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Testicular Failure and Male Infertility - New Insights and Evolution of Treatment Options

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  • 1. EOFF 2012, Dubai - UAE Sandro Esteves, MD, PhD Director, ANDROFERTCenter for Male Reproduction and Infertility Campinas, BRAZIL
  • 2. Learning Objectives Understand the concept of testicular failure Learn the treatment options and results for men with testicular failure in the current ART era Update on new treatment options and what the future holds for men with testicular failure seeking fertilityEsteves, 2
  • 3. Review this lecture at:http://www.androfert.com.br/review Pdf slides Movie
  • 4. Sperm Count in Humans General Population of Unscreened Men Centiles 2.5% 50% 97.5% Sperm count per mL (x106) 4 64 237 Azoospermia • Complete absence of sperm in the ejaculate • 1-3% male population • ~10-15%% male infertility populationEsteves, 4 Cooper et al. Hum Reprod Update 2009; Esteves et al, CLINICS 2011
  • 5. Semen Analysis and Azoospermia Centrifugation at 3,000g for 15 minutes The supernatant is discharged and the pellet is examinedEsteves, 5
  • 6. Types of Azoospermia Non- Obstructive obstructive • Normal sperm production • Absent or minimal sperm • Mechanical blockage anywhere production within the along the reproductive tract testicles • Epididymis • Vas Deferens • Testicular failure • Ejaculatory DuctEsteves, 6
  • 7. Esteves, 7 UN Census Estimates, 2008
  • 8. Testicular Failure: Etiology Congenital Testicular dysgenesis/cryptorchidism Genetic abnormalities (Klinefelter’s syndrome, Yq microdeletions) Germ cell aplasia (SCO syndrome) Spermatogenic (maturation) arrest Acquired Testicular torsion; Trauma Post-inflammatory (eg. mump’s orchitis) Exogenous factors (steroid medications, cytotoxic drugs, irradiation, heat) Testicular Cancer; Systemic diseases (liver cirrhosis, renal failure) Varicocele Idiopathic (Unknown etiology)Esteves, 8
  • 9. Understand the concept of testicular failure 1. Azoospermia is a descriptive term of ejaculates that lack spermatozoa without implying a specific underlying cause. 2. Testicular failure is synonymous of non- obstructive azoospermia (most severe form of male infertility). It represents a spectrum of testicular disorders that cannot be treated.Esteves, 9
  • 10. Testicular Failure: The PAST NOA Untreatable condition Small testes Elevated FSH AID Adoption “Sterile” Esteves et al. An update on the initial assessment of the infertile male.Esteves, 10 CLINICS 2011;66:1-10.
  • 11. Testicular Failure: The FACT 600-800 seminiferous tubules/testis 30-50% cases: minimal production for sperm to appear in the ejaculate • Heterogeneity of sperm production • Foci of sperm production may exist in dysfunctional testes Esteves SC & Agarwal A. Sperm Retrieval Techniques; In: Gardner D et al (Eds.), Human Assisted Reproductive Technology. Cambridge University Press, pp. 41-53, 2011Esteves, 11
  • 12. Testicular Failure: The PRESENT  Single focus of production adequate to retrieve sperm for ICSI  Goal: To identify and retrieve sperm for ICSI Esteves SC & Agarwal A. Sperm Retrieval Techniques; In: Gardner D et al (Eds.), HumanEsteves, 12 Assisted Reproductive Technology. Cambridge University Press, pp. 41-53, 2011.
  • 13. Testicular Failure: The PRESENT Technique AcronymTesticular Sperm Aspiration TESA; TEFNA NOATesticular Sperm Extraction TESE(single or multiple biopsies) Untreatable conditionMicrosurgical Testicular Sperm Micro-TESEExtraction Sperm Retrieval and ICSI Esteves et al. Sperm Retrieval Techniques for Assisted Reproduction.Esteves, 13 Int Braz J Urol 2011; 37(5):570-83
  • 14. Testicular Failure: The PRESENT Critical Issues Which is the best technique to retrieve sperm? What are the Is it possible success to predict rates and success in risks of sperm ICSI? retrieval?Esteves, 14
  • 15. Sperm Retrieval in Testicular Failure: which is the best technique? TESE Conventional • 15%- • 20%- • 40%- TESA Micro-TESE 50% 63% 67% SRR SRR SRR Friedler et al. 1997; Ezeh et al. 1998; Schlegel 1999; Amer et al. 2000; Okada et al. 2002; Okubu et al. 2002; Tsujimura et al. 2002; Ramon et al. 2003;Esteves, 15 Verza Jr. & Esteves 2011.
  • 16. Sperm Retrieval in Testicular Failure: which is the best technique? Schlegel 1999 Amer et al. 2000 Micro- Controlled Series Okada et al. 2002 TESE 43%-53% Okubu et al. 2002 Tsujimura et al. 2002 TESE 25%-41% Ramon et al. 2003 Esteves et al. 2011Esteves, 16
  • 17. Goals of Sperm Retrieval in Testicular Failure Immediate Obtain use for sperm ICSI for ICSI Cryopreservation Future retrievals Minimize damage Testicular functionEsteves, 17
  • 18. Available at http://androfert.com.br/videos
  • 19. In Testicular Failure, higher chances of sperm harvesting by micro-TESEEsteves, 19
  • 20. Is it possible to predict success of sperm retrieval? FSH levels Testosterone Testicular Testicular levels Volume Histopathology No Markers reflect global spermatogenic function but not the presence of an advanced site of sperm production in a dysfunctional testis. Esteves, Miyaoka & Agarwal. Surgical Treatment of Male Infertility in the ICSI Era. Clinics 2011; 66:1463-77; Verza Jr. & Esteves. Fertil Steril 2011; 96: S53;Esteves, 20 Carpi et al. Fertil Steril 2009.
  • 21. Is it possible to predict success of sperm retrieval? Etiology Retrieval Rate Cryptorchidism 52-74% Varicocele 63-68% Post-infection 67% Torsion >50% Post-chemotherapy/RT 25-75% Genetic (Klinefelter, AZFc Yq microdeletions) 25-70% Idiopathic 50-60% No Presence of an advanced site of sperm production is not related to the etiology of testicular failure. Esteves et al., Fertil Steril 94; 2010; Raman and Schlegel. J Urol.170; 2003;Esteves, 21 Hopps et al. Hum Reprod. 180, 2003; Damani et al. JCO. 15; 2002
  • 22. Is it possible to predict success of sperm retrieval? Y Chromosome Microdeletion Screening Prevalence of Yq microdeletions: 1:2.000-3.000 newborns Men with testicular failure: 5-12%Esteves, 22 Esteves & Agarwal. Novel concepts in male infertility. Int Braz J Urol 2011.
  • 23. Is it possible to predict success of sperm retrieval? Y Chromosome Microdeletion Screening AZFa AZFb AZFc deletion deletion deletion No chance to No chance to Sperm retrieved in find sperm find sperm ~70% of cases Yes The only unfavorable indicator for SR is the presence of microdeletions in the AZFa and/or AZFb regions of the Y chromosome long arm Esteves SC & Agarwal A. Novel concepts in male infertility. Int Braz J Urol 2011; 37:5-15.Esteves, 23
  • 24. What are the success rates of ART in testicular failure ? Testicular Failure (n=228) Ejaculated sperm (n=621) Obstructive azoospermia (n=243) 64.5 62.9 *P<0.01 43.7 * * 45.3 47.8 52.5 37.5 * 32.3 19.2 19.6 21.0 21.4 %2PN Fertilization %Top quality % Miscarriage % Live birth embryos Esteves & Agarwal. Reproductive outcomes including neonatal data of sperm injection in men with obstructive and nonobstructive azoospermia: case seriesEsteves, 24 and systematic review. CLINICS, in press
  • 25. What are the success rates and risks of ART in testicular failure ? Testicular Failure (n=63) Ejaculated Sperm (n=247) Obstructive Azoospermia (n=117) 273.3 244.6 257.7 P = NS 35.7 36.9 37.0 6.3 2.0 2.5 3.2 1.2 1.7 Gestational age Birth weight % Perinatal death % Birth defects (wks) (gramsx10) Esteves & Agarwal. Reproductive outcomes including neonatal data of sperm injection in men with obstructive and nonobstructive azoospermia: case series and systematic review. CLINICS, in pressEsteves, 25
  • 26. What are the success rates and risks of ART in testicular failure ? N children Region Testicular Outcomes Main findings failure vs OA Palermo et USA 22 vs 158 Congenital 4.5% TF vs 1.3% OA (ns) al. 1999 abnormalities Vernaeve et Belgium 61 vs 196 Perinatal data Lower gestational age al. 2005 (singletons); Increased frequency of premature twins Congenital 4% TF vs 3% OA (ns) abnormalities Fedder et al Denmark 76 vs 282 Congenital 0% TF vs 4.0% OA (ns) 2007 abnormalities Belva et al.; Belgium 193 vs 474 Perinatal data; Similar perinatal outcomes; 2011 Congenital 4.2% TF vs 5.2% OA (ns) abnormalities Esteves et al. Reproductive outcomes including neonatal data of sperm injection in men with obstructive and nonobstructive azoospermia: case series and systematic review.Esteves, 26 CLINICS, accepted
  • 27. Learn the treatment options and results for men with testicular failure in the current ART era 1. Men with testicular failure are not sterile. 2. Sperm retrieval and ICSI using testicular sperm viable option to achieve biological fatherhood. 3. So far, post-natal follow-up of babies born from such fathers are reassuring.Esteves, 27
  • 28. Testicular Failure New Insights & Future Perspectives Medication Surgery; Artificial Sperm Male Retrieval Gamete TechniquesEsteves, 28
  • 29. Testicular Failure: New Insights (1) Medication prior to Sperm Retrieval  Case series: 68 men with testicular failure (non-mosaic Positive response Klinefelter Syndrome; micro- 72 TESE  Medication to boost 55 testosterone production: P = 0.03 Aromatase inhibitor, hCG, anti- estrogens (min. 2-3 months)  Positive response: increase in TT >100 ng/dL from baseline Sperm Retrieval Rate (%) levelsEsteves, 29 Ramasamy et al., J Urol. 2009; 182: 1108-13.
  • 30. Testicular Failure: New Insights (2) Anti-estrogens Microsurgical 43 pts. with favorable testicular Varicocele Repair histopathology, no controls; Meta-analysis of case series; CC 50mg every other day; 39% men had motile sperm in 64% men had sperm in the ejaculates postop. (mean: 1.6 M/mL) ejaculates (mean: 3.8 M/mL); Weedin JW et al, J Urol. 2010 All who remained azoospermic Increased the chances of Sperm had success in Sperm Retrieval. Retrieval by 2.6-fold in men who remained azoospermic. Hussein et al, J Androl 2005 Inci et al, J Urol. 2009Esteves, 30
  • 31. Testicular Failure: The Future (1) Novel Sperm Retrieval Methods forIdentification of Confocal fluorescence microscopySpermatogenic (in vivo; murine model) Sites Multi-photon microscopy (ex vivo; human model) Full-field optical coherence tomography (ex vivo; rat model) Najari et al, J Urol 2012; Smith et al J Urol 2012; Ramasamy et al., J Pathol Inform 2012
  • 32. Testicular Failure: The Future (2) NOA Treatable condition Biotechnology Methods to Create Artificial Gametes Aponte PM, Schlatt S, Franca LR. Biotechnological possibilities for the treatment of aspermatogenic men. Clinics 2012Esteves, 32
  • 33. Be informed on the new treatment options and what the future holds for men with testicular failure seeking fertility 1. Aromatase inhibitors, anti- estrogens and varicocele repair may improve outcomes in selected cases. 2. Novel methodologies of sperm harvesting are under research. 3. Novel biotechnological methodologies are under research to rescue fertility while maintaining biological fatherhood.Esteves, 33
  • 34. Thank you.