Testicular Sperm Retrieval and Poor Sperm Yield: How do we manage?
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Testicular Sperm Retrieval and Poor Sperm Yield: How do we manage?
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Testicular Sperm Retrieval and Poor Sperm Yield: How do we manage?
- 1. 2nd SGH SOAR, Singapore 2014 Testicular Sperm Retrieval and Poor Sperm Yield How do we manage? Sandro C. Esteves, MD, PhD Medical Director, ANDROFERT Campinas, Brazil
- 2. Learning objectives At the completion of this presentation, participants should be able to: • Differentiate obstructive and non-obstructive azoospermia • Identify who are at risk of poor sperm yield on testicular retrievals • Learn what can be done to improve sperm yield at testicular retrievals ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2014 SEPTEMBER
- 3. Testicular Sperm Retrieval and Poor Sperm Yield How do we manage? http://www.androfert.com.br/review ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2014 SEPTEMBER
- 4. Sperm Output Where we stand compared to our ‘relatives’ 100 lbs 64 cc >1 billion/ mL 600 lbs 14 cc 5 million/ mL 180 lbs 20 cc 64 million/ mL Chimpanzee Human Gorilla ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 4 2014 SEPTEMBER
- 5. Sperm Count General Population of Unscreened Men 2.5% 50% 97.5% 4 M/mL 64 M/mL 237 M/mL Azoospermia: Complete lack of sperm in the ejaculate 1-3% male population 10-15% male infertility population Cooper et al. Hum Reprod Update 2009; Esteves et al, Clinics 2011 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2014 SEPTEMBER
- 6. Semen Analysis in Azoospermia DiagnCoenstirsif u-‐g Sa+eomn en Analysis (x2) at 3,000g for 15 minutes The supernatant is discharged and the pellet is examined ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2014 SEPTEMBER
- 7. Differential Diagnosis in Azoospermia Azoospermia ObstrucIve Non-‐ obstrucIve Subtypes TesIcular failure Hypo-‐hypo Spermatogenesis Normal Disrupted Clinical Picture NL testes NL FSH, LH, TT Mechanical block FSH/LH: ! or nl TT: low/nL Testes: small/nL FSH/LH <1.2 mUI/mL Low TT Small tesIs Poor virilizaIon ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2014 SEPTEMBER
- 8. Frequency of Azoospermia Categories ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2014 SEPTEMBER Esteves et al. Clinics 2011;66(4):691-700.
- 9. Hypogonadotropic Hypogonadism • Deficient virilization; hypotrophic testes • Azoospermia • Low FSH and LH (<1.2 mIU/L) • Low testosterone levels (<300 ng/dL) Congenital: Ø Kallman syndrome Ø Prader-Willi Acquired: Ø Pituitary tumor; Steroid abuse Ø Testosterone replacement therapy ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2014 SEPTEMBER Fraietta et al. Clinics 68; 2013
- 10. Adult onset hypo- hypo Specific medical therapy Classic treatment for male hypogonadism and infertility Urinary hCG 1,000-2,000 UI IM injections; twice or t.i.w; minimum 12 weeks Rec-hCG: SC self-injection w/pre-filled syringe, qw Fraietta et al., Clinics 2013;68(Suppl.1):81-8. ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2014 SEPTEMBER
- 11. Rec-‐hCG for male hypo-‐hypo Series of men with adult-onset HH; Recombinant hCG (Ovitrelle 250 mcg) Baseline Posttreatment Esteves & Papanikolaou Fertil Steril 2011 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2014 SEPTEMBER
- 12. Obstructive Azoospermia: Etiology Congenital Congenital bilateral absence of vas deferens (CBAVD) Ejaculatory duct and prostatic cysts Post-infection (epididymitis, prostatitis, seminal vesiculitis) Acquired Post-surgical (vasectomy, epididymal cysts, hernia, scrotal surgery, bladder neck surgery, prostatectomy) Iatrogenic (urological endoscopic instrumentation) Idiopathic (Unknown etiology) Esteves et al. Clinics 2011;66(4):691-700 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2014 SEPTEMBER
- 13. Obstructive Azoospermia (OA) Surgical Treatment sperm retrieval and ICSI Management ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2014 SEPTEMBER
- 14. Sperm Retrieval in OA Technique Acronym Percutaneous Epididymal Sperm Aspiration PESA Microsurgical Epididymal Sperm Aspiration MESA Testicular Sperm Aspiration TESA Esteves & Agarwal. Sperm Retrieval Techniques. Cambridge University Press, 2011 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2014 SEPTEMBER
- 15. Sperm yield in OA is usually great ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2014 SEPTEMBER
- 16. Sperm retrieval in CBAVD 146 patients OBSTRUCTIVE AZOOSPERMIA 100% 96.6% 96.3% CBAVD Vasectomy Post-‐infection PESA + rescue TESA PESA alone ~100% 78.1% Successful Retrievals Esteves et al. J Urol. 2013;189(1):232-7 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2014 SEPTEMBER
- 17. ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2014 SEPTEMBER Esteves et al. J Urol. 2013;189(1):232-7
- 18. Non-obstructive Azoospermia: Etiology Congenital Testicular dysgenesis/cryptorchidism Genetic abnormalities (Klinefelter syndrome, Yq microdeletions, etc.) Acquired Testicular torsion; Trauma Post-inflammatory (eg. Mumps orchitis) Exogenous factors (steroids, cytotoxic drugs, irradiation) Testicular Cancer Systemic diseases (liver cirrhosis, renal failure) Idiopathic (Unknown etiology) Untreatable condition Sperm Retrieval and ICSI ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2014 SEPTEMBER Esteves et al. Clinics 2011;66(4):691-700.
- 19. Non-obstructive Azoospermia (NOA) Overall, 40%-50% men with NOA have minimal production within the testis, but not enough for sperm to appear in ejaculate — Goal is to identify site of production and retrieve sperm for ICSI — Geographic location unpredictable Esteves SC & Agarwal A. Sperm Retrieval Techniques; In: Gardner D et al (Eds.), Human Assisted Reproductive Technology. Cambridge University Press, pp. 41-53, 2011 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 19 2014 SEPTEMBER
- 20. Sperm retrieval in NOA Technique Acronym Success Testicular Sperm Aspiration TESA 15-50% Testicular Sperm Extraction TESE 20-60% Microdissection Testicular Sperm Extraction Micro- TESE 40-67% Esteves et al. Sperm Retrieval Techniques. Int Braz J Urol 2013;37(5):570-83 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2014 SEPTEMBER
- 21. 1. Azoospermia is descriptive term of ejaculates lacking sperm without implying specific underlying causes 2. Differential diagnosis include hypo-hypo, obstructive azoospermia (OA) and non-obstructive azoospermia (NOA) 3. Specific medical and surgical treatments exist for hypo-hypo and OA, with overall good results ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2014 SEPTEMBER
- 22. 4. Obstructive azoospermia is not associated with poor sperm yield; success is high regardless of retrieval method and cause of obstruction ANDROFERT androfert.com.br 5. SR only option for men with NOA associated with spermatogenic failure; testis is the target organ for sperm retrieval attempt 6. In general, men with NOA are at risk of poor sperm yield at testicular retrievals ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2014 SEPTEMBER
- 23. How to Manage Testicular Retrievals Diagnosis To Avoid Poor Sperm Yield Identify who are at risk for poor sperm yield Select who could benefit from interventions prior to testicular SR Select the best testicular SR method Proper lab handling of surgically-extracted testicular gametes ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2014 SEPTEMBER
- 24. SelecIng candidates for SR Can biomarkers predict SR success? Sperm yield in testicular retrievals Do biomarkers play a role? FSH levels Testosterone levels Testicular Volume Esteves, Miyaoka & Agarwal. Clinics 2011; Verza Jr. & Esteves. Fertil Steril 2011; Carpi et al. Fertil Steril 2009. No Markers reflect global spermatogenic function but not the presence of a site of sperm production in a dysfunctional testis ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 24 2014 SEPTEMBER
- 25. Sperm yield in testicular retrieval Does histopathology play a role? Sperm Retrieval Success Rates 93% Micro-TESE (N=60) 64% 20% Hypospermatogenesis Maturation Arrest Sertoli-cell Only Verza Jr & Esteves. Fertil Steril 2011 Testicular Histopathology ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2014 SEPTEMBER
- 26. Sperm yield in testicular retrieval Does etiology play a role? Etiology category SR success Cryptorchidism 52-74% Post-infection 67% Torsion >50% Post-chemotherapy/RT 25-75% Genetic (Klinefelter, AZFc Yq microdeletions) 25-70% Genetic (AZFa and AZFb Yq microdeletions) 0% Idiopathic 50-60% Esteves et al., Fertil Steril 94; 2010; Raman and Schlegel. J Urol.170; 2003; Hopps et al. Hum Reprod. 180, 2003; Damani et al. JCO. 15; 2002 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2014 SEPTEMBER
- 27. Sperm yield in testicular retrieval Yq microdeletion screening ✕ ✕ ✕ SRR=0% 0% 50-70% Hamada et al. 2013; Krausz et al. 2014; Esteves et al. 2013 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2014 SEPTEMBER
- 28. Who is at risk of poor sperm yield at testicular retrievals Key Messages Sertoli cell-only hystopathology and non-mosaic Klinefelter syndrome Yq microdeletions AZFa, AZFb and AZFb+c associated with virtually no chance of sperm acquisition Yq microdeletion screening mandatory to “deselect” men from testicular retrieval attempts ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2014 SEPTEMBER
- 29. Who benefit from interventions prior to testicular retrieval? can benefit from intervenIons prior to sperm retrieval? NOA and hypogonadism (TT<300ng/dL) NOA and clinical varicocele ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2014 SEPTEMBER
- 30. Medical therapy prior to testicular retrieval Klinefelter Syndrome Positive response P = 0.03 Ramasamy et al., J Urol. 2009 Ø 68 men with non-mosaic KS Ø NOA and hypogonadism Ø Medication to boost testosterone production: Aromatase inhibitor, hCG, anti-estrogens (2-3 months) Ø Micro-TESE as SR method Ø Positive response: increase in TT >100 ng/dL from baseline levels 72 55 Sperm Retrieval Rate (%) ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2014 SEPTEMBER
- 31. Medical therapy prior to testicular retrievals Favorable testicular histology 64% men had sperm in the ejaculates post-Tx (mean: 3.8 M/mL) Spermatozoa obtained by SR in all who remained azoospermic 43 patients with NOA and hypospermatogenesis on testicular histopathology Anti-estrogen (CC 50mg) every other day; no controls Hussein et al, J Androl 2005 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2014 SEPTEMBER
- 32. Medical therapy before SR General population of men with NOA and hypogonadism Positive response (n=252) No response (n=55) ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2014 SEPTEMBER 51 51 Sperm retrieval rate (%) Ø Case series (n=307) Ø Hypogonadism (TT<300) Ø Micro-TESE Ø Aromatase inhibitor, hCG, anti-estrogens (min. 2-3 months) Ø Positive response post-Tx TT >250 ng/dL Ramasamy et al., J Urol. 2011
- 33. hCG in non-obstructive azoospermia prior to testicular sperm retrieval PCNA expression Shinjo E et al Andrology 2013;1(6):929-35; Shiraishi et al Hum Reprod 2012;27(2):331-9. ITT (ng/dl) 273 1348 Before After Increase in ITT levels Increase in spermatogonial DNA synthesis ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2014 SEPTEMBER
- 34. hCG in non-obstructive azoospermia prior to sperm retrieval • Successful SR in ~15% of patients with previous failed SR attempts after hCG alone or hCG+FSH Shiraishi et al Hum Reprod 2012;27(2):331-9 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2014 SEPTEMBER
- 35. Medication prior SR in NOA Androfert algorithm Estradiol Levels Total Testosterone levels <300 ng/dL (10.4 nmol/L) T/E ratio <10 Hypogonadism category T/E ratio >10 (nl) Aromatase hyperactivity Pure Treatment Aromatase inhibitors (anastrozole 1mg qid, 12 weeks Rec-hCG 250 mcg 1x/week; CC 25mg qid; 12 week ANDROFERT androfert.com.br Klinefelter syndrome; Obesity SCO; Hypospermatogenesis ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2014 SEPTEMBER
- 36. Varicocele repair prior testicular retrieval in NOA Meta-analysis of 11 series (N=233) 39% men had motile sperm in postop. ejaculates (mean: 1.6 M/mL) Weedin JW et al, J Urol. 2010 Retrospective study with 96 pts. with treated and untreated varicocele SR success: 53% vs 30% (increased by 2.6-fold in treated pts.) Inci et al, J Urol. 2009 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2014 SEPTEMBER
- 37. Interventions in men with NOA prior to testicular retrieval Key Messages AI, CC, hCG may increase sperm yield in some patients, particularly those with hypogonadism Microsurgical varicocelectomy may be useful in selected patients with clinical varicocele ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2014 SEPTEMBER
- 38. Testicular sperm retrieval in NOA which is the best technique? Schlegel 1999 Amer et al. 2000 Okada et al. 2002 Okubu et al. 2002 Tsujimura et al. 2002 Ramon et al. 2003 Esteves et al. 2011 43%-63% 17%-45% Controlled Series TESE Esteves et al. Int Braz J Urol 2011; Deruyver et al. Andrology 2014 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2014 SEPTEMBER
- 39. Esteves SC, Int Braz J Urol 2013; 39(3):440 http://androfert.com.br/videos
- 40. Microsurgical vs Single-Biopsy TESE in NOA according to testicular histology Controlled series (N=60) 45% Sperm Retrieval Success Rates Micro-TESE single-biopsy TESE 93% 64% 64% Histology categories pairwise Comparisons: p<0.0001 25% 20% 9% 6% Overall Hypospermatogenesis Maturation Arrest Sertoli-cell Only Verza Jr & Esteves. Fertil Steril 2011 Method P=0.0005 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 40 2014 SEPTEMBER
- 41. Selecting the best retrieval method is key to increase sperm yield at testicular retrievals Deruyver et al. Microdissection TESE compared with conventional TESE in non-obstructive ANDROFERT androfert.com.br Higher retrieval rates with micro-TESE in patients at risk of poor sperm yield, such as those with NOA ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 41 2014 SEPTEMBER azoospermia: a systematic review. Andrology 2014; 2(1):20-4
- 42. Laboratory handling of surgically-retrieved Sperm yield in testicular retrieval spermatozoa Does the lab play a role? Optimize sperm retrieval Mechanical mincing Enzymatic tissue digestion Avoid iatrogenic damage ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 42 2014 SEPTEMBER
- 43. Tissue removed (mg) Open Large Single-Biopsy TESE Micro- TESE P-value 65 ± 25 8.9 ± 2.5 <0.01 Quantity of tissue extracted does matter Conven+onal TESE Micro-‐TESE Fragment weight Fragment weight Verza Jr & Esteves Fertil Steril 2011; Esteves & Varghese J Reprod Sci 2013 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 43 2014 SEPTEMBER
- 45. Sperm Retrieval and ICSI Outcome Non-obstructive Obstructive P<0.01 Esteves et al. Asian J Androl. 2014;16(4):602-6 41.4 47 43.3 20 100 64 61 34.2 Sperm retrieval (%) 2PN Fertilization (%) Top Quality Embryos (%) Live Birth (%) OR=0.033 95% CI: 0.007-0.164; p<0.001 OR=0.38 95% CI: 0.23-0.61; p<0.001 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 45 2014 SEPTEMBER
- 46. NeonaHtael aOluthtc oomf oeff osf pBraibnige s Region N children NOA vs OA Born Outcomes Main findings Palermo et al. 1999 USA 22 vs 158 Congenital abnormalities 4.5% TF vs 1.3% OA (ns) Vernaeve et al. 2005 Belgium 61 vs 196 Perinatal data Congenital abnormalities Lower gestational age (singletons); Increased frequency of premature twins 4% TF vs 3% OA (ns) Fedder et al 2007 Denmark 76 vs 282 Congenital abnormalities 0% TF vs 4.0% OA (ns) Belva et al.; 2011 Belgium 193 vs 474 Perinatal data; Congenital abnormalities Similar perinatal outcomes; 4.2% TF vs 5.2% OA (ns) 352 children No major difference Esteves & Agarwal. Clinics 2013;68(Suppl.1):141-50 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 46 2014 SEPTEMBER