1. Sandro C. Esteves, MD., PhD.
Director, ANDROFERT
Andrology & Human Reproduction Clinic
Campinas, BRAZIL
Medical Management of
Male Infertility
Reproductive Andrology Surgery Workshop 2014
Al Jahra Hospital, KUWAIT
ISO 9001:2008

2. Available at:
h"p://www.androfert.com.br/review
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Medical Management of
Male Infertility

3. Lecture
Outline
Overview
Empiric Tx of idiopathic oligozoospermia
Specific Tx for subclinical MAGI
Hormonal Tx for hypo-hypo
Aromatase inhibitors in obese-related male
infertility
Antioxidants for oxidative-stress alleviation
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4. Empirical medical Tx of
idiopathic oligozoospermia
Guidelines on Male Infertility.
European Association of Urology 2012
In
general,
NOT
EFFECTIVE
Androgens
hCG/HMG/FSH
Aromatase inhibitors
Anti-estrogens
Bromocriptine
Alpha-blockers
Systemic corticosteroids
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5. Injectable testosteroned
GnRH
FSH/LH
Azoospermia
Marked fall in ITT levels
Between the seminiferous
tubules, Leydig cells produce
testosterone
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6. Who benefit from medical Tx?
Estradiol
levels
FSH & LH
levels
Total
Testosterone
levels
<300
ng/dL
(10.4 nmol/L)
Normal/
Elevated
T/E ratio
<10
<1.2 mUI/
mL
Hypogonadism
category
T/E ratio
>10 (nl)
Hypo-
hypo
Aromatase
hyperactivity
Pure
Treatment
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7. Deficient virilization; Hypotrophic testes
Azoospermia
Low FSH and LH (<1.2 mIU/L)
Low total testosterone (<300 ng/dL)
Hypogonadotropic hypogonadism
Specific medical therapy
• Congenital:
Kallman syndrome
Prader-Willi
• Acquired:
Pituitary tumor
Steroid abuse
Testosterone replacement therapy
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8. 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-
injection w/pre-filled
syringe, qw
Fraietta & Esteves Clinics 2013
Adult onset hypo- hypo
Specific medical therapy
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9. Rec-hCG for male hypo-hypo
Baseline
Posttreatment
Esteves & Papanikolaou Fertil Steril 2011
Series of men with adult-onset HH;
Recombinant hCG (Ovitrelle 250 mcg)
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10. Who benefit from medical Tx?
Total
Testosterone
levels
<300ng/dL
(10.4 nmol/L)
FSH & LH
levels
Normal/
Elevated
<1.2 mUI/
mL
Estradiol
levels
T/E ratio
<10
T/E ratio
>10 (nl)
Hypogonadism
category
Hypo-
hypo
Aromatase
hyperactivity
Pure
Treatment
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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
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13. Oligozoospermia in obese 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. Hum Reprod Update. 2013
Meta-analysis of 21 studies; 13,077 men
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14. Obesity in men at reproductive age
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15. Total Testosterone (ng/dL) and
Estradiol (pg/mL) Levels
T/E2 Ratio
Normal > 10
Zumoff et al. Metabolism 2003;
Raman & Schlegel J Urol 2002
T/E2 <10
Aromatase Hyperactivity
Aromatase inhibitors in obese-
related oligozoospermia
Anastrozole 1 mg
q1d 60 days
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16. Raman & Schlegel. J Urol. 2002
5.9
2.9
5.5
15.6
3.5
15.6
0
5
10
15
20
T/E ratio Ejaculate volume
(mL)
Sperm Count
(million/mL)
Anastrazole (1mg q1d for 3-6 months)
in Oligozoospermia
Pre-treatment Post-treatment
Aromatase Inhibitors for
Obesity-related Male Infertility
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17. Who benefit from medical Tx?
Estradiol
levels
FSH & LH
levels
Total
Testosterone
levels
<300ng/
dL
Normal/
Elevated
T/E ratio
<10
<1.2 mUI/
mL
Hypogonadism
category
T/E ratio
>10 (nl)
Hypo-
hypo
Aromatase
hyperactivity
Pure
Treatment
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18. Pure hypogonadism
ART Candidates
Severe oligozoospermia
Non-obstructive azoospermia
Options
Anti-estrogens
u-hCG/rec-hCG
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19. Ramasamy et al., J Urol. 2009
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
72
55
Sperm Retrieval Rate (%)
Positive response
P
=
0.03
Medication before sperm retrieval in
Klinefelter syndrome men (47,XXY)
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20. 51
51
Sperm retrieval rate (%)
Positive response (n=252)
No response (n=55)
Ø Case series (n=307): unselected
group of men with testicular failure
and low testosterone levels
(300 nd/dL)
Ø Micro-TESE
Ø Medication to boost testosterone
production: Aromatase inhibitor,
hCG, anti-estrogens (min. 2-3
months)
Ø Positive response: posttreatment
TT >250 ng/dL
Medication prior to SR in
unselected men with NOA
Ramasamy et al., J Urol. 2011
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21. 800
Before
Clomiphene
After
90d; 25mg/d
Da Ros CT, Averbeck MA
Int Braz J Urol 2012
Anti-estrogens in Hypogonadism
1000
1200
1400
600
400
200
0
ng/dL
Upper Limit
Lower Limit
Lower
Sperm
Counts
ITT levels
fall
Normal Testosterone
Levels
Negative
central
feedback
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22. Medical Tx - Key Messages (1)
Empirical medication for idiopathic
oligozoospermia not recommended
Infertile males with hypogonadism
(TT<300) candidates for Tx
hCG is the treatment of choice for
adult-onset hypogonadotropic
hyponadism
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23. Medical Tx - Key Messages (2)
Aromatase inhibitors helpful for
overweight/obese men with aromatase
hyperactivity (T/E<10) and
oligozoospermia
hCG/anti-estrogens helpful to boost
testosterone production (sperm
production?) in selected ART candidates
Minimum Tx duration 8 weeks; monitor TT
levels regularly to dose titration
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24. Lecture
Outline
Overview
Empiric Tx of idiopathic oligozoospermia
Specific Tx for subclinical MAGI
Hormonal Tx for hypo-hypo
Aromatase inhibitors in obese-related male
infertility
Antioxidants for oxidative-stress alleviation
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25. Subclinical Male Genital Tract
Infection
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Urethritis, prostatitis
AnN-­‐bacterial
properNes
(Zinc)

26. Yanushpolsky et al 1996,
Saleh & Agarwal 2002,
Aziz et al 2004
Leukocytospermia
>1.0 x 106 leukocytes per mL of semen
marker of reproductive
tract inflammation
MacrophageNeutrophils
Subclinical Male Genital Tract
Infection (MAGI)
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25%
34%
39%
Normal Abnormal Abnl &
Leukocytospermia
% DNA Damage (SCSA)

27. Seminal Leukocytes
Endtz Test
Simple diagnostic method
Peroxidase-negative
Peroxidase-positive
Granulocytes (Neutrophils)
substrate
+
H2O2
+
semen
Esteves et al. CLINICS 2011; 66:1-10.
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28. • Yanushpolsky et al, 1995; Erel et al., 1997
• Branigan et al., 1995
Antibiotics
• Lackner et al., 2006
• Gambera et al., 2007
Cicloxigenase-2
Inhibitors
• Oliva & Mutigner, 2006
Antihistamines
• Tremellen et al., 2007
• Piombini et al., 2008
Antioxidants
Treatment of Subclinical Male Genital
Tract Infection and Associated
Inflammatory Changes
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29. Subclinical Male Genital Tract
Infection
Azitromycin 1.0g single dose (couple)+ frequent
ejaculation (every 2-3 days) + Antioxidants
42% leukocytospermia resolution (N=278; Androfert)
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30. OxidaNve
Stress
30%-80% of infertile men
have elevated markers of OS
Agarwal et al., Urology 2006
An
emerging
explanaNon
for
several
cases
of
male
inferNlity
Oral Antioxidants
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31. Chemical species with unpaired
electron capable to oxidize lipids,
proteins and nucleic acids:
Superoxide anion (•O-2)
Hydroxyl radical (•OH)
Hydrogen peroxide (H2O2)
Peroxyl radical (ROO•)
Hypochlorite ion (OCl-)
Generated from aerobic metabolism
of sperm and leukocytes’
mitochondria
Lampiao et al., 2012
Reactive Oxygen Species (ROS)
Sperm and Seminal Plasma Antioxidants:
Enzymatic (SOD, catalase, GPX): inactivate ROS by conversion into
other substances
Non-enzymatic (ascorbic acid, alpha-tocopherol, carnitine, etc.):
neutralize ROS
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32. Rationale of Oral
Antioxidants use
OA classified according to
their mechanism of action:
Catalytic: enhances the
already present antioxidant
enzymes (Glutathione, N-
acetyl-cysteine).
Scavenging:
Water soluble: react with
oxidants in the cytosol
(Vitamin C)
Lipid soluble: protect cell
membrane from lipid
peroxidation (Vitamin E)
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33. Outcome
No. studies
Effect size
(OR; 95% CI)
Live birth
3
4.85 [1.92, 12.24]
Pregnancy rate
15
4.18 [2.65, 6.59]
DNA fragmentation
1
-13.80 [-17.50,
-10.10]
Miscarriage, sperm
count, sperm motility
6-16
No effect
Oral Antioxidants
Showell MG et al. Cochrane Database Syst Rev 2011
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34. Oral Antioxidants
• Short-term use
appear to be safe
• Caution against
indiscriminate use
of high dosages
for long periods
Beneficial
Kodama 1997
Dawson, 1992
Kessopoulou, 1995
Vezina, 1996
Vicari, 2001; 2002
Lenzi, 2003; 2004
Cavallini, 2004
Comhaire, 2005
Grecco 2005
Menezo 2007
Tremellen 2007
Piomboni 2008
Gil Villa 2009
No effect
Giovenco, 1987
Moilanen, 1993
Iwanier, 1995
Rolf, 1999
Sigman, 2006
Detrimental
long-term use and high
doses;
increased mortality in
cancer population-
based studies.
Heinonen, 1994
Lonn, 2005
Bjelakovic, 2007
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35. How to use Antioxidant Therapy
Ascorbic acid (Vit. C)
α- tocopherol (Vit. E)
Glutathione
N-acetyl-cysteine
Carnitine, Coenzyme Q10
Lycopene. Picnogenol
Pentoxifylline. Selenium
Shao-Fu-Zhu-Yu-Tang
Astaxanthin
Lepidium meyenii
α -linolenic acid and lignans
Folic acid, Zinc
Select antioxidant
formulation and dosage
Testing for
Leukocytes in Semen
Differentiate between
sperm and leukocyte
source of ROS
Varicocele
Genital Infection
Smoking
Medication
Drug abuse
Systemic diseases
Pollution
Radiation
Focus on identifying
and controlling source
of increased ROS
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36. Oral Antioxidants
How I prescribe
Vitamin C 500mg; Vitamin E 400 mg
Folic acid 2 mg, Zinc 25 mg
Selenium 26 mcg
Minimum 2 months
Old concept ~80 days
New concept ~60
days
From initiation of sperm production to ejaculation
Misell LM et al. J Urol. 2006
Esteves & Agarwal. Novel concepts in male infertility. Int Braz J Urol 2011
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37. Asymptomatic leukocytospermia is mainly
caused by urethritis
ROS production increase with an increase in
leukocyte numbers
Antibiotic therapy is suggested, but effect on
fertility is still unclear (GR-B)
Medical Tx - Key Messages (3)
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38. Oxidative stress impairs sperm function and
is a risk factor for male infertility (GR-A)
OA supplementation for subfertile males
improve the chances of live birth for couples
undergoing ART (GR-A)
Well-designed studies are needed to
determine the best candidates for OA therapy
and which formulation and dosages yield
better results
Medical Tx - Key Messages (4)
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39. Thank you Obrigado
‫شكرا‬