Management of Non Obstructive Azoospermia

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Management of Non Obstructive Azoospermia

  1. 1. ISAR  2014,  Ahmedabad  INDIA       Management  of    Non-­‐obstrucFve   Azoospermia   Sandro  C.  Esteves,  MD.,  PhD.   Director,  ANDROFERT   Campinas,  Brazil  
  2. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 19. Esteves  SC,  Int  Braz  J  Urol  2013   hMp://androfert.com.br/videos    
  20. 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. 21. Laboratory handling of surgicallyretrieved spermatozoa Avoid iatrogenic damage Optimize sperm retrieval Optimize ICSI outcomes Esteves, 21 ANDROFERT, Referral Center for Male Reproduction
  22. 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. 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
  24. 24.   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
  25. 25.   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
  26. 26. 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  
  27. 27. 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
  28. 28. Thank  You

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