43%

ÇÇayan et al, Urology, 2000ayan et al, Urology, 2000 ÇÇayan et al, Urology, 2001ayan et al, Urology, 2001 Çayan et al, J Urol, 2002Çayan et al, J Urol, 2002

Çayan & Kadıoğlu, Submitted Review, Eur Urol, 2008Çayan & Kadıoğlu, Submitted Review, Eur Urol, 2008

Varikosel tedavisinde en iyi Varikosel tedavisinde en iyi teknik hangisi?teknik hangisi?

Dahil edilme kriterleri:Dahil edilme kriterleri: İnfertiliteİnfertilite Anormal semen analiziAnormal semen analizi Palpabl varikoselPalpabl varikosel Tüm tedavi gruplarıTüm tedavi grupları

Açık cerrahi Açık cerrahi LaparoskopikLaparoskopik RadyolojikRadyolojik

Karşılaştırma:Karşılaştırma: Spontan gebelik oranlarıSpontan gebelik oranları KomplikasyonlarKomplikasyonlar

36 klinik çalışma:36 klinik çalışma: Yüksek ligasyon, Palomo Yüksek ligasyon, Palomo

(n:10)(n:10) Mikrocerrahi (n:12)Mikrocerrahi (n:12) Laparoskopik (n:5)Laparoskopik (n:5) Radyolojik (n:6)Radyolojik (n:6) Makroskopik (n:3)Makroskopik (n:3)

P=0.001

Varikosel tedavisinde en iyi Varikosel tedavisinde en iyi teknik hangisi?teknik hangisi?

Ortalama gebelik: % 39.07 (1748/4473)Ortalama gebelik: % 39.07 (1748/4473)

Yüksek ligasyon:Yüksek ligasyon: % 37.69% 37.69 Mikrocerrahi:Mikrocerrahi: % 41.97% 41.97 Laparoskopik:Laparoskopik: % 30.07% 30.07 Radyolojik:Radyolojik: % 33.2% 33.2 Makroskopik:Makroskopik: % 36% 36

P değeri: 0.001P değeri: 0.001

Çayan & Kadıoğlu, Submitted Review, Eur Urol, 2008Çayan & Kadıoğlu, Submitted Review, Eur Urol, 2008

P=0.001

Varikosel tedavisinde en iyi Varikosel tedavisinde en iyi teknik hangisi?teknik hangisi?

Nüks (%)Nüks (%)Hidrosel (%)Hidrosel (%)

Yüksek ligasyon:Yüksek ligasyon: 14.9714.97 8.248.24 Mikrocerrahi:Mikrocerrahi: 1.051.05 0.440.44 Laparoskopik:Laparoskopik: 4.34.3 2.842.84 Radyolojik:Radyolojik: 12.712.7 Makroskopik:Makroskopik: 2.632.63 7.37.3

P değeri: P değeri: 0.0010.001 0.0010.001

Radyolojik başarısız girişim: % 13.05Radyolojik başarısız girişim: % 13.05Laparoskopik major komplikasyon: % 7.59Laparoskopik major komplikasyon: % 7.59

Çayan & Kadıoğlu, Submitted Review, Eur Urol, 2008Çayan & Kadıoğlu, Submitted Review, Eur Urol, 2008

Microsurgical Varicocelectomy

n=n=540540Postop follow-up:Postop follow-up: 36.4 ± 22.8 36.4 ± 22.8 monthsmonths

(14 (14 -- 64) 64)

PoPozitive response:zitive response: 50.250.2%%

NegatiNegative response:ve response: 49.849.8%%

* * 50% increase in TMS50% increase in TMS

Spontaneous pregnancy: Spontaneous pregnancy: 36.636.6%%

Time to achieve pregnancy: Time to achieve pregnancy: 7 ± 7 ± 3.4 3.4 months months (1 (1 -- 19 19 months)months)

Çayan S et al, J Urol, 2002Çayan S et al, J Urol, 2002

Time to pregnancy (Months)

20.018.016.014.012.010.08.06.04.02.0

# of

cou

ples

50

40

30

20

10

0

Preoperative TMS- Post op. Spontaneous pregnancy

0

10

20

30

40

50

60

0-1.5million

1.5-5million

5-20million

20million<

Pregnancy (% )

%

Kadıoğlu A & Çayan S, ASRM 2001

0%

20%

40%

60%

80%

100%

ICSIcandidates(n=154)

IVFcandidates

(n=79)

IUIcandidates(n=151)

Spontaneouspregnancycandidates(n=156)

Spontaneous pregnancycandidates

IUI candidates

IVF candidates

ICSI candidates

POSTOPERATIVE

PREOPERATIVE Çayan S & Kadıoğlu A, J Urol 2002

ART vs. Varicocelectomy?ART vs. Varicocelectomy?Changes in ART CandidacyChanges in ART Candidacy

CostCost

Per deliveryPer delivery

_ ICSI:ICSI: 89,091 USD89,091 USD_ Varicocelectomy: 26,268 USDVaricocelectomy: 26,268 USD

Schlegel , Urology, 1997Schlegel , Urology, 1997

Effect of Varicocelectomy Effect of Varicocelectomy on ART Successon ART Success

First IVF-ET-unsuccess; then First IVF-ET-unsuccess; then varicocelectomy, Pregnancy:varicocelectomy, Pregnancy:31% 31% (Yamamoto 1994)(Yamamoto 1994)

40% 40% (Ashkenazi 1989)(Ashkenazi 1989)

Varicocelectomy versus IUI ?Varicocelectomy versus IUI ?PregnancyPregnancy DeliveryDelivery

Op - (n:34):Op - (n:34): 6.3%6.3% 1.6%1.6%Op + (n:24):Op + (n:24): 11.8%11.8% 11.8%11.8%

Daitch et al, J Urol, 2001Daitch et al, J Urol, 2001

Poor prognosis for Poor prognosis for IUI IUI

_ Female age (>37)Female age (>37)_ Previous pelvic surgeryPrevious pelvic surgery_ Decreased semen parametersDecreased semen parameters

_ Total motile sperm count<5 Total motile sperm count<5 millionmillion

_ Sperm motility (<40%)Sperm motility (<40%)_ Untreated varicoceleUntreated varicocele

Preop Preop PostopPostop

Kibar Y et al.Kibar Y et al. 2.6%2.6% 10.2%10.2%J Urol, 2002J Urol, 2002

Çayan S et al.Çayan S et al. 3.3%3.3% 4.7% 4.7% J Urol, 2002J Urol, 2002

In 13%, seminal response (-) In 13%, seminal response (-) Pregnancy (+) Pregnancy (+) Kruger: 3.7% Kruger: 3.7% 6.2%6.2%

Improvement in Kruger morphology may predict Improvement in Kruger morphology may predict pregnancy. pregnancy.

Sperm morphology (Kruger)Sperm morphology (Kruger)

The best treatment modality is microsurgical repair with The best treatment modality is microsurgical repair with the lowest complication rate and the highest the lowest complication rate and the highest spontaneous pregnancy rates.spontaneous pregnancy rates.

Varicocelectomy has significant potential not only to Varicocelectomy has significant potential not only to obviate the need for ART, but also to downstage the obviate the need for ART, but also to downstage the level of ART needed to bypass male factor infertility.level of ART needed to bypass male factor infertility.

A cost effective treatment of infertility:A cost effective treatment of infertility: Upgrade to normal semen: Allow natural pregnancy (40%)Upgrade to normal semen: Allow natural pregnancy (40%) Upgrade from azoospermia to oligospermia (20-30%)Upgrade from azoospermia to oligospermia (20-30%) Allow fresh sperm for IUI or IVF/ICSIAllow fresh sperm for IUI or IVF/ICSI Even if patients remain azoospermic, it may preserve foci of Even if patients remain azoospermic, it may preserve foci of

spermatogenesis for Testicular sperm recovery (TESA/TESE)spermatogenesis for Testicular sperm recovery (TESA/TESE)

Varicocele repairVaricocele repair

Infertility - Azoospermia: 5-20%

0

10

20

30

40

50

60

70

80

90

100

Obstruction Endocrine Genetic Testicular failure

%

Correctable Pathologies in Azoospermic Men

Non-obstructive azoospermiaNon-obstructive azoospermiaVaricoceleVaricoceleEndocrine-Hormonal abnormalitiesEndocrine-Hormonal abnormalitiesGonadotoxinsGonadotoxins

SmokingSmoking, tobacco, alcohol, mariuhana, cocaine, tobacco, alcohol, mariuhana, cocaine RadiationRadiation Drugs: Drugs: Cimetidine, nitrofurantoin, GABA agonists, nifedipin, Cimetidine, nitrofurantoin, GABA agonists, nifedipin,

sulfonamide, ketoconazol, diethilstilbestrol, Chemotherapeutics, sulfonamide, ketoconazol, diethilstilbestrol, Chemotherapeutics, corticosteroidscorticosteroids

Insecticide (DDT), pesticideInsecticide (DDT), pesticide Termal (heating, hut tub, saunas), Pb, solventTermal (heating, hut tub, saunas), Pb, solvent

Treatment: Treatment: Treatment of underlying pathologyTreatment of underlying pathologySemen analysis after 3-12 monthsSemen analysis after 3-12 months

Obstructive azoospermiaObstructive azoospermiaEpidEpidiiddymalymal obstr obstructionuctionVVas deferensas deferens obstruction obstructionDistal ejaDistal ejaculatory duct culatory duct obstrobstructionuction

Treatment:Treatment: Surgery Surgery

Surgical treatment Surgical treatment alternativesalternatives

_ Obstructive azoospermia:Obstructive azoospermia: VasovasostomyVasovasostomy EpididymovasostomyEpididymovasostomy MESAMESA Macroscopic TESAMacroscopic TESA TUR-EDTUR-ED_ Non-obstructive azoospermia:Non-obstructive azoospermia: Microscopic TESEMicroscopic TESE Microscopic varicocelectomyMicroscopic varicocelectomy

Vasovasostomy- Vasovasostomy- EpididymovasostoEpididymovasostomymy

_ Patency: 60-99.5%Patency: 60-99.5%

_ Spontaneous pregnancy: 40-60%Spontaneous pregnancy: 40-60%

Transurethral resection Transurethral resection of Ejaculatory Duct of Ejaculatory Duct (TUR-ED)(TUR-ED)

Endoscopic resection of veru-montanumEndoscopic resection of veru-montanum

Total Total

(n: 38)(n: 38)Improvement Improvement

in seminal in seminal parameters parameters

(74%)(74%)

SpontaneoSpontaneous us

pregnancy pregnancy

(13%)(13%)

Complet Complet obs.obs.

59%59% 9%9%

Partial obs.Partial obs. 94%94% 19%19%

Kadıoğlu et al, Fertil Steril, 2001

Results of TUR-EDResults of TUR-EDPostop. follow-up: 26 Postop. follow-up: 26 8.5 months (12-63)8.5 months (12-63)

Upgrading from Upgrading from “Nothing” to “Nothing” to “Something“Something

Obstructive azoospermiaObstructive azoospermia

Microsurgical reconstructionMicrosurgical reconstruction Success rate: 60-100%Success rate: 60-100% Pregnancy: 30-60%Pregnancy: 30-60%

No need for additional surgical procedure for No need for additional surgical procedure for sperm retrievalsperm retrieval

Candidates for IUI or ICSI with fresh motile sperm Candidates for IUI or ICSI with fresh motile sperm from ejaculatefrom ejaculate

Upgrade from azoospermia to normal semen Upgrade from azoospermia to normal semen parametersparameters

Upgrade from azoospermia to oligospermia for IUI or Upgrade from azoospermia to oligospermia for IUI or ICSIICSI

Ejaculatory Dysfunction-Anejaculation

PVS

EEJ

TESE

Reasons for anejaculation:Reasons for anejaculation:

·· Spinal cord injury Spinal cord injury ·· Pelvic and retroperitoneal surgery Pelvic and retroperitoneal surgery ·· Psychogenic causesPsychogenic causes·· IdiopathicIdiopathic·· Multiple sclerosisMultiple sclerosis·· DiabetesDiabetes·· ProlactinomaProlactinoma

IVF/ICSI

IVF

ICI

IUI

Çayan & Turek, Fertil Steril, 2001

Overall 61.1% (11/18) of couples achieved pregnancyOverall 61.1% (11/18) of couples achieved pregnancy

Achieving natural pregnancy, while ideal, should not be the only Achieving natural pregnancy, while ideal, should not be the only measurement of treatment efficacymeasurement of treatment efficacy..

Clinicians should offer treatment that improves the long term Clinicians should offer treatment that improves the long term fertility status of the couples, not just to achieve immediate fertility status of the couples, not just to achieve immediate pregnancy.pregnancy.

Pathophysiologic specific treatment in male infertility Pathophysiologic specific treatment in male infertility has has significant potential not only to obviate the need for ART, but also significant potential not only to obviate the need for ART, but also to downstage the level of ART needed to bypass male factor to downstage the level of ART needed to bypass male factor infertility.infertility.

Effective treatment may be surgical, medical or simple lifestyle Effective treatment may be surgical, medical or simple lifestyle modifications.modifications.

Upgrade from nothing to IVF/ICSIUpgrade from nothing to IVF/ICSI Upgrade from IVF/ICSI to IUIUpgrade from IVF/ICSI to IUI Upgrade from IUI to natural pregnancy Upgrade from IUI to natural pregnancy

SummarySummary