Surgical Treatment of Male Infertility Selahittin Çayan, M.D. Associate Professor of Urology Department of Urology University of Mersin School of Medicine

Surgical sperm retrieval Donor sperm insemination Upgrading Fertility Status Natural conception IUI IVF/ICSI Increased Desirability Decreasing Risk and Cost Ejaculated sperm Surgical sperm retrieval for IVF/ICSI Donor sperm insemination Adoption

Why Evaluate the Infertile Male in Era of ART? Pathophysiology-specific treatment Diagnose correctable pathologies Varicocele → Progressive damage Total loss of fertility possible ↓ Testosterone →Erectile dysfunction, decreased lipido Diagnose life threatened disease 37 times higher incidence of testis cancer Prolactinoma Detect genetic disease 30-100 times higher incidence of genetic abnormalities

Positive effect of pathophysiologic specific treatment of male infertility on ART To obviate the need for ART To downstage the level of ART needed to bypass male factor infertility From IUI to spontaneous pregnancy F rom IVF/ICSI to IUI To increase pregnancy rates with ART in cases who had improved sperm morphology after the treatment

Radiologic evaluation Advanced fertility tests Evaluation of Infertile Man History Physical examination Semen analysis (2x) 10 Varicocele Hormonal evaluation Radiologic evaluation TREATMENT 20 Advanced fertility tests Genetic tests Biopsy/Cytology Obstruction Non-obstruction 30

Total Motile Sperm Count Ejaculate volume x sperm density x motile fraction (a+b) Volume: 3 ml. Density: 10 million/ml. Motility: 30% 9 million

Reasonable Alternatives Total Motile Sperm Count* Sex >20 million IUI 5-20 million IVF 1.5 -5 million ICSI <1.5 million * TMC: Ejaculate volume x sperm concentration x motile fraction

Etiology of Male Factor Infertility %

Correctable Pathologies of Male Infertility Varicocele Obstructive azoospermia Ejaculatory duct obstruction Hormonal abnormality Infection Ejaculatory dysfuntion Gonadotoxin exposure

Varicocele Semen abnormalities Density Motility Morphology Testicular volume ↓ Leydig cell function ↓ WHO, Fertil Steril, 1992

Approach in infertile men with varicocele Treatment of Varicocele Surgery (Open, laparoscopic) Microsurgical Varicocelectomy Radiologic embolization Assisted Reproductive Technologies IUI, IVF/ICSI

Guidelines on Treatment of Varicocele Varicocelectomy should not be offered to improve fertility, since pregnancy rates do not increase. National Collaborating Centre for Women’s and Children’s Health 2005 Treatment of varicocele should be offered to infertile men with palpable varicocele and abnormal semen analysis. Best Policies Practice Groups of the AUA 2002 Best Policies Practice Groups of the ASRM 2004 Treatment of varicocele is still controversial, although it improves spontaneous pregnancy rates. EAU Guideline on Male infertility 2004

Treatment of Varicocele: Systematic review-2003 Selected 7 studies or abstracts (1979-2002) Inclusion-exclusion criterias: ? Treatment Control Pregnancy rates 21.7% 19.3% Odds ratio: 1.01 (95% CI: 0.73-1.4) Recommendation: Treatment of varicocele does not improve fertility in unexplained infertility. Evers and Collin, Lancet, 2003

Varicocelectomy- Meta analiysis-2004 Selected 8 randomized controlled study (1985-2004) Inclusion criterias: Subclinic varicocele (3 papers) Clinical varicocele + normal semen analiysis (2 papers) Varicocele ? + Abnormal semen parameters (3 papers) Comparison: Pregnancy rates Peto Odds ratio: 1.1 (95% CI: 0.73-1.68) Recommendation: Treatment of varicocele does not improve fertility in unexplained infertility. Evers and Collin, Cochrane Database Syst Rev 2004

Turkish Society of Andrology: Guidelines on Varicocele

Varicocele: Diagnosis and Evaluation Physical examination: Grade 1: Palpable with Valsalva Grade 2: Direct palpable Grade 3: Visible with no palpation Türk Androloji Derneği, Varikosel Kılavuzu, 2005

Endications for treatment of Varicocele Infertility Symptomatic varicocele Türk Androloji Derneği Varikosel Kılavuzu, 2005

Varicocelectomy-Meta analysis-2006 Selected 8 randomized clinical studies Exclusion criterias from the meta-analysis: Subclinical varicocele Normal semen analysis Inclusion criterias to the meta-analysis: Clinical palpable varicocele Abnormal semen parameters 3 randomized studies matching to the criterias Tedavi grubu (n: 120) Kontrol grubu (n: 117) Ficarra V et al, Eur Urol 2006

Varicocelectomy-Meta analysis-2006 Treatment Control P value Pregnancy rates 36.4% 20% 0.009 Ficarra V et al, Eur Urol 2006

Inclusion criterias: Infertility Abnormal semen analysis Palpable varicocele Surgical techniques: High ligation Inguinal Microsurgical 24 months of postop follow-up Spontaneous pregnancy rates

Varicocelectomy- Meta-analysis-2007 5 randomized clinical studies Treatment group (n: 396) Control group (n: 174) Treatment Control Pregnancy rates 33% 15.5% Marmar J et al, Fertil Steril 2007

Best Candidates for Varicocelectomy Palpable, large varicocele Normal testicular volume Normal FSH/testosterone, inhibin B↓ Total Motile Sperm> 5 million No genetic abnormality Short infertility duration Fretz PC & Sandlow JI, Urol Clin North Am, 2002 Türk Androloji Derneği, Varikosel Kılavuzu, 2005

Improvement after Varicocelectomy Sperm concentration 66% Sperm motility 70% Pryor and Howards, 1987 50% increase in TMC 34 - 54% Spontaneous pregnancy 31 - 43% Çayan et al, Urology, 2000 Çayan et al, Urology, 2001 Çayan et al, J Urol, 2002

Varikosel tedavisinde en iyi teknik hangisi? Dahil edilme kriterleri: İnfertilite Anormal semen analizi Palpabl varikosel Tüm tedavi grupları Açık cerrahi Laparoskopik Radyolojik Karşılaştırma: Spontan gebelik oranları Komplikasyonlar 36 klinik çalışma: Yüksek ligasyon, Palomo (n:10) Mikrocerrahi (n:12) Laparoskopik (n:5) Radyolojik (n:6) Makroskopik (n:3) Çayan & Kadıoğlu, Submitted Review, Eur Urol, 2008

Varikosel tedavisinde en iyi teknik hangisi? Ortalama gebelik: % 39.07 (1748/4473) Yüksek ligasyon: % 37.69 Mikrocerrahi: % 41.97 Laparoskopik: % 30.07 Radyolojik: % 33.2 Makroskopik: % 36 P değeri: 0.001 P=0.001 Çayan & Kadıoğlu, Submitted Review, Eur Urol, 2008

Varikosel tedavisinde en iyi teknik hangisi? Nüks (%) Hidrosel (%) Yüksek ligasyon: 14.97 8.24 Mikrocerrahi: 1.05 0.44 Laparoskopik: 4.3 2.84 Radyolojik: 12.7 Makroskopik: 2.63 7.3 P değeri: 0.001 0.001 Radyolojik başarısız girişim: % 13.05 Laparoskopik major komplikasyon: % 7.59 P=0.001 Çayan & Kadıoğlu, Submitted Review, Eur Urol, 2008

Microsurgical Varicocelectomy n=540 Postop follow-up: 36.4 ± 22.8 months (14 - 64) Pozitive response: 50.2% Negative response: 49.8% * 50% increase in TMS Spontaneous pregnancy: 36.6% Time to achieve pregnancy: 7 ± 3.4 months (1 - 19 months) Çayan S et al, J Urol, 2002

Preoperative TMS- Post op. Spontaneous pregnancy % Kadıoğlu A & Çayan S, ASRM 2001

ART vs. Varicocelectomy? Changes in ART Candidacy POSTOPERATIVE Çayan S & Kadıoğlu A, J Urol 2002 PREOPERATIVE

Cost Per delivery ICSI: 89,091 USD Varicocelectomy: 26,268 USD Schlegel , Urology, 1997

Effect of Varicocelectomy on ART Success First IVF-ET-unsuccess; then varicocelectomy, Pregnancy: 31% (Yamamoto 1994) 40% (Ashkenazi 1989) Varicocelectomy versus IUI ? Pregnancy Delivery Op - (n:34): 6.3% 1.6% Op + (n:24): 11.8% 11.8% Daitch et al, J Urol, 2001

Poor prognosis for IUI Female age (>37) Previous pelvic surgery Decreased semen parameters Total motile sperm count<5 million Sperm motility (<40%) Untreated varicocele

Sperm morphology (Kruger) Preop Postop Kibar Y et al. 2.6% 10.2% J Urol, 2002 Çayan S et al. 3.3% 4.7% In 13%, seminal response (-)  Pregnancy (+) Kruger: 3.7%  6.2% Improvement in Kruger morphology may predict pregnancy.

Varicocele repair The best treatment modality is microsurgical repair with the lowest complication rate and the highest spontaneous pregnancy rates. Varicocelectomy has significant potential not only to obviate the need for ART, but also to downstage the level of ART needed to bypass male factor infertility. A cost effective treatment of infertility: Upgrade to normal semen: Allow natural pregnancy (40%) Upgrade from azoospermia to oligospermia (20-30%) Allow fresh sperm for IUI or IVF/ICSI Even if patients remain azoospermic, it may preserve foci of spermatogenesis for Testicular sperm recovery (TESA/TESE)

Infertility - Azoospermia: 5-20%

Correctable Pathologies in Azoospermic Men Non-obstructive azoospermia Varicocele Endocrine-Hormonal abnormalities Gonadotoxins Smoking, tobacco, alcohol, mariuhana, cocaine Radiation Drugs: Cimetidine, nitrofurantoin, GABA agonists, nifedipin, sulfonamide, ketoconazol, diethilstilbestrol, Chemotherapeutics, corticosteroids Insecticide (DDT), pesticide Termal (heating, hut tub, saunas), Pb, solvent Treatment: Treatment of underlying pathology Semen analysis after 3-12 months Obstructive azoospermia Epididymal obstruction Vas deferens obstruction Distal ejaculatory duct obstruction Treatment: Surgery

Surgical treatment alternatives Obstructive azoospermia: Vasovasostomy Epididymovasostomy MESA Macroscopic TESA TUR-ED Non-obstructive azoospermia: Microscopic TESE Microscopic varicocelectomy

Vasovasostomy- Epididymovasostomy Patency: 60-99.5% Spontaneous pregnancy: 40-60%

Transurethral resection of Ejaculatory Duct (TUR-ED) Endoscopic resection of veru-montanum Results of TUR-ED Postop. follow-up: 26 8.5 months (12-63) Total (n: 38) Improvement in seminal parameters (74%) Spontaneous pregnancy (13%) Complet obs. 59% 9% Partial obs. 94% 19% Kadıoğlu et al, Fertil Steril, 2001

Upgrading from “Nothing” to “Something Obstructive azoospermia Microsurgical reconstruction Success rate: 60-100% Pregnancy: 30-60% No need for additional surgical procedure for sperm retrieval Candidates for IUI or ICSI with fresh motile sperm from ejaculate Upgrade from azoospermia to normal semen parameters Upgrade from azoospermia to oligospermia for IUI or ICSI

Ejaculatory Dysfunction-Anejaculation Reasons for anejaculation: · Spinal cord injury · Pelvic and retroperitoneal surgery · Psychogenic causes · Idiopathic · Multiple sclerosis · Diabetes · Prolactinoma Overall 61.1% (11/18) of couples achieved pregnancy Çayan & Turek, Fertil Steril, 2001

Summary Achieving natural pregnancy, while ideal, should not be the only measurement of treatment efficacy. Clinicians should offer treatment that improves the long term fertility status of the couples, not just to achieve immediate pregnancy. Pathophysiologic specific treatment in male infertility has significant potential not only to obviate the need for ART, but also to downstage the level of ART needed to bypass male factor infertility. Effective treatment may be surgical, medical or simple lifestyle modifications. Upgrade from nothing to IVF/ICSI Upgrade from IVF/ICSI to IUI Upgrade from IUI to natural pregnancy