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Management of Non Obstructive Azoospermia
This document discusses the management of non-obstructive azoospermia (NOA). It begins by defining NOA and providing statistics on prevalence. It then discusses the process of diagnosing NOA, including semen analysis and differential diagnosis. Etiologies of NOA including congenital and acquired causes are presented. Key points are made about selecting candidates for sperm retrieval based on etiology, biomarkers and genetic screening. Interventions prior to sperm retrieval for men with NOA and hypogonadism or clinical varicocele are discussed. The importance of proper laboratory handling of surgically extracted gametes is also mentioned. Overall, the document provides an overview of evaluating and managing men with NOA.
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Management of Non Obstructive Azoospermia
- 1. ISAR 2014, Ahmedabad INDIA Management of Non-‐obstrucFve Azoospermia Sandro C. Esteves, MD., PhD. Director, ANDROFERT Campinas, Brazil
- 2. Management of NOA ISAR 2014, Ahmedabad INDIA Available at: hMp://www.androfert.com.br/review Esteves, 2 ANDROFERT, Referral Center for Male ReproducFon
- 3. Sperm Count in Humans General PopulaFon of Unscreened Men CenFles 2.5% 50% 97.5% 4 64 237 Sperm count per mL (x106) Azoospermia Complete lack of sperm in ejaculate 1-‐3% male populaFon 10-‐15% male inferFlity populaFon Cooper et al. Hum Reprod Update 2009; Esteves et al, Clinics 2011 Esteves, 3 ANDROFERT, Referral Center for Male ReproducFon
- 4. Management of Non-obstructive Azoospermia(NOA) Select the Diagnosis candidates for sperm retrieval and ICSI Select who could benefit Select the best SR from intervenFons method prior to SR ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 4 2014 FEBRUARY Proper lab handling of surgically-‐ extracted gametes ANDROFERT androfert.com.br
- 5. Diagnosis -‐ Semen Analysis (x2) Centrifuga2on at 3,000g for 15 minutes The supernatant is discharged and the pellet is examined Esteves, 5 ANDROFERT, Referral Center for Male ReproducFon
- 6. Azoospermia – DifferenFal Diagnosis Azoospermia Subtypes ObstrucFve Clinical Picture Spermatogenesis NL tesFs NL FSH, LH, TT Mechanical block Normal Hypo-‐hypo Non-‐ obstrucFve Esteves, 6 TesFcular failure High FSH/LH (NL) Low TT (NL) Small tesFs (NL) FSH/LH <1.2 mUI/mL Low TT Small tesFs Poor virilizaFon Disrupted ANDROFERT, Referral Center for Male ReproducFon
- 7. NOA & TesFcular Failure EFology Congenital TesFcular dysgenesis/cryptorchidism GeneFc abnormaliFes (Klinefelter syndrome, Yq microdeleFons, etc.) Acquired TesFcular torsion; Trauma Post-‐inflammatory (eg. Mumps orchiFs) Exogenous factors (steroids, cytotoxic drugs, irradiaFon) TesFcular Cancer; Systemic diseases (liver cirrhosis, renal failure) Varicocele Idiopathic (Unknown etiology) Untreatable condiFon Sperm Retrieval and ICSI Esteves SC & Agarwal A. An update on the clinical assessment of the infer2le male. Clinics 66; 2011 Esteves, 7 ANDROFERT, Referral Center for Male ReproducFon
- 8. SelecFng candidates for SR Does e2ology play a role? Etiology category Cryptorchidism Varicocele Post-infection Torsion Post-chemotherapy/RT Genetic (Klinefelter, AZFc Yq microdeletions) Idiopathic No SR success rate 52-74% 63-68% 67% >50% 25-75% 25-70% 50-60% Presence of a site of sperm producFon is not related to the eFology of NOA Esteves et al., Fer%l Steril 94; 2010; Raman and Schlegel. J Urol.170; 2003; Hopps et al. Hum Reprod. 180, 2003; Damani et al. JCO. 15; 2002 Esteves, 8 ANDROFERT, Referral Center for Male Reproduction
- 9. SelecFng candidates for SR Can biomarkers predict SR success? FSH levels No Testosterone levels TesFcular Volume TesFcular Histopathology Markers reflect global spermatogenic funcFon but not the presence of a site of sperm producFon in a dysfuncFonal tesFs Esteves, Miyaoka & Agarwal. Clinics 2011; Verza Jr. & Esteves. Fertil Steril 2011; Carpi et al. Fertil Steril 2009. Esteves, 9 ANDROFERT, Referral Center for Male Reproduction
- 10. SelecFng candidates for SR YCMD screening by PCR AZFa deleted Sertoli Cell Only SRR = 0% AZFc deleted AZFb deleted Matura2on Arrest (RBMY; PRY) SRR = 0% Hypospermatogenesis, Matura2on arrest, SCO SRR ~70% Hamada et al. 2012; Esteves & Agarwal Int Braz J Urol 2011; Foresta et al Endocr Rev 2001. Esteves, 10 ANDROFERT, Referral Center for Male Reproduction
- 11. Management of NOA Key Messages (1) Azoospermia is a descripFve term of ejaculates that lack spermatozoa without implying a specific underlying cause. NOA due to tesFcular failure is the most severe male inferFlity condiFon. It represents a spectrum of congenital or acquired tesFcular disorders that cannot be treated. All men with tesFcular failure are candidate for SR but those with YCMD in subregions AZFa and/or AZFb. Esteves, 11 ANDROFERT, Referral Center for Male ReproducFon
- 12. Who can benefit from intervenFons prior to sperm retrieval? NOA and hypogonadism (TT<300ng/dL) Esteves, 12 NOA and clinical varicocele ANDROFERT, Referral Center for Male ReproducFon
- 13. Who can benefit from intervenFons prior to sperm retrieval? Principle Boost testosterone produc2on NOA and hypogonadism (TT<300ng/dl) OpFons AnF-‐estrogens Aromatase inhibitors u-‐hCG/rec-‐hCG Esteves, 13 ANDROFERT, Referral Center for Male ReproducFon
- 14. Medical therapy before SR Hypogonadism Klinefelter Syndrome with NOA and hypogonadism; N=91 Positive Tx response (increase in TT) No response 72 55 P = 0.03 Sperm Retrieval Rate (%) Ramasamy et al., J Urol. 2009 Esteves, 14 NOA and favorable tesFcular hystopathology; N=43 Anti-estrogen (CC 50mg) every other day; no controls 64% men had sperm in the ejaculates post-Tx (mean: 3.8 M/mL); Spermatozoa obtained by SR in all who remained azoospermic. Hussein et al, J Androl 2005 ANDROFERT, Referral Center for Male ReproducFon
- 15. hCG for men with NOA and hypogonadism Classic treatment Urinary hCG 1,000-2,000 UI IM injections; twice or t.i.w; minimum 12 weeks SC self-‐injec2on w/ pre-‐filled syringe, qw FraieMa & Esteves Clinics 2013; Esteves & Papanikolaou FerFl Steril 2011 Esteves, 15 ANDROFERT, Referral Center for Male ReproducFon
- 16. NOA and clinical varicocele Microsurgical Varicocele Repair Meta-analysis of 11 case 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 SR in 96 pts. with treated and untreated varicocele Success: 53% vs 30% (increased by 2.6fold in treated pts.) Inci et al, J Urol. 2009 Miyaoka & Esteves. Adv Urol 2012 Esteves, 16 ANDROFERT, Referral Center for Male ReproducFon
- 17. Which is the best sperm retrieval technique in NOA ? 30-‐50% cases: minimal producFon within the tesFs, but not enough for sperm to appear in ejaculate Goal is to iden2fy site of produc2on and retrieve sperm for ICSI Geographic loca2on unpredictable Esteves, 17 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, Referral Center for Male ReproducFon
- 18. Sperm retrieval in NOA which is the best technique? Schlegel 1999 Controlled Series Amer et al. 2000 Okada et al. 2002 Okubu et al. 2002 Tsujimura et al. 2002 Ramon et al. 2003 43%-‐53% TESE 25%-‐41% Esteves et al. 2011 Esteves et al. Sperm retrieval Techniques. Int Braz J Urol 2011 Esteves, 18 ANDROFERT, Referral Center for Male Reproduction
- 19. Esteves SC, Int Braz J Urol 2013 hMp://androfert.com.br/videos
- 20. Management of NOA Key Messages (2) Men with hypogonadism (TT<300) and clinical varicocele may benefit from intervenFons prior to SR, but evidence is modest Men with NOA are not sterile. Foci of sperm producFon is found in 30-‐50% of cases. Micro-‐TESE best method to idenFfy areas of sperm producFon; minimal Fssue removal facilitaFng sperm search and processing Esteves, 20 ANDROFERT, Referral Center for Male ReproducFon
- 21. Laboratory handling ofsurgicallyretrieved spermatozoa Avoid iatrogenic damage Optimize sperm retrieval Optimize ICSI outcomes Esteves, 21 ANDROFERT, Referral Center for Male Reproduction
- 22. ICSI Outcome in Azoospermia Non-‐obstrucFve (N=151) ObstrucFve (N=146) 100 41.4 47 64 Sperm retrieval (%) 2PN FerFlizaFon (%) OR=0.033 95% CI: 0.007-‐0.164; p<0.001 P<0.01 43.3 61 20 Top Quality Embryos (%) 34.2 Live Birth (%) OR=0.38 95% CI: 0.23-‐0.61; p<0.001 Esteves et al. Asian J Androl. In press Esteves, 22 ANDROFERT, Referral Center for Male ReproducFon
- 23. Conven2onal TESE Micro-‐TESE Fragment weight Microsurgical vs single-‐biopsy TESE Fragment weight Tissue removed (mg) Open Large Micro-TESE PSingle-Biopsy value TESE 65 ± 25 Esteves, 23 8.9 ± 2.5 <0.01 Verza Jr & Esteves. Fer5l Steril 2011; Esteves & Varghese, 2013 ANDROFERT, Referral Center for Male Reproduction
- 25. Health of Babies Born in NOA NOA (n=63) Ejaculated Sperm (n=247) ObstrucFve Azoospermia (n=117) 244.6 273.3 257.7 P = NS 35.7 36.9 37.0 GestaFonal age (wks) 6.3 Birth weight (gramsx10) 2.0 2.5 % Perinatal death 3.2 1.2 1.7 % Birth defects Esteves & Agarwal. Reproductive outcomes including neonatal data of sperm injection in men with obstructive and nonobstructive azoospermia: case series and systematic review. CLINICS, 2013 Esteves, 25 ANDROFERT, Referral Center for Male Reproduction
- 26. Neonatal Outcome of Babies Born Region Palermo et al. 1999 Vernaeve et al. 2005 N children TesFcular failure vs OA Outcomes Main findings USA 22 vs 158 Congenital abnormali2es 4.5% TF vs 1.3% OA (ns) Belgium 61 vs 196 Perinatal data Congenital abnormali2es Congenital abnormali2es Perinatal data; Lower gesta2onal age (singletons); Increased frequency of premature twins ajor n childre 352 Fedder et al 2007 Denmark 76 vs 282 Belva et al.; 2011 Belgium 193 vs 474 Congenital abnormali2es No m 4% TF vs ference dif 3% OA (ns) 0% TF vs 4.0% OA (ns) Similar perinatal outcomes; 4.2% TF vs 5.2% OA (ns) Esteves & Agarwal. Reproductive outcomes including neonatal data of sperm injection in men with obstructive and nonobstructive azoospermia: case series and systematic review. CLINICS, 2013
- 27. Management of NOA Key Messages (3) SR rates and reproducFve outcomes arer ICSI are differenFally affected by NOA Controlled lab condiFons and techniques important to improve SR and ICSI outcomes Health of neonates not differenFally affected by NOA; limited data Esteves, 27 ANDROFERT, Referral Center for Male ReproducFon
- 28. Management of NOA Summary Improve SR Semen analyses and differenFaFon between azoospermia subtype 1. Diagnosis Medical Tx in hypogonadism 2. Select candidates for SR YCMD Microsurgical repair of clinical varicoceles 3. Check who benefit of intervenFons prior to SR ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2014 FEBRUARY 4. Select the best SR method Micro-‐ TESE Avoid iatrogenic damage Not jeopardize ICSI outcomes 5. OpFmal lab condiFons and techniques ANDROFERT androfert.com.br
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