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 of surgicallyretrieved 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

29. Thank
You