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Antioxidants: To whom and how Seminal Reactive Oxygen Species (ROS) (Log ROS + 1; cpm) 2,5 2 1,5 1 0,5 0 Fertile Infertile Pasqualotto et al., Fertil Steril 2000Esteves, 5
Evidence-based Use of Antioxidants in Male Infertility Author Antioxidant Agent ResultsGeva et al., 1996 Vit E 200 mg Increased fertilization in IVFSuleiman et al, 1996 Vit E 100 mg Decreased ROS; increased spontaneous PRWong et al., 2002 Folic acid 5 mg + Zinc Increased total sperm count 66 mgGreco et al., 2005 Vit C 1.0 g + E 1.0 g Improved sperm DNA integrityGreco et al., 2005 Vit C 1.0 g + Vit E 1.0 g Increased CPR and IR in ICSI cyclesTremellen et al., Menevit® (vit C + E; Increased IR/PR in IVF/ICSI2007 zinc 25 mg; selenium 26 cycles mcg; lycopene 6 mg)Boxmeer et al., 2009 Decreased folate in Increased sperm DNA seminal plasma fragmentation
Antioxidant Treatment Cochrane Review 2011 Outcome N N Effect size studies participants (OR; 95% CI)Live birth 3 214 4.85 [1.92, 12.24]Pregnancy rate 15 964 4.18 [2.65, 6.59]DNA fragmentation 1 64 -13.80 [-17.50, -10.10]Miscarriage, sperm 6-16 242-700 No effectcount, sperm motilityAdverse effects 6 426 No effectImprove the outcomes of live birth and pregnancy rate for subfertile couples undergoing ART cycles Showell MG, Brown J, Yazdani A, Stankiewicz MT, Hart RJ. Antioxidants for male subfertility. Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD007411. DOI: 10.1002/14651858.CD007411.pub2.
Antioxidants in Male Infertility To whom? Everyone How? q.d. Vitamic C 500mg Vitamin E 400 UI Folic acid 2 mg Zinc 25 mg Selenium 26 mcg How long? Esteves et al. What the gynecologist should know about male infertility:Esteves, 8 an update. Arch Gynecol Obstet 2012; Epub March 6
From Initiation of Sperm Production to Ejaculation Old concept ~80 daysNew concept ~60 days Misell LM et al.: A stable isotope-mass spectrometric method for measuring human spermatogenesis kinetics in vivo. J Urol. 2006; 175: 242-6.
Semen analysis: New WHO StandardsSemen Parameter WHO 1999 WHO 20101Volume (mL) ≥2.0 1.5Count (x106/mL) ≥20 15Total sperm number per ejaculate ≥40 39Motility (%) ≥50 (a+b) 32 (a+b)Vitality (%) ≥75 58Morphology (%)2 (14) 4Leukocytes (x106/mL) <1.0 <1.01Lower Limit (5% percentile), Recent fathers; 2Strict criteriaGrade a = rapid progressive motility; Grade b = slow/sluggish progressive motility
Percentile distribution of semen characteristics values of recent fathers (1,953) whose partners had a TTP ≤ 12 months, used to establish the reference limits in the 2010 WHO manual Centiles 5% 50%* 95% Volume (mL) 1.5 3.7 6.8 Sperm count per mL (x106) 15.0 73.0 213.0 Sperm count per ejaculate (x106) 39.0 255.0 802.0 % Motility (total) 40 61 78 % Motility (progressive) 32 55 72 % Normal (strict criteria) 4 15 44 % Alive (eosin-nigrosin staining) 58 79 91 Cooper et al: World Health Organization reference values for human semen characteristics. Hum Reprod Update 16: 231-245, 2010Esteves, 11
New WHO standards Should we adopt them? Critical Appraisal of the WHO New ReferenceValues for Human Semen and Impact on Diagnosis and Treatment of Subfertile MenSandro Esteves, BRAZILArmand Zini, CANADANabil Aziz, UNITED KINGDOM Urology 2012Juan Alvarez, SPAIN Jan;79(1):16-22.Edmund Sabanegh, USAAshok Agarwal, USA
New WHO standards Critical Appraisal - Summary Reasons for lower Merits Demerits cutt-off Different way of Controlled studies No systematic review generating data: of fertile populations: • Method for semen Recent fathers with • Not representative of analysis (higher QC known TTP global fertile male standards; strict population morphology) Standardized semen Morphology using • Population studied analysis different criteria Single semen specimen of each individualEsteves, 13
Oslo Turku Norway FinlandColumbia,Minneapolis EdimburghUSA UK Copenhagen Paris Denmark France Melbourne Australia Critical Appraisal of the WHO New Reference Values for Human Semen and Impact on Diagnosis and Treatment of Subfertile Men Esteves, Zini, Aziz et al, Urology, in press
New WHO Standards: Implications • Reclassification of semen analysis reports Couples (N=987) with infertility duration > 12 months Abnormal results WHO 1999 Reclassified as “Normal” WHO 2010 Morphology results (38.7%) accounted for 53% of reclassificationEsteves, 15 Source: ANDROFERT, Brazil
New WHO Standards Not accurate to discriminate fertile and infertile men A comprehensive infertility workup, including sperm function testing, is crucial to assess the male fertility potential Esteves, Miyaoka & Agarwal. An update on the initial assessment of the infertile male.Esteves, 16 CLINICS 2011; 66:1-10.
New Diagnostic Tests• Beyond routine semen analysis • Sperm DNA Integrity Testing • Y Chromosome Microdeletion Screening Esteves SC & Agarwal A. Novel concepts in male infertility. Int Braz J Urol 2011; 37:5-15.
Sperm DNA Integrity Testing • Normal sperm chromatin essential for Background paternal genetic transmission • Infertility Sperm DNA • Recurrent pregnancy loss Damage • Poor outcomes in IUI and IVF • Quantification of sperm DNA strand Principle breaks Specimen • Semen • Nuclear dyes (Acridine orange, SCSA) Techniques • Direct assessment (TUNEL, COMET) • Nuclear matrix assays (SCD)Esteves, 18
Sperm DNA Integrity Testing & ART Pregnancy by Sperm Pregnancy by Sperm DNA DNA Integrity Results in Integrity Results in IVF and IUI ICSI 20% 50,00% * <.05 15% 40,00% 30,00% * 10% 20,00% 5% OR 0.07 (0.01-0.48) 10,00% 0% 0,00% DFI ≤30% DFI >30% IVF ICSI Live birth (%) DFI>30% Bungum et al. Sperm DNA integrity assessment in prediction of assisted 19 reproduction technology outcome. Hum Reprod 2007; 22: 174-9.Esteves
Y Chromosome Microdeletion • Deletions linked to Genetic Causes ofBackground spermatogenic failure Male Infertility • Severe oligozoospermia 5%To whom? 10% and NOA 5% • PCR of the long arm of Principle Y-chromosome 80% Specimen • Peripheral blood • Diagnosis and Klinefelter Syndrome (47,XXY) Clinical predictive value for Y-chromosome microdeletionSignificance sperm retrieval Congenital Vas Absence Esteves SC & Agarwal A. Novel concepts in male infertility. Int Braz J Urol 2011; 37:5-15.
Predictive Value of Yq Microdeletion Screening for Sperm Retrieval in NOA AZFa AZFb AZFc deletion deletion deletion No retrievable No retrievable Sperm retrieved in sperm sperm 70% of cases Esteves SC & Agarwal A. Novel concepts in male infertility.Esteves, 21 Int Braz J Urol 2011; 37:5-15.
Surgical Treatment of VaricoceleFertilityRestorationSpontaneousPregnancy
Varicocelectomy for Fertility Restoration Fertil Steril 2007;88:639–48.Esteves, 23
Surgical Treatment of Varicocele • It can improve success of ART Fertility ImprovementFertility ICSIRestoration OutcomesSpontaneousPregnancy Fertility Improvement Sperm Retrieval in Azoospermia
Varicocele Repair Before ICSIClinical Outcome of Intracytoplasmic Sperm Injection in Infertile Men With Treated and Untreated Clinical Varicocele SC Esteves, FV Oliveira, RP Bertolla. ANDROFERT, Center for Male Reproduction, Campinas, BRAZIL and Division of Urology, São Paulo Federal University, São Paulo, BRAZIL.The Journal of Urology Vol. 184,1442-1446, October 2010 Total Number of Motile Microsurgical Sperm (x106) varicocele repair prior 15.4 to ICSI (N=80) P<0.01 6.7 ICSI in the presence of varicocele (N=162) Pre-op Post-op
Varicocele and ICSI Outcomes Treated Varicocele Untreated Varicocele 78%* 66% *P<0.05 46%* 31% 31% 22% Fertilized Eggs Live Birth (%) Miscarriage (%) (%2PN)Odds ratio 1.87 0.4395% CI 1.08 - 3.25 0.22 – 0.84P-value 0.03 0.01Esteves SC, Oliveira FV, Bertolla RP. Clinical Outcome of ICSI in Infertile Men with Treated and Untreated Clinical Varicocele. J Urol 2010;184:1442-1446
Varicocele Repair Before Sperm Retrieval Sperm Retrieval and Intracytoplasmic Sperm Injection in Men With Nonobstructive Azoospermia, and Treated and Untreated Varicocele K Inci, M Hascicek, O Kara et al. Department of Urology, School of Medicine, Hacettepe University, Ankara, Turkey.The Journal of Urology Vol. 182,1500-1505, October 2009 Successful Sperm Retrieval Microsurgical Rate varicocele repair priorto sperm retrieval ICSI OR: 2.63 (95% CI: 1.05-6.60; P=0.03) (N=66) 53% 30%Sperm Retrieval in thepresence of varicocele (N=30) Treated Varicocele Untreated Varicocele
Azoospermia • It is not a synonymous of sterility Non-Obstructive obstructive• Normal sperm production • Sperm production deficient or absent• Mechanical blockage • Cryptorchidism, Radiation,• Vasectomy, Post- Chemotherapy, Trauma, infectious, Congenital Genetic, Orchitis, Varicocele, Gonadotoxins, Unexplained
Obstructive Azoospermia • MicrosurgicalPotentially reconstruction treatable • TURED Sperm • Epididymis • Testis retrieval • Simple and for ART effective Esteves, Miyaoka & Agarwal. Surgical Treatment of Male Infertility in the ICSI Era. CLINICS 2011; 66:1463-77.
Esteves SC, et al. Success of percutaneous sperm retrieval andintracytoplasmic sperm injection (ICSI) in obstructive azoospermic (OA) men according to the cause of obstruction. Fertil Steril. 2010;94 (Suppl):S233.
Non-obstructive Azoospermia Sperm • Sperm productionUntreatable reduced or absent Retrieval condition • Geographic location for ART unpredictableTESATESE
Non-obstructive Azoospermia TESA vs. TESE
Micro-TESE vs TESESuccess Rates in Controlled SeriesSchlegel 1999Amer et al. 2000Okada et al. 2002Okubu et al. 2002 53% 41%Tsujimura et al. 2002Ramon et al. 2003 TESE Micro-TESEEsteves et al. 2011 OR = 1.63 (95% CI: 1.32 – 2.01)
Sperm Retrieval and Reproductive Potential of Men with OA and NOA with ICSI 97.9% Obstructive (N=142) Non-obstructive (N=172) 55.2% 38.2% 25.0% Sperm Retrieval Live Birth Odds ratio 43.0 1.86 95% CI 10.3 – 179.5 1.03 – 2.89 P-value <0.01 0.03 Prudencio C, Seoul B, Esteves SC. Reproductive potential of azoospermic men undergoing intracytoplasmic sperm injection is dependent on the type of azoospermia. Fertil Steril 2010; 94(4):S232-3.
Take-home Messages (1) Antioxidants helpful to decrease oxidative stress. Treatment effect is noted > 60 days later. New WHO standards have several shorcomings. Caution to interpret results. Sperm DNA integrity and Y-chromosome microdeletion testing have prognostic value in ART.Esteves, 37
Take-home Messages (2) Treatment of Clinical Varicoceles prior to ICSI may be beneficial for patient subgroups of severe oligozoospermia and NOA. Most azoospermic men are not sterile. Sperm retrieval and reproductive potential is dependent on the type of azoospermia.Esteves, 38