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Management	
  of	
  male	
  
infer.lity	
  and	
  role	
  of	
  
gonadotropin	
  
Sandro	
  C.	
  Esteves,	
  MD.,	
  PhD.	
  
Medical	
  Director,	
  ANDROFERT	
  
Andrology	
  &	
  Human	
  Reproduc=on	
  Clinic	
  
	
  Campinas,	
  BRAZIL	
  
UAE Reproductive Symposium 2015 - Dubai
Learning	
  Objec.ves	
  
1.  Understand	
  the	
  WHO	
  reference	
  values	
  
for	
  semen	
  analysis	
  and	
  the	
  role	
  of	
  
sperm	
  DNA	
  fragmenta.on	
  tes.ng	
  
2.  Appraise	
  which	
  interven.ons	
  may	
  
benefit	
  infer.le	
  men	
  candidates	
  to	
  ART	
  	
  
3.  Learn	
  how	
  to	
  manage	
  infer.le	
  males	
  
with	
  azoospermia	
  and	
  the	
  role	
  of	
  
gonadotropin	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 2
2015
ANDROFERT
 Semen	
  analysis	
  is	
  s.ll	
  the	
  most	
  
widely	
  used	
  biomarker	
  to	
  predict	
  
male	
  fer.lity	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 3
2015
ANDROFERT
 	
   1980	
   1987	
   1992	
   1999	
  
Volume	
  (mL)	
   ND	
   ≥2	
   ≥2	
   ≥2	
  
Count	
  (106/mL)	
   20-­‐200	
   ≥20	
   ≥20	
  	
   ≥20	
  	
  
Total	
  count	
  (106)	
   ND	
   ≥40	
   ≥40	
   ≥40	
  	
  
Mo.lity	
  (%)	
   ≥	
  60	
   ≥50	
   ≥50	
   ≥50	
  	
  
Progressive	
  (%)	
   ≥	
  2	
   ≥25%	
   ≥25%	
  (a)	
   ≥25%	
  (a)	
  
Vitality	
  (%)	
   ND	
   ≥50	
   ≥75	
   ≥75	
  	
  
Morphology	
  (%)	
   80.5	
   ≥50	
   ≥30	
   (14)*	
  
Leukocytes	
  (106/mL)	
   <4.7	
   <1.0	
   <1.0	
  	
   <1.0	
  	
  
*Strict	
  criteria	
  (Tygerberg);	
  Esteves	
  et	
  al.	
  Urology	
  2012	
  
	
  
WHO	
  reference	
  values	
  have	
  
changed	
  
	
  2010	
  
≥1.5	
  	
  
≥15	
  	
  
≥39	
  	
  
≥40	
  
≥32%	
  
≥58	
  
≥4*	
  
1.0	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 4
2015
ANDROFERT
~2,000	
  specimens;	
  	
  
	
  recent	
  fathers
Percen.le
5% 50% 95%
Volume	
  (mL) 1.5 3.7 6.8
Count	
  (x106/mL) 15.0 73.0 213.0
Total	
  count	
  (x106) 39.0 255.0 802.0
%	
  Mo.le	
   40 61 78
%	
  Progressive	
  mo.lity 32 55 72
%	
  Normal	
  (Kruger) 4 15 44
%	
  Alive 58 79 91
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 5
2015
ANDROFERT
Urology 2012; 79(1):16-22
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 6
2015
ANDROFERT
Proposal	
  for	
  a	
  new	
  report	
  template	
  
Esteves,	
  Int	
  Braz	
  J	
  Urol	
  2014;	
  40:443-­‐53	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 7
2015
ANDROFERT
History	
  taking,	
  physical	
  
examina.on,	
  	
  
endocrine	
  profile	
  and	
  
laboratory	
  sperm	
  
func.on	
  tes.ng	
  are	
  
minimum	
  standards	
  
Esteves	
  Int	
  Braz	
  J	
  Urol	
  2014	
  	
  
Male	
  infer.lity	
  evalua.on	
  must	
  go	
  
beyond	
  a	
  simple	
  semen	
  analysis	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 8
2015
ANDROFERT
Conven.onal	
  semen	
  analysis	
  is	
  
not	
  enough	
  
single-strand
break mis-match
damaged base
double-strand
break inter-strand
crosslink
intra-strand
crosslink
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 9
2015
ANDROFERT
DNA	
  
Damage	
  
Environmental	
  factors	
  
Phtalate exposure,
radiation, temperature
Diseases	
  
Varicocele, GTI, fever
Life-­‐style	
  
Obesity, smoking, medication
Aging	
  


Factors	
  associated	
  with	
  sperm	
  DNA	
  
fragmenta.on	
  
Rubes	
  et	
  al	
  2007;	
  Esteves	
  &	
  Agarwal	
  2011	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 10
2015
ANDROFERT
Frequency	
  of	
  elevated	
  SDF	
  in	
  men	
  with	
  
unexplained	
  infer.lity	
  
Elevated	
  
SDF	
  	
  
(27%)	
  
Androfert; N=987
Elevated	
  SDF	
  
(27%)	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 11
2015
ANDROFERT
19%
1.5%
Normal Elevated
Live birth rates with IUI
N=387;	
  OR	
  =	
  0.07	
  	
  
[95%	
  CI:	
  0.01-­‐0.48]	
  
Bungum	
  et	
  al.	
  Hum	
  Reprod	
  2007	
  	
  
IUI	
  outcome	
  is	
  nega.vely	
  affected	
  
by	
  elevated	
  SDF	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 12
2015
ANDROFERT
26%
42%
IVF
 ICSI
Pregnancy in cases of elevated
sperm DNA fragmentation
IVF	
  outcome	
  is	
  nega.vely	
  
affected	
  by	
  elevated	
  SDF	
  
Robinson	
  et	
  al.	
  Hum	
  Reprod	
  2012	
  	
  
Meta-­‐analysis	
  of	
  16	
  
studies;	
  2,969	
  
couples:	
  	
  
Increased	
  miscarriage	
  
in	
  	
  IVF/ICSI	
  associated	
  
to	
  	
  high	
  SDF;	
  RR	
  =	
  2.16	
  	
  
95%	
  CI:	
  1.54-­‐3.03;	
  p<0.00001	
  
Bungum	
  et	
  al.	
  Hum	
  Reprod	
  2007	
  	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 13
2015
ANDROFERT
Fer.lity	
  and	
  Sterility	
  2014;	
  101(1):58-­‐63	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 14
2015
ANDROFERT
Andrologia	
  2014;	
  46(6):	
  602–9	
  
	
  
Pa.ents	
  with	
  
varicocele	
  have	
  
higher	
  
propor.on	
  of	
  
sperm	
  with	
  
massive	
  DNA	
  
damage	
  
	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 15
2015
ANDROFERT
SDF	
  is	
  part	
  of	
  rou.ne	
  work-­‐up	
  of	
  
male	
  infer.lity	
  at	
  Androfert	
  
Does the
patient have
high SDF?
Semen
analysis
including SDF
testing (SCD
assay)
High SDF if
results >30%
What does the
doctor need
to know?
Determine
test and
internal
validation
Lab SOP with
post-analytical
info for clinical
decision
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 16
2015
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 17
2015
ANDROFERT
Role	
  of	
  interven.ons	
  to	
  
infer.le	
  men	
  candidates	
  
to	
  ART	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 18
2015
ANDROFERT
Outcome	
   Effect	
  size	
  	
  
(OR;	
  95%	
  CI)	
  
Live	
  birth	
   4.85	
  [1.92,	
  12.24]	
  
DNA	
  fragmenta.on	
   -­‐13.80	
  [-­‐17.50,	
  -­‐10.10]	
  
Oral	
  an.oxidants	
  decrease	
  SDF	
  and	
  
improve	
  ART	
  outcomes	
  
Showell	
  et	
  al.	
  Cochrane	
  Database	
  Syst	
  Rev	
  2011	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 19
2015
ANDROFERT
Oral	
  an.oxidants	
  to	
  infer.le	
  males	
  
Prescrip.on:	
  
Vitamin	
  C	
  500mg;	
  Vitamin	
  E	
  400	
  mg	
  
Folic	
  acid	
  2	
  mg,	
  Zinc	
  25	
  mg	
  
Selenium	
  26	
  mcg	
  
Dura.on:	
  minimum	
  2	
  months	
  
Old	
  concept	
  ~90	
  days	
  
New	
  concept	
  ~60	
  days	
  
Misell	
  et	
  al.	
  J	
  Urol	
  2006;	
  Esteves	
  &	
  Agarwal	
  Int	
  Braz	
  J	
  Urol	
  2011	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 20
2015
ANDROFERT
Sperm	
  DNA	
  damage	
  in	
  tes.cular	
  and	
  
ejaculated	
  samples	
  using	
  the	
  SCD	
  test*	
  	
  
40.7%	
  
8.3%	
  
Ejaculate	
  
Tes.s	
  
P<0.001	
  
Sánchez-­‐Marqn,	
  Esteves	
  &	
  Gosálvez,	
  in	
  prepara@on	
  
*Dual	
  fluorescent	
  cocktail	
  probe	
  	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 21
2015
ANDROFERT
Wang	
  YJ	
  et	
  al.	
  	
  
Reprod	
  Biomed	
  Online	
  2012;25:307-­‐14	
  
Meta-­‐analysis	
  of	
  7	
  
studies	
  including	
  336	
  
pts.	
  indicated	
  that	
  SDF	
  
is	
  significantly	
  
decreased	
  auer	
  
varicocele	
  repair	
  
(MD=3.4%;	
  95%	
  CI	
  -­‐4.1	
  
to	
  -­‐2.6;	
  p<0.0001)	
  
Effect	
  of	
  varicocele	
  surgery	
  on	
  SDF	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 22
2015
ANDROFERT
•  Varicocele	
  
treated	
  prior	
  
to	
  ICSI	
  (N=80)	
  
•  ICSI	
  with	
  
untreated	
  
varicocele	
  
(N=162)	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 23
2015
ANDROFERT
Microsurgical	
  subinguinal	
  varicocele	
  
repair	
  with	
  aid	
  of	
  intraopera.ve	
  doppler	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 24
2015
ANDROFERT
Management	
  of	
  	
  
azoospermia	
  and	
  the	
  
role	
  of	
  gonadotropin	
  
therapy	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 25
2015
ANDROFERT
Azoospermia:	
  the	
  complete	
  lack	
  of	
  
sperm	
  in	
  ejaculate	
  auer	
  centrifuga.on	
  
10-15% infertile
males
1-3% male
population
Cooper	
  et	
  al.	
  Hum	
  Reprod	
  Update	
  2009;	
  	
  
Esteves	
  &	
  Agarwal,	
  Clinics	
  2013	
  	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 26
2015
ANDROFERT
Obstruc.ve	
  
Non-­‐
obstruc.ve	
  
	
  
	
  
	
  
Hypo-­‐hypo	
  
Spermatogenic	
  
failure	
  
Clinical	
  picture	
  
FSH/LH:	
  ñ	
  or	
  nl	
  
TT:	
  low	
  or	
  nL	
  
Testes:	
  	
  small	
  or	
  nl	
  
Normal	
  testes	
  &	
  
endocrine	
  profile;	
  
Mechanical	
  blockage	
  
FSH/LH	
  <1.2	
  mUI/
mL,	
  	
  
Low	
  TT,	
  small	
  tes.s,	
  
poor	
  viriliza.on	
  
Disrupted	
  
Normal	
  
Spermatogenesis	
  
Esteves	
  et	
  al,	
  Clinics	
  2011	
  	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 27
2015
ANDROFERT
Prognosis	
  and	
  management	
  differen.ally	
  
affected	
  by	
  type	
  of	
  azoospermia	
  	
  
•  Low FSH and LH (<1.2 mIU/L)
•  Low total testosterone (<300 ng/dL)
•  Hypotrophic testes 


Hypogonadotropic	
  hypogonadism	
  
Congenital:
Kallman syndrome
Prader-Willi 
Acquired:
Pituitary tumor
Steroid abuse
Testosterone replacement therapy
 Fraieva	
  et	
  al.	
  Clinics	
  68;	
  2013	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 28
2015
ANDROFERT
Classic	
  treatment	
  for	
  male	
  
hypogonadism	
  and	
  infer.lity	
  
u-­‐hCG	
  1,000-­‐2,000	
  IU;	
  IM	
  
injec.ons;	
  twice	
  or	
  t.i.w;	
  	
  
minimum	
  12	
  weeks	
  
Rec-­‐hCG:	
  SC	
  self-­‐
injec.on	
  qw	
  
Pre-­‐filled	
  syringe	
  
Pen	
  device	
  
Fraieva	
  et	
  al.	
  Clinics	
  2013;	
  68(Suppl.1):81-­‐8	
  
Specific	
  therapy	
  in	
  adult	
  onset	
  
hypo-­‐	
  hypo	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 29
2015
ANDROFERT
Rec-­‐hCG	
  for	
  male	
  hypo-­‐hypo	
  
Esteves	
  &	
  Papanikolaou	
  Fer@l	
  Steril	
  2011;96:S230	
  
Series	
  of	
  men	
  with	
  adult-­‐onset	
  HH;	
  	
  
Recombinant	
  hCG	
  (250	
  mcg	
  qw	
  for	
  12	
  weeks)	
  
Baseline	
   Pos`reatment	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 30
2015
ANDROFERT
Tes.cular	
  torsion;	
  trauma	
  
Post-­‐inflammatory	
  (eg.	
  Mumps	
  orchi=s)	
  
Exogenous	
  factors	
  (eg.	
  Cytotoxic	
  drugs,	
  irradia=on)	
  
Tes.cular	
  cancer	
  	
  
Systemic	
  diseases	
  (eg.	
  Liver	
  cirrhosis,	
  renal	
  failure)	
  
Congenital	
  
Tes.cular	
  dysgenesis/cryptorchidism	
  
Gene.c	
  abnormali.es	
  (Klinefelter	
  syndrome,	
  Yq	
  microdele=ons,	
  etc.)	
  
Acquired	
  
Idiopathic	
  (unknown	
  e.ology)	
  
Esteves	
  et	
  al.	
  Clinics	
  2011;	
  66:691-­‐700	
  
NOA	
  due	
  to	
  spermatogenic	
  
failure:	
  an	
  irreversible	
  condi.on	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 31
2015
ANDROFERT
Esteves	
  et	
  al.	
  Int	
  Braz	
  J	
  Urol	
  2011;37:570-­‐83	
  

40-­‐50%	
  of	
  men	
  with	
  SF	
  have	
  residual	
  
spermatogenesis	
  within	
  the	
  tes.s	
  
§ Not	
  enough	
  for	
  sperm	
  to	
  appear	
  
in	
  ejaculate	
  
§ 600-­‐800	
  seminiferous	
  tubules	
  
§ Goals	
  are:	
  	
  
i.  Op=mize	
  sperm	
  produc=on	
  (if	
  possible)	
  
ii.  Iden=fy	
  site	
  of	
  sperm	
  produc=on	
  (if	
  
present)	
  and	
  retrieve	
  sperm	
  for	
  ICSI	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 32
2015
ANDROFERT
Challenges	
  faced	
  by	
  health	
  professionals	
  
providing	
  care	
  for	
  men	
  with	
  SF	
  
§  Counseling	
  about	
  the	
  chances	
  of	
  finding	
  
tes.cular	
  sperm	
  
§  Usefulness	
  of	
  any	
  medical	
  interven.on	
  
before	
  sperm	
  retrieval	
  
§  Which	
  sperm	
  retrieval	
  method	
  to	
  apply	
  	
  
§  Reproduc.ve	
  poten.al	
  of	
  retrieved	
  gametes	
  
in	
  ICSI	
  treatment	
  
§  Health	
  of	
  offspring	
  	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 33
2015
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 34
2015
ANDROFERT
Complete	
  AZFa,	
  AZFb	
  or	
  AZFa+b	
  
microdele.ons	
  unfavorable	
  prognosis	
  
YCMD	
   SR	
  
success	
  
AZFa	
   nil	
  
AZFb	
   nil	
  
AZFc	
   50-­‐70%	
  
Krausz	
  et	
  al.	
  2014;	
  Esteves	
  et	
  al.	
  2013;	
  Esteves	
  2015	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 35
2015
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 36
2015
ANDROFERT
Interven.ons	
  to	
  infer.le	
  males	
  men	
  with	
  
SF	
  prior	
  to	
  a	
  sperm	
  retrieval	
  avempt	
  
Matura.on	
  arrest	
  and	
  hypospermatogenesis	
  
favorable	
  prognosis	
  
Weedin	
  et	
  al	
  J	
  Urol	
  2010;183:2309-­‐15	
  
Among	
  233	
  men	
  with	
  SF	
  and	
  treated	
  
varicocele,	
  1/3	
  had	
  mo.le	
  sperm	
  in	
  postop.	
  
ejaculate	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 37
2015
ANDROFERT
Inci	
  et	
  al	
  J	
  Urol	
  2009;182:1500-­‐5;	
  	
  
Haydardedeoglu	
  et	
  al	
  Urology	
  2010;75:83-­‐6	
  	
  
§ Inci	
  2009	
  	
  
OR:	
  2.63	
  	
  
(95%	
  CI:	
  1.05-­‐6.60;	
  p=0.03)	
  	
  
Although	
  2/3	
  remain	
  azoospermic	
  auer	
  
varicocele	
  repair,	
  SRR	
  increased	
  
§ Haydardedeoglu	
  2010	
  
53
30
Treated (N=66)
 Untreated
(N=30)
SR success (%)
61
38
Treated (N=31)
 Untreated
(N=65)
p<0.01	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 38
2015
ANDROFERT
Medica.on	
  
Hypogonadism	
  (TT<300	
  ng/dl)	
  in	
  up	
  to	
  50%	
  
men	
  with	
  SF	
  	
  
	
  High	
  ITT	
  levels	
  essen=al	
  for	
  regula=ng	
  
spermatogenesis	
  in	
  combina=on	
  with	
  Sertoli	
  
cell	
  s=mula=on	
  by	
  FSH	
  
Paradoxically	
  weak	
  s.mula.on	
  of	
  Leydig	
  and	
  
Sertoli	
  cells	
  by	
  endogenous	
  gonadotropins	
  
	
  Due	
  to	
  high	
  baseline	
  FSH	
  and	
  LH	
  levels	
  the	
  
rela=ve	
  amplitudes	
  are	
  low	
  	
  
Shiraishi	
  et	
  al	
  Hum	
  Reprod	
  2012;27:331-­‐9;	
  	
  
Sussman	
  et	
  al	
  Urol	
  Clin	
  N	
  Am	
  2008;35:147-­‐55	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 39
2015
ANDROFERT
Study Study design Study group Medication Findings
Pavlovich
et al. 2001
Case series
43 men with
T/E ratio <10
Testolactone No effect
Hussein et
al. 2005
Prospective
cohort
42 men with
favorable
hystology
Clomiphene
Sperm found in SA in 64.3%; All men
who remained azoospermic had
success at SR
Selman et
al. 2006
Prospective
cohort
49 men with
maturation
arrest
rec-hFSH and hCG
No return of sperm in ejaculate;
posttreatment SRR were 21.4%
Ramasamy
et al. 2009
Case series
56 men with
nonmosaic
Klinefelter
Testolactone or anastrozole,
alone or combined with hCG
SRR increased by 1.4-fold
Reifsnyder
et al. 2012
Retrospective
cohort
307 men with
hypogonadis
m
Aromatase inhibitors, hCG or
Clomiphene, alone or
combined
No effect
Shiraishi et
al. 2012
Prospective
cohort
28 men with
idiopathic SF
hCG alone or combined with
rec-hFSH
SR success in 21% of the treated men
vs. none in untreated men
Hussein et
al. 2013
Prospective
cohort
612
unselected
men
Clomiphene alone or
combined with hCG or hMG
Sperm found in SA in 10.9% of treated
males; SRR higher in men who
remained azoospermic and treated
(57.0 vs. 33.6%, p<0.001)
!
Aromatase	
  inhibitors	
  and	
  gonadotropins	
  
have	
  been	
  used	
  with	
  variable	
  results	
  
Esteves	
  Asian	
  J	
  Androl	
  2015;17:1-­‐12	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 40
2015
ANDROFERT
ITT	
  levels	
  increase	
  auer	
  hCG;	
  s.mulatory	
  
effect	
  on	
  residual	
  spermatogenic	
  areas	
  
Shinjo	
  E	
  et	
  al	
  Andrology	
  2013;1:929-­‐35;	
  Shiraishi	
  et	
  al	
  Hum	
  Reprod	
  2012;27:331-­‐9	
  
273
1348
Before
 After
ITT (ng/dl)
ITT	
  levels	
  increased	
  auer	
  
hCG-­‐based	
  therapy	
  
Spermatogonial	
  DNA	
  
synthesis	
  increased	
  
PCNA	
  expression	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 41
2015
ANDROFERT
1Shiraishi	
  et	
  al	
  Hum	
  Reprod	
  2012;27:331-­‐9;	
  Esteves	
  Int	
  Braz	
  J	
  Urol	
  2013;39:440	
  
hCG-­‐based	
  therapy	
  may	
  increase	
  SR	
  
success	
  in	
  men	
  with	
  SF	
  
Microdissec.on	
  TESE	
  
Rescue	
  ~15%	
  of	
  pa.ents	
  
with	
  previous	
  failed	
  SR	
  
avempts1	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 42
2015
ANDROFERT
Testosterone	
  and	
  
estradiol	
  levels	
  

<300	
  
ng/dL	
  
(10.4	
  nmol/L)	
  
Hypogonadism	
  
category	
  

Pure	
  
Medica.on	
  algorithm	
  at	
  Androfert	
  
Tx	
  aimed	
  at	
  
boos.ng	
  T
Aromatase	
  inhibitor	
  
(anastrozole	
  1mg	
  orally	
  
qid)	
  
Rec-­‐hCG	
  	
  
(250	
  mcg	
  SC	
  qw);	
  	
  
rec-­‐FSH	
  added	
  
(75	
  IU	
  SC	
  biw)	
  if	
  FSH	
  
levels	
  <1.5	
  mIU/ml	
  









T/E	
  ra.o	
  
<10	
  
Aromatase	
  
hyperac.vity	
  
T/E	
  ra.o	
  
>10	
  (nl)	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 43
2015
ANDROFERT
Esteves	
  Asian	
  J	
  Androl	
  2015;17:1-­‐12	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 44
2015
ANDROFERT
Sperm	
  retrieval	
  methods	
  in	
  NOA	
  due	
  to	
  
spermatogenic	
  failure	
  
Technique	
   Acronym	
   Success	
  
Tes.cular	
  sperm	
  
aspira.on	
   TESA	
   15-­‐50%	
  
Tes.cular	
  sperm	
  
extrac.on	
   TESE	
   20-­‐60%	
  
Microdissec.on	
  
tes.cular	
  sperm	
  
extrac.on	
  
Micro-­‐
TESE	
   40-­‐67%	
  
Esteves	
  et	
  al	
  Int	
  Braz	
  J	
  Urol	
  2013;37:570-­‐83;	
  Deruyver	
  et	
  al	
  	
  Andrology	
  2014;2:20-­‐4	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 45
2015
ANDROFERT
http://androfert.com.br/videos 
Esteves SC Int Braz J Urol 2013; 39(3):440
41.4
 47
 43.3
20
100
64
 61
34.2
Sperm
retrieval (%)
2PN
Fertilization
(%)
Top Quality
Embryos (%)
Live Birth (%)
Non-obstructive (N=365)
 Obstructive (N=146)
P<0.01	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 47
2015
ANDROFERT
Morphometric	
  evalua.on	
  of	
  seminiferous	
  
tubules	
  increases	
  SR	
  efficiency	
  	
  
Median
25%-75%
5%-95%
Raw Data
yes No
Presence of Sperm
160
180
200
220
240
260
280
300
320
340
360
380
400
420
Max.TubuleDiameter
Verza	
  Jr	
  S,	
  Esteves	
  SC.	
  Fer@l	
  Steril	
  2012;	
  98:	
  S242;	
  	
  
Esteves	
  &	
  Varghese	
  J	
  Reprod	
  Sci	
  2012;	
  5(3):233-­‐43	
  	
  
N=54; Tubule Diameter: KW-H (1;54) = 25.2; P<0.001
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 48
2015
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 49
2015
ANDROFERT
On	
  average,	
  one	
  top-­‐quality	
  addi.onal	
  embryo	
  
for	
  transfer	
  or	
  cryopreserva.on	
  
Clean	
  Room	
  Technology	
  &	
  ICSI	
  Results	
  
2,315	
  pa.ents;	
  14,660	
  embryos	
  
Esteves	
  &	
  Bento.	
  Reprod	
  Biomed	
  Online	
  2013;26:9-­‐21	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 50
2015
ANDROFERT
 3,412	
  cycles	
  
Tailored	
  COS	
  strategy	
  to	
  increase	
  LBR	
  in	
  
ICSI	
  cycles	
  involving	
  severe	
  male	
  factor	
  
0%	
  
10%	
  
20%	
  
30%	
  
40%	
  
50%	
  
60%	
  
1	
   2	
   3	
   4	
   5	
   6	
   7	
   8	
   9	
   10	
   11	
   12	
   13	
   14	
   15	
   20	
   25	
  
Number	
  of	
  oocytes	
  retrieved	
  
Clinical	
  pregnancy	
  
Live	
  birth	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 51
2015
ANDROFERT
Conclusions	
  
1.  Conven.onal	
  semen	
  analysis	
  limited	
  as	
  
surrogate	
  for	
  assessing	
  fer.lity;	
  SDF	
  tes.ng	
  
valuable	
  laboratory	
  tool	
  for	
  clinical	
  decision	
  	
  
2.  An.oxidant	
  therapy,	
  microsurgical	
  varicocele	
  
repair	
  and	
  TESA-­‐ICSI	
  may	
  improve	
  ART	
  
outcome	
  in	
  selected	
  individuals	
  	
  
3.  Best	
  management	
  of	
  azoospermia	
  includes	
  
proper	
  diagnosis,	
  interven.ons	
  to	
  op.mize	
  
sperm	
  produc.on,	
  microsurgical	
  SR,	
  state-­‐of-­‐
art	
  laboratory	
  care	
  and	
  tailored	
  COS	
  to	
  ART	
  
candidates	
  
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 52
2015
ANDROFERT
Thank	
  you	
  	
  	
  	
  ‫ا‬‫شكر‬ Obrigado	
  
This	
  presenta.on	
  is	
  available	
  at	
  
hvp://www.slideshare.net/
sandroesteves	
  

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Management of Male fertility and gonodotropin role

  • 1.         Management  of  male   infer.lity  and  role  of   gonadotropin   Sandro  C.  Esteves,  MD.,  PhD.   Medical  Director,  ANDROFERT   Andrology  &  Human  Reproduc=on  Clinic    Campinas,  BRAZIL   UAE Reproductive Symposium 2015 - Dubai
  • 2. Learning  Objec.ves   1.  Understand  the  WHO  reference  values   for  semen  analysis  and  the  role  of   sperm  DNA  fragmenta.on  tes.ng   2.  Appraise  which  interven.ons  may   benefit  infer.le  men  candidates  to  ART     3.  Learn  how  to  manage  infer.le  males   with  azoospermia  and  the  role  of   gonadotropin   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2015 ANDROFERT
  • 3.  Semen  analysis  is  s.ll  the  most   widely  used  biomarker  to  predict   male  fer.lity   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2015 ANDROFERT
  • 4.     1980   1987   1992   1999   Volume  (mL)   ND   ≥2   ≥2   ≥2   Count  (106/mL)   20-­‐200   ≥20   ≥20     ≥20     Total  count  (106)   ND   ≥40   ≥40   ≥40     Mo.lity  (%)   ≥  60   ≥50   ≥50   ≥50     Progressive  (%)   ≥  2   ≥25%   ≥25%  (a)   ≥25%  (a)   Vitality  (%)   ND   ≥50   ≥75   ≥75     Morphology  (%)   80.5   ≥50   ≥30   (14)*   Leukocytes  (106/mL)   <4.7   <1.0   <1.0     <1.0     *Strict  criteria  (Tygerberg);  Esteves  et  al.  Urology  2012     WHO  reference  values  have   changed    2010   ≥1.5     ≥15     ≥39     ≥40   ≥32%   ≥58   ≥4*   1.0   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 4 2015 ANDROFERT
  • 5. ~2,000  specimens;      recent  fathers Percen.le 5% 50% 95% Volume  (mL) 1.5 3.7 6.8 Count  (x106/mL) 15.0 73.0 213.0 Total  count  (x106) 39.0 255.0 802.0 %  Mo.le   40 61 78 %  Progressive  mo.lity 32 55 72 %  Normal  (Kruger) 4 15 44 %  Alive 58 79 91 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2015 ANDROFERT
  • 6. Urology 2012; 79(1):16-22 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2015 ANDROFERT
  • 7. Proposal  for  a  new  report  template   Esteves,  Int  Braz  J  Urol  2014;  40:443-­‐53   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2015 ANDROFERT
  • 8. History  taking,  physical   examina.on,     endocrine  profile  and   laboratory  sperm   func.on  tes.ng  are   minimum  standards   Esteves  Int  Braz  J  Urol  2014     Male  infer.lity  evalua.on  must  go   beyond  a  simple  semen  analysis   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2015 ANDROFERT
  • 9. Conven.onal  semen  analysis  is   not  enough   single-strand break mis-match damaged base double-strand break inter-strand crosslink intra-strand crosslink ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2015 ANDROFERT
  • 10. DNA   Damage   Environmental  factors   Phtalate exposure, radiation, temperature Diseases   Varicocele, GTI, fever Life-­‐style   Obesity, smoking, medication Aging   Factors  associated  with  sperm  DNA   fragmenta.on   Rubes  et  al  2007;  Esteves  &  Agarwal  2011   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2015 ANDROFERT
  • 11. Frequency  of  elevated  SDF  in  men  with   unexplained  infer.lity   Elevated   SDF     (27%)   Androfert; N=987 Elevated  SDF   (27%)   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2015 ANDROFERT
  • 12. 19% 1.5% Normal Elevated Live birth rates with IUI N=387;  OR  =  0.07     [95%  CI:  0.01-­‐0.48]   Bungum  et  al.  Hum  Reprod  2007     IUI  outcome  is  nega.vely  affected   by  elevated  SDF   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2015 ANDROFERT
  • 13. 26% 42% IVF ICSI Pregnancy in cases of elevated sperm DNA fragmentation IVF  outcome  is  nega.vely   affected  by  elevated  SDF   Robinson  et  al.  Hum  Reprod  2012     Meta-­‐analysis  of  16   studies;  2,969   couples:     Increased  miscarriage   in    IVF/ICSI  associated   to    high  SDF;  RR  =  2.16     95%  CI:  1.54-­‐3.03;  p<0.00001   Bungum  et  al.  Hum  Reprod  2007     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2015 ANDROFERT
  • 14. Fer.lity  and  Sterility  2014;  101(1):58-­‐63   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2015 ANDROFERT
  • 15. Andrologia  2014;  46(6):  602–9     Pa.ents  with   varicocele  have   higher   propor.on  of   sperm  with   massive  DNA   damage     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2015 ANDROFERT
  • 16. SDF  is  part  of  rou.ne  work-­‐up  of   male  infer.lity  at  Androfert   Does the patient have high SDF? Semen analysis including SDF testing (SCD assay) High SDF if results >30% What does the doctor need to know? Determine test and internal validation Lab SOP with post-analytical info for clinical decision ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2015 ANDROFERT
  • 17. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2015 ANDROFERT
  • 18. Role  of  interven.ons  to   infer.le  men  candidates   to  ART   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2015 ANDROFERT
  • 19. Outcome   Effect  size     (OR;  95%  CI)   Live  birth   4.85  [1.92,  12.24]   DNA  fragmenta.on   -­‐13.80  [-­‐17.50,  -­‐10.10]   Oral  an.oxidants  decrease  SDF  and   improve  ART  outcomes   Showell  et  al.  Cochrane  Database  Syst  Rev  2011   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 19 2015 ANDROFERT
  • 20. Oral  an.oxidants  to  infer.le  males   Prescrip.on:   Vitamin  C  500mg;  Vitamin  E  400  mg   Folic  acid  2  mg,  Zinc  25  mg   Selenium  26  mcg   Dura.on:  minimum  2  months   Old  concept  ~90  days   New  concept  ~60  days   Misell  et  al.  J  Urol  2006;  Esteves  &  Agarwal  Int  Braz  J  Urol  2011   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2015 ANDROFERT
  • 21. Sperm  DNA  damage  in  tes.cular  and   ejaculated  samples  using  the  SCD  test*     40.7%   8.3%   Ejaculate   Tes.s   P<0.001   Sánchez-­‐Marqn,  Esteves  &  Gosálvez,  in  prepara@on   *Dual  fluorescent  cocktail  probe     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2015 ANDROFERT
  • 22. Wang  YJ  et  al.     Reprod  Biomed  Online  2012;25:307-­‐14   Meta-­‐analysis  of  7   studies  including  336   pts.  indicated  that  SDF   is  significantly   decreased  auer   varicocele  repair   (MD=3.4%;  95%  CI  -­‐4.1   to  -­‐2.6;  p<0.0001)   Effect  of  varicocele  surgery  on  SDF   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2015 ANDROFERT
  • 23. •  Varicocele   treated  prior   to  ICSI  (N=80)   •  ICSI  with   untreated   varicocele   (N=162)   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2015 ANDROFERT
  • 24. Microsurgical  subinguinal  varicocele   repair  with  aid  of  intraopera.ve  doppler   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 24 2015 ANDROFERT
  • 25. Management  of     azoospermia  and  the   role  of  gonadotropin   therapy   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2015 ANDROFERT
  • 26. Azoospermia:  the  complete  lack  of   sperm  in  ejaculate  auer  centrifuga.on   10-15% infertile males 1-3% male population Cooper  et  al.  Hum  Reprod  Update  2009;     Esteves  &  Agarwal,  Clinics  2013     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2015 ANDROFERT
  • 27. Obstruc.ve   Non-­‐ obstruc.ve         Hypo-­‐hypo   Spermatogenic   failure   Clinical  picture   FSH/LH:  ñ  or  nl   TT:  low  or  nL   Testes:    small  or  nl   Normal  testes  &   endocrine  profile;   Mechanical  blockage   FSH/LH  <1.2  mUI/ mL,     Low  TT,  small  tes.s,   poor  viriliza.on   Disrupted   Normal   Spermatogenesis   Esteves  et  al,  Clinics  2011     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2015 ANDROFERT Prognosis  and  management  differen.ally   affected  by  type  of  azoospermia    
  • 28. •  Low FSH and LH (<1.2 mIU/L) •  Low total testosterone (<300 ng/dL) •  Hypotrophic testes Hypogonadotropic  hypogonadism   Congenital: Kallman syndrome Prader-Willi Acquired: Pituitary tumor Steroid abuse Testosterone replacement therapy Fraieva  et  al.  Clinics  68;  2013   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2015 ANDROFERT
  • 29. Classic  treatment  for  male   hypogonadism  and  infer.lity   u-­‐hCG  1,000-­‐2,000  IU;  IM   injec.ons;  twice  or  t.i.w;     minimum  12  weeks   Rec-­‐hCG:  SC  self-­‐ injec.on  qw   Pre-­‐filled  syringe   Pen  device   Fraieva  et  al.  Clinics  2013;  68(Suppl.1):81-­‐8   Specific  therapy  in  adult  onset   hypo-­‐  hypo   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2015 ANDROFERT
  • 30. Rec-­‐hCG  for  male  hypo-­‐hypo   Esteves  &  Papanikolaou  Fer@l  Steril  2011;96:S230   Series  of  men  with  adult-­‐onset  HH;     Recombinant  hCG  (250  mcg  qw  for  12  weeks)   Baseline   Pos`reatment   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2015 ANDROFERT
  • 31. Tes.cular  torsion;  trauma   Post-­‐inflammatory  (eg.  Mumps  orchi=s)   Exogenous  factors  (eg.  Cytotoxic  drugs,  irradia=on)   Tes.cular  cancer     Systemic  diseases  (eg.  Liver  cirrhosis,  renal  failure)   Congenital   Tes.cular  dysgenesis/cryptorchidism   Gene.c  abnormali.es  (Klinefelter  syndrome,  Yq  microdele=ons,  etc.)   Acquired   Idiopathic  (unknown  e.ology)   Esteves  et  al.  Clinics  2011;  66:691-­‐700   NOA  due  to  spermatogenic   failure:  an  irreversible  condi.on   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2015 ANDROFERT
  • 32. Esteves  et  al.  Int  Braz  J  Urol  2011;37:570-­‐83   40-­‐50%  of  men  with  SF  have  residual   spermatogenesis  within  the  tes.s   § Not  enough  for  sperm  to  appear   in  ejaculate   § 600-­‐800  seminiferous  tubules   § Goals  are:     i.  Op=mize  sperm  produc=on  (if  possible)   ii.  Iden=fy  site  of  sperm  produc=on  (if   present)  and  retrieve  sperm  for  ICSI   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2015 ANDROFERT
  • 33. Challenges  faced  by  health  professionals   providing  care  for  men  with  SF   §  Counseling  about  the  chances  of  finding   tes.cular  sperm   §  Usefulness  of  any  medical  interven.on   before  sperm  retrieval   §  Which  sperm  retrieval  method  to  apply     §  Reproduc.ve  poten.al  of  retrieved  gametes   in  ICSI  treatment   §  Health  of  offspring     ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2015 ANDROFERT
  • 34. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2015 ANDROFERT
  • 35. Complete  AZFa,  AZFb  or  AZFa+b   microdele.ons  unfavorable  prognosis   YCMD   SR   success   AZFa   nil   AZFb   nil   AZFc   50-­‐70%   Krausz  et  al.  2014;  Esteves  et  al.  2013;  Esteves  2015   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2015 ANDROFERT
  • 36. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2015 ANDROFERT Interven.ons  to  infer.le  males  men  with   SF  prior  to  a  sperm  retrieval  avempt  
  • 37. Matura.on  arrest  and  hypospermatogenesis   favorable  prognosis   Weedin  et  al  J  Urol  2010;183:2309-­‐15   Among  233  men  with  SF  and  treated   varicocele,  1/3  had  mo.le  sperm  in  postop.   ejaculate   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2015 ANDROFERT
  • 38. Inci  et  al  J  Urol  2009;182:1500-­‐5;     Haydardedeoglu  et  al  Urology  2010;75:83-­‐6     § Inci  2009     OR:  2.63     (95%  CI:  1.05-­‐6.60;  p=0.03)     Although  2/3  remain  azoospermic  auer   varicocele  repair,  SRR  increased   § Haydardedeoglu  2010   53 30 Treated (N=66) Untreated (N=30) SR success (%) 61 38 Treated (N=31) Untreated (N=65) p<0.01   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2015 ANDROFERT
  • 39. Medica.on   Hypogonadism  (TT<300  ng/dl)  in  up  to  50%   men  with  SF      High  ITT  levels  essen=al  for  regula=ng   spermatogenesis  in  combina=on  with  Sertoli   cell  s=mula=on  by  FSH   Paradoxically  weak  s.mula.on  of  Leydig  and   Sertoli  cells  by  endogenous  gonadotropins    Due  to  high  baseline  FSH  and  LH  levels  the   rela=ve  amplitudes  are  low     Shiraishi  et  al  Hum  Reprod  2012;27:331-­‐9;     Sussman  et  al  Urol  Clin  N  Am  2008;35:147-­‐55   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 39 2015 ANDROFERT
  • 40. Study Study design Study group Medication Findings Pavlovich et al. 2001 Case series 43 men with T/E ratio <10 Testolactone No effect Hussein et al. 2005 Prospective cohort 42 men with favorable hystology Clomiphene Sperm found in SA in 64.3%; All men who remained azoospermic had success at SR Selman et al. 2006 Prospective cohort 49 men with maturation arrest rec-hFSH and hCG No return of sperm in ejaculate; posttreatment SRR were 21.4% Ramasamy et al. 2009 Case series 56 men with nonmosaic Klinefelter Testolactone or anastrozole, alone or combined with hCG SRR increased by 1.4-fold Reifsnyder et al. 2012 Retrospective cohort 307 men with hypogonadis m Aromatase inhibitors, hCG or Clomiphene, alone or combined No effect Shiraishi et al. 2012 Prospective cohort 28 men with idiopathic SF hCG alone or combined with rec-hFSH SR success in 21% of the treated men vs. none in untreated men Hussein et al. 2013 Prospective cohort 612 unselected men Clomiphene alone or combined with hCG or hMG Sperm found in SA in 10.9% of treated males; SRR higher in men who remained azoospermic and treated (57.0 vs. 33.6%, p<0.001) ! Aromatase  inhibitors  and  gonadotropins   have  been  used  with  variable  results   Esteves  Asian  J  Androl  2015;17:1-­‐12   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 40 2015 ANDROFERT
  • 41. ITT  levels  increase  auer  hCG;  s.mulatory   effect  on  residual  spermatogenic  areas   Shinjo  E  et  al  Andrology  2013;1:929-­‐35;  Shiraishi  et  al  Hum  Reprod  2012;27:331-­‐9   273 1348 Before After ITT (ng/dl) ITT  levels  increased  auer   hCG-­‐based  therapy   Spermatogonial  DNA   synthesis  increased   PCNA  expression   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 41 2015 ANDROFERT
  • 42. 1Shiraishi  et  al  Hum  Reprod  2012;27:331-­‐9;  Esteves  Int  Braz  J  Urol  2013;39:440   hCG-­‐based  therapy  may  increase  SR   success  in  men  with  SF   Microdissec.on  TESE   Rescue  ~15%  of  pa.ents   with  previous  failed  SR   avempts1   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 42 2015 ANDROFERT
  • 43. Testosterone  and   estradiol  levels   <300   ng/dL   (10.4  nmol/L)   Hypogonadism   category   Pure   Medica.on  algorithm  at  Androfert   Tx  aimed  at   boos.ng  T Aromatase  inhibitor   (anastrozole  1mg  orally   qid)   Rec-­‐hCG     (250  mcg  SC  qw);     rec-­‐FSH  added   (75  IU  SC  biw)  if  FSH   levels  <1.5  mIU/ml   T/E  ra.o   <10   Aromatase   hyperac.vity   T/E  ra.o   >10  (nl)   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 43 2015 ANDROFERT
  • 44. Esteves  Asian  J  Androl  2015;17:1-­‐12   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 44 2015 ANDROFERT
  • 45. Sperm  retrieval  methods  in  NOA  due  to   spermatogenic  failure   Technique   Acronym   Success   Tes.cular  sperm   aspira.on   TESA   15-­‐50%   Tes.cular  sperm   extrac.on   TESE   20-­‐60%   Microdissec.on   tes.cular  sperm   extrac.on   Micro-­‐ TESE   40-­‐67%   Esteves  et  al  Int  Braz  J  Urol  2013;37:570-­‐83;  Deruyver  et  al    Andrology  2014;2:20-­‐4   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 45 2015 ANDROFERT
  • 46. http://androfert.com.br/videos Esteves SC Int Braz J Urol 2013; 39(3):440
  • 47. 41.4 47 43.3 20 100 64 61 34.2 Sperm retrieval (%) 2PN Fertilization (%) Top Quality Embryos (%) Live Birth (%) Non-obstructive (N=365) Obstructive (N=146) P<0.01   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 47 2015 ANDROFERT
  • 48. Morphometric  evalua.on  of  seminiferous   tubules  increases  SR  efficiency     Median 25%-75% 5%-95% Raw Data yes No Presence of Sperm 160 180 200 220 240 260 280 300 320 340 360 380 400 420 Max.TubuleDiameter Verza  Jr  S,  Esteves  SC.  Fer@l  Steril  2012;  98:  S242;     Esteves  &  Varghese  J  Reprod  Sci  2012;  5(3):233-­‐43     N=54; Tubule Diameter: KW-H (1;54) = 25.2; P<0.001 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 48 2015 ANDROFERT
  • 49. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 49 2015 ANDROFERT
  • 50. On  average,  one  top-­‐quality  addi.onal  embryo   for  transfer  or  cryopreserva.on   Clean  Room  Technology  &  ICSI  Results   2,315  pa.ents;  14,660  embryos   Esteves  &  Bento.  Reprod  Biomed  Online  2013;26:9-­‐21   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 50 2015 ANDROFERT
  • 51.  3,412  cycles   Tailored  COS  strategy  to  increase  LBR  in   ICSI  cycles  involving  severe  male  factor   0%   10%   20%   30%   40%   50%   60%   1   2   3   4   5   6   7   8   9   10   11   12   13   14   15   20   25   Number  of  oocytes  retrieved   Clinical  pregnancy   Live  birth   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 51 2015 ANDROFERT
  • 52. Conclusions   1.  Conven.onal  semen  analysis  limited  as   surrogate  for  assessing  fer.lity;  SDF  tes.ng   valuable  laboratory  tool  for  clinical  decision     2.  An.oxidant  therapy,  microsurgical  varicocele   repair  and  TESA-­‐ICSI  may  improve  ART   outcome  in  selected  individuals     3.  Best  management  of  azoospermia  includes   proper  diagnosis,  interven.ons  to  op.mize   sperm  produc.on,  microsurgical  SR,  state-­‐of-­‐ art  laboratory  care  and  tailored  COS  to  ART   candidates   ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 52 2015 ANDROFERT
  • 53. Thank  you        ‫ا‬‫شكر‬ Obrigado   This  presenta.on  is  available  at   hvp://www.slideshare.net/ sandroesteves