1. Delhi
&
Chennai,
INDIA
2013
Medical
Management
of
Male
InferDlity
Sandro
C.
Esteves,
MD.,
PhD.
Director,
ANDROFERT
Campinas,
Brazil

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. 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. 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.
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. 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. 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. 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. 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. 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

12. 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

13. 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

14. Obesity in men at reproductive age
Esteves, 14
ANDROFERT, Referral Center for Male Reproduction

15. 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

16. 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

17. 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

18. Pure
hypogonadism
ART
Candidates
Severe
oligozoospermia
Non-­‐obstrucDve
azoospermia
OpDons
AnD-­‐estrogens
u-­‐hCG/rec-­‐hCG
Esteves,
18
ANDROFERT,
Referral
Center
for
Male
ReproducDon

19. 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

20. 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

21. 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

22. 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

23. 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