Medical Management of Male Infertility

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Medical Management of Male Infertility

  1. 1. Delhi  &  Chennai,  INDIA  2013       Medical  Management  of  Male     InferDlity   Sandro  C.  Esteves,  MD.,  PhD.   Director,  ANDROFERT   Campinas,  Brazil  
  2. 2. Medical  Management  of  Male  Infer1lity   Delhi  &  Chennai,  INDIA  2013       Available  at:     hMp://www.androfert.com.br/review   Esteves,  2   ANDROFERT,  Referral  Center  for  Male  ReproducDon  
  3. 3. Lecture  Outline   Medical  Management  Overview     Empiric  Tx  of  idiopathic   oligozoospermia     Hormonal  Tx  for  hypo-­‐hypo   Aromatase  inhibitors  in  obese-­‐related   male  inferDlity   Specific  Tx  for  subclinical  MAGI   AnDoxidants  for  oxidaDve-­‐stress   alleviaDon     Esteves,  3   ANDROFERT,  Referral  Center  for  Male  ReproducDon  
  4. 4. Empirical  medical  Tx  of  idiopathic   oligozoospermia   Androgens   hCG/HMG/FSH   Aromatase  inhibitors   AnD-­‐estrogens   BromocripDne   Alpha-­‐blockers   Systemic  corDcosteroids     Esteves,  4   In  general,   NOT   EFFECTIVE   Guidelines on Male Infertility. European Association of Urology 2012   ANDROFERT,  Referral  Center  for  Male  ReproducDon  
  5. 5.     Injectable  testosterone  is  bad   GnRH   Azoospermia   FSH/LH   Marked  fall  in  ITT  levels   Between  the  seminiferous   tubules,  Leydig  cells  produce   testosterone   Esteves,  5   ANDROFERT,  Referral  Center  for  Male  ReproducDon  
  6. 6. Who  may  benefit  from  medical  Tx?         FSH  &  LH   levels   Normal/ Elevated   <300ng/dL   (10.4  nmol/L)   Esteves,  6   <1.2  mUI/ mL   Hypogonadism   category   T/E  raDo   <10   Aromatase   hyperacDvity   T/E  raDo   >10  (nl)   Pure   Treatment   Total   Testosterone   levels     Estradiol     levels   Hypo-­‐hypo   ANDROFERT,  Referral  Center  for  Male  ReproducDon  
  7. 7. Male  hypogonadotropic  hypogonadism   Specific  medical  therapy   Deficient  viriliza1on;  Hypotrophic  testes     Azoospermia   Low  FSH  and  LH  (<1.2  mIU/L)   Low  total  testosterone  (<300  ng/dL)   • Congenital:    Kallman  syndrome   Prader-­‐Willi     • Acquired:   Pituitary  tumor   Steroid  abuse   Testosterone  replacement  therapy   Esteves,  7   ANDROFERT,  Referral  Center  for  Male  ReproducDon  
  8. 8. 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-­‐ injecDon  w/pre-­‐ filled  syringe,  qw   FraieMa  &  Esteves  Clinics  2013   Esteves,  8   ANDROFERT,  Referral  Center  for  Male  ReproducDon  
  9. 9. Rec-­‐hCG  for  hypo-­‐hypo  males   Series  of  men  with  adult-­‐onset  HH;  Recombinant  hCG  (Ovitrelle  250  mcg)   Baseline   Esteves,  9   PosMreatment   Esteves  &  Papanikolaou  FerDl  Steril  2011   ANDROFERT,  Referral  Center  for  Male  ReproducDon  
  10. 10. Who  may  benefit  from  medical  Tx?         FSH  &  LH   levels   Normal/ Elevated   <300ng/dL   (10.4  nmol/L)   Esteves,  10   <1.2  mUI/ mL   Hypogonadism   category   T/E  raDo   <10   Aromatase   hyperacDvity   T/E  raDo   >10  (nl)   Pure   Treatment   Total   Testosterone   levels     Estradiol     levels   Hypo-­‐hypo   ANDROFERT,  Referral  Center  for  Male  ReproducDon  
  11. 11. Estradiol  levels  in  obese  men  is   modulated  by  aromatase  polymorphism     Aromatase is a product of the CYP19 gene Most common polymorphism is tetranucleotide repeat (TTTAn) Higher TTTAn (X-X) repeat associated with increased E2 levels Esteves, 12 ANDROFERT, Referral Center for Male Reproduction
  12. 12. Oligozoospermia in obese men Meta-analysis of 21 studies; 13,077 men Risk of Oligozoospermia: Overweight*: OR=1.28 (95% CI 1.06-1.55) (95% CI 1.59-2.62) *BMI greater than or equal to 25; **BMI greater than or equal to 30; Sermondade et al. BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis. Hum Reprod Update. 2013 Esteves, 13 ANDROFERT, Referral Center for Male Reproduction
  13. 13. Obesity in men at reproductive age Esteves, 14 ANDROFERT, Referral Center for Male Reproduction
  14. 14. Aromatase inhibitors in obeserelated oligozoospermia Total Testosterone (ng/dL) and Estradiol (pg/mL) Levels T/E2 Ratio Normal > 10 T/E2 <10 Aromatase Hyperactivity Anastrozole 1 mg q1d 60 days Zumoff et al. Metabolism 2003; Raman & Schlegel J Urol 2002 Esteves, 15 ANDROFERT, Referral Center for Male Reproduction
  15. 15. Aromatase Inhibitors for Obesity-related Male Infertility Anastrazole (1mg q1d for 3-6 months) in Oligozoospermia 20 15.6 15 10 5.9 15.6 2.9 5 3.5 5.5 0 T/E ratio Ejaculate volume (mL) Pre-treatment Sperm Count (million/mL) Post-treatment Raman & Schlegel. J Urol. 2002 Esteves, 16 ANDROFERT, Referral Center for Male Reproduction
  16. 16. Who  may  benefit  from  medical  Tx?         FSH  &  LH   levels   Normal/ Elevated   <300ng/dL   <1.2  mUI/ mL   Esteves,  17   Hypogonadism   category   T/E  raDo   <10   Aromatase   hyperacDvity   T/E  raDo   >10  (nl)   Pure   Treatment   Total   Testosterone   levels     Estradiol     levels   Hypo-­‐hypo   ANDROFERT,  Referral  Center  for  Male  ReproducDon  
  17. 17. Pure  hypogonadism   ART  Candidates   Severe  oligozoospermia   Non-­‐obstrucDve  azoospermia         OpDons   AnD-­‐estrogens   u-­‐hCG/rec-­‐hCG       Esteves,  18   ANDROFERT,  Referral  Center  for  Male  ReproducDon  
  18. 18. Medication before sperm retrieval in Klinefelter syndrome men (47,XXY) Ø  68 men with non-mosaic KS Ø  Non-obstructive azoospermia and hypogonadism Ø  ART candidates 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 Positive response 72 55 P  =  0.03   Sperm Retrieval Rate (%) Ramasamy  et  al.,  J  Urol.  2009     Esteves, 19 ANDROFERT, Referral Center for Male Reproduction
  19. 19. MedicaDon  prior  to  SR  in  unselected   men  with  NOA   Ø  Case  series  (n=307):  unselected   group  of  men  with  tesDcular   failure  and  low  testosterone   levels  (300  nd/dL)   Ø  Micro-­‐TESE   Posi1ve  response  (n=252)   No  response  (n=55)   51   51   Ø  MedicaDon  to  boost  testosterone   producDon:  Aromatase  inhibitor,   hCG,  anD-­‐estrogens  (min.  2-­‐3   months)   Ø  PosiDve  response:  posMreatment   TT  >250  ng/dL   Sperm  retrieval  rate  (%)   Ramasamy et al., J Urol. 2011 Esteves, 20 ANDROFERT, Referral Center for Male Reproduction
  20. 20. AnD-­‐estrogens  for  hypogonadism   1400   1200   ITT  levels   tral     fall   cen a1ve   ack   Neg edb fe ng/dL   1000   Upper  Limit   800   600   Normal  Testosterone   Levels   400   200   0   Esteves,  21   Lower   Sperm   Counts   Lower  Limit   Before   Clomiphene   AZer   90d;  25mg/d     Da  Ros  CT,  Averbeck  MA  Int  Braz  J  Urol  2012   ANDROFERT,  Referral  Center  for  Male  ReproducDon  
  21. 21. Medical  Tx  -­‐    Key  Messages  (1)   Empirical  medicaDon  for  idiopathic   oligozoospermia  not  recommended   InferDle  males  with  hypogonadism   (TT<300)  candidates  for  Tx   hCG  is  the  treatment  of  choice  for  adult-­‐ onset  hypogonadotropic  hyponadism   Esteves,  22   ANDROFERT,  Referral  Center  for  Male  ReproducDon  
  22. 22. Medical  Tx  -­‐    Key  Messages  (2)   Aromatase  inhibitors  helpful  for   overweight/obese  men  with  aromatase   hyperacDvity  (T/E<10)  and  oligozoospermia   hCG/anD-­‐estrogens  helpful  to  boost   testosterone  producDon  (sperm   producDon?)  in  selected  ART  candidates     Minimum  Tx  duraDon  8  weeks;  monitor  TT   levels  regularly  to  dose  DtraDon   Esteves,  23   ANDROFERT,  Referral  Center  for  Male  ReproducDon  

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