advancements in the medical management of male infertility
TRANSCRIPT
Sandro Esteves, MD, PhD
Director, ANDROFERT
Center for Male Reproduction
Campinas, BRAZIL
Esteves, 2
Learning Objectives
Overview of Male Infertility Conditions Subjected to Specific Medical Treatment
Conventional Specific Medical Treatment
Novel Specific Medical Treatment
Life-style and its Effect on Male Fertility
8% of men at
reproductive age
seek medical
assistance for
fertility-related
problems
Vital and Health Statistics, series 23, no. 26, CDC 2002; www.cdc.gov
Esteves, 4
US Census Bureau Estimates, 2004
2,383 subfertile
males
19% candidates for medical treatment
Male Infertility Etiology
Categories
Esteves et al.
An update on the initial assessment of the infertile male. CLINICS 2011; 66:1-10. Esteves, 6
Specific Medical Treatment
Overview
Conventional
Subclinical Male Genital
Tract Infection
Endocrine Disorders
Ejaculatory Disorders
Novel
Excessive Oxidative
Stress
Obesity-related Male
Infertility
Esteves, 7
Specific Medical Treatment
Overview
Conventional
Subclinical Male Genital
Tract Infection
Endocrine Disorders
Ejaculatory Disorders
Esteves, 8
Subclinical GTI
Hypogonadotropic Hypogonadism
Subclinical Male Genital
Tract Infection
Prevalence: 10-20%
Primary target organs:
Epididymis
Prostate
Seminal Vesicles
Significant cause of idiopathic
male infertility
Bacteria E. Coli
N. Gonorrhoeae
C. Trachomatis
U. Urealyticum
M. hominis
Virus HPV
Herpes simplex 2
Epstein-Barr
CMV, HIV
hepatitis B
Protozoa T. vaginalis
T. gondii
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Gram-negative
bacilli
Neisseria
gonorrhoeae
Chlamydia
trachomatis
Ureaplasma
urealyticum
Mycoplasma
hominis
Culture
Culture, nucleic
acid
amplification
tests (NAAT)
Culture, direct
fluorescent
antibodies,
immunoassay,
NAAT
Culture,
NAAT
Immunoassay,
NAAT,
Culture
fluorquinolones
penicillin,
fluorquinolones,
cefalosporins
azithromycin,
doxycycline,
ofloxacin
azithromycin,
doxycycline
azithromycin,
doxycycline
Anti-bacterial properties
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Subclinical Male Genital Tract Infection
Endtz Test Simple diagnostic method
Peroxidase-negative
Peroxidase-positive
Granulocytes
substrate +
H2O2
+
semen
Yanushpolsky et al 1996, Erenpreiss et al 2002,
Sharma et al 2002, Saleh & Agarwal 2002, Aziz et al 2004
Leukocytospermia >1.0 x106 leukocytes per milliliter of semen
marker of reproductive
tract inflammation
Subclinical Male Genital Tract Infection
granulocyte macrophage lymphocyte
Henkel R et al, AJA 2007; Alvarez et al. Fertil Steril 2002
• 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
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Treatment of Subclinical Male Genital
Tract Infection and Associated
Inflammatory Changes
Treatment of Subclinical Male Genital
Tract Infection and Associated
Inflammatory Changes
Max
Min
75th %
25th %
Median
-10
10
30
50
70
90
110
LEUCO_PR
LEUCO_PO
MOT_PRE
MOT_POS
MORF_PRE
MORF_POS
VIT_PRE
VIT_POS
P=0.001
P=0.04
P=0.50
P=0.58
Azitromycin 1.0g single dose (couple)+ frequent ejaculation (every 2-3 days) + Antioxidants
N = 278
Androfert 1999-2009
42% leukocytospermia
resolution
Specific Medical Treatment
Overview
Conventional
Subclinical Male Genital
Tract Infection
Endocrine Disorders
Ejaculatory Disorders
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Subclinical GTI
Hypogonadotropic Hypogonadism
Features Low levels of FSH, LH,
testosterone
Absent/low virilization, hypotrophic testes, azoospermia
Main Causes:
● Congenital:
Kallmann syndrome
Prader-Willi
● Acquired:
Pituitary tumor
Pituitary radiation
Steroid abuse
Testosterone replacement therapy
Hypogonadotropic Hypogonadism
MR
I
hCG 1000-2000 UI IM injections; twice or t.i.w;
minimum 12 weeks
Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week 10 Week 11 Week 12 Maintenance
Adult onset Hypo-hypo: Treatment to restore spermatogenesis and androgenic status
Standard Treatment:
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hCG
preparations
Brand
names
Manufacturer LH activity
(IU/ampule
or vial)
Ampoule/
vial filling
method
% Protein
Contamination
Source Technology
used
Route of
administration
Urinary hCG Pregnyl Schering-
Plough;
Organon
10,000 Filled-by-
bioassay
<5% Urine Chemical
extraction
IM
Choragon Ferring 5,000
Filled-by-
bioassay
<5% Urine
Chemical
extraction
IM
Choriomon IBSA 5,000 Filled-by-
bioassay
<5% Urine
Chemical
extraction
IM
Corion,
Choriolife,
Pubergen,
LG IVF C,
Origen,
etc.
Win-Medicare,
Life-Medicare,
Sun Pharmac.,
Uni-Sankyo,
LG, etc
1,000;
2,000;
5,000
Filled-by-
bioassay
Unknown Urine
Chemical
extraction
IM
Recombinant
hCG
Ovidrel,
Ovitrelle
MerckSerono 250µg Filled-by-
mass
(FbM)
Negligible Transfected
CHO cells
Recombinant
DNA
SC
Adult onset Hypo-hypo: hCG Preparations
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Evolution of hCG Preparations
Urine-derived
Recombinant technology
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Clinical Efficacy, Safety and Tolerability of Recombinant hCG
to Restore Spermatogenesis and Androgenic Status of
Hypogonadotropic Hypogonadism Males
Esteves SC, Papanikolaou V; Fertil Steril 2011; Vol 96: S230
Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week 10 Week 11 Week 12 Evaluation
Case Series of 11 azoospermic males
Adult onset hypo-hypo
Causes:
Pituitary tumor; n=7
Steroid abuse; n=1
Testosterone replacement therapy; n=2
Cranioencephalic trauma; n=1
Mean ± SD hormone levels (mUI/mL) FSH: 0.46 ± 0.28; LH: 0.39 ± 0.32
Once a week SC self-administration of
250µg rec-hCG using a ready-to-use prefilled
syringe
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Mean TotalTestosterone
(ng/dL)Mean CombinedTestis Volume
(cm3)Mean Sperm
Count (x106/mL)
41.3 24
0
647.5
33 36.0
Baseline Posttreatment
Recombinant hCG to Treat Men with Hypo-hypo Esteves SC, Papanikolaou V; Fertil Steril 2011; Vol 96: S230
Restoration of spermatogenesis and androgen production: 10/11 men
Side-effects not reported in men who responded to therapy
Pretreatment
Abnormal virilization
Posttreatment
Normal hair distribution
Pretreatment
Hypotrophic scrotum/reduced testes
Posttreatment
Normal scrotum and testes
Figure 2. Photographs illustrating a patient with gigantism associated with a pituitary tumor secreting growth hormone and prolactin cured by
transsphenoidal hypophysectomy. Secondary hypo-hypo was treated with rec-hCG leading to a marked improvement in virilization and testicular
volume (with patient permission).
Baseline Posttreatment
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Specific Medical Treatment
Overview
Conventional
Subclinical Male Genital
Tract Infection
Endocrine Disorders
Ejaculatory Disorders
Novel
Excessive Oxidative Stress
Obesity-related Male Infertility
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Esteves, 24
Excessive Oxidative Stress
0
0,5
1
1,5
2
2,5
Fertile Infertile
Seminal Reactive Oxygen
Species (ROS) (Log ROS + 1; cpm)
Pasqualotto et al., Fertil Steril 2000
How Oxidative Stress Can be
Measured?
Indirect Assessment
• Lipid Peroxidation (Malondialdehyde)
• Protein oxidation products (eg. 8-OHdG)
• Sperm DNA integrity
Direct Assessment
• Total Antioxidant Capacity
• Seminal ROS levels
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Esteves et al. What every GYN should know about male infertility.
Arch Gynecol Obstet 2012, Epub March 6
DNA Damage is the Main
Expression of ROS Production
and Oxidative Stress
• Quantification of sperm DNA strand breaks Principle
• Spermatozoa Specimen
• Nuclear dyes (Acridine orange, SCSA)
• Direct assessment (TUNEL, COMET)
• Sperm Chromatin Dispersion (SCD) Techniques
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Sperm DNA Integrity and Assisted
Conception Results
19%
1.5%
Normal Elevated
Live Birth Rates by Intrauterine
Insemination
OR = 0.07 [95% CI: 0.01-0.48]
Adapted from Bungum et al., Hum Reprod 2007
26%
42%
IVF ICSI
Pregnancy by Method in Cases of Elevated Sperm DNA
Fragmentation
P <0.05
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Evidence-based Use of
Antioxidants in Male Infertility
Author Antioxidant Agent Results
Geva et al., 1996 Vit E 200 mg Increased fertilization in IVF
Suleiman et al, 1996 Vit E 100 mg Decreased ROS; increased
spontaneous PR
Wong et al., 2002 Folic acid 5 mg + Zinc
66 mg
Increased total sperm count
Greco et al., 2005 Vit C 1.0 g + E 1.0 g Improved sperm DNA integrity
Greco et al., 2005 Vit C 1.0 g + Vit E 1.0 g Increased CPR and IR in ICSI
cycles
Tremellen et al.,
2007
Menevit® (vit C + E;
zinc 25 mg; selenium 26
mcg; lycopene 6 mg)
Increased IR/PR in IVF/ICSI
cycles
Boxmeer et al., 2009 Decreased folate in
seminal plasma
Increased sperm DNA
fragmentation
Antioxidant Treatment Cochrane Review 2011
Outcome N
studies
N
participants
Effect size
(OR; 95% CI)
Live birth 3 214 4.85 [1.92, 12.24]
Pregnancy rate 15 964 4.18 [2.65, 6.59]
DNA fragmentation 1 64 -13.80 [-17.50, -10.10]
Miscarriage, sperm
count, sperm motility 6-16 242-700 No effect
Adverse effects 6 426 No effect
Improve the outcomes of live birth and pregnancy rate for
subfertile couples undergoing ART cycles
Showell MG et al. Antioxidants for male subfertility.
Cochrane Database Syst Rev 2011 Jan 19;(1):CD007411.
Antioxidants in Male
Infertility To whom?
Men at risk of eOS
How? q.d.
Vitamic C 500mg
Vitamin E 400 UI
Folic acid 2 mg
Zinc 25 mg
Selenium 26 mcg
How long?
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Esteves et al. What the gynecologist should know about male infertility:
an update. Arch Gynecol Obstet 2012; Epub March 6
From Initiation of Sperm
Production to Ejaculation
Misell LM et al.: A stable isotope-mass spectrometric method for measuring
human spermatogenesis kinetics in vivo.
J Urol. 2006; 175: 242-6.
Old concept ~80 days
New concept ~60 days
Empirical Medical Treatment
for Idiopathic Male Infertility
Androgens
hCG/HMG
FSH
Anti-oestrogens
Bromocriptine
Alpha-blockers
Systemic corticosteroids
Magnesium supplementation
No demonstrable cause for altered semen parameters
Guidelines on Male Infertility.
European Association of Urology 2012
Specific Medical Treatment
Overview
Novel
Obesity-related Male Infertility
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Obesity in Men at Reproductive Age
WHO: Global database on BMI, 2011 Esteves, 34
Esteves, 35
Jensen et al. Fertil Steril 2004; 82: 863; Hammoud et al. Fertil Steril 2008; 90: 2222;
Kriegel et al. RBM Online 2009; 19: 660;
Martini et al. Fertil Steril 2010; 94: 1739. Esteves, 36
Esteves, 37
Esteves, 38
Serum Levels of Total Testosterone and Estradiol
T/E2 Ratio Normal > 10
Eg.: 4.9 =350 𝑛𝑔/𝑑𝐿
62 𝑝𝑔/𝑚𝐿
T/E2 Ratio Normalization and Sperm Count Improvement
T/E2 <10
Aromatase Hyperactivity
Anastrozole 1 mg q1d 60 days
Zumoff et al. Reversal of the hypogonadotropic hypogonadism of obese men by administration of
the aromatase inhibitor testolactone. Metabolism 2003; 52: 1126. Raman & Schlegel Aromatase
inhibitors for male infertility. J Urol 2002; 167: 624. Esteves, 39
Medical Treatment for Klinefelter Syndrome Men Seeking Fertility
Esteves et al. Surgical treatment of male infertility in the era of ICSI – new insights.
CLINICS 2011; 66:1463-77.
Klin
efe
lter Karyotype:
47,XXY
47,XXY/46,XY
Features:
Azoospermia (>90%)
Small testes
Elevated FSH
Low Testosterone
Hypogonadism
Elevated testis expression
aromatase CYP19
Seekin
g F
ert
ility
Sperm Retrieval
and ICSI
Managem
ent Medical
Treatment prior
to Sperm
Retrieval
Foci of sperm
production (~40%) Sciurano et al., Hum
Reprod. 2009
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Klinefelter Syndrome
Medical Treatment Prior to Sperm Retrieval
180
330
150
220
Baseline Testosterone Post-treatment TT
Positive Response to Therapy No response
Ramasamy et al., J Urol. 2009; 182: 1108-13.
72%
SRR: 72%
SRR: 55%
Series of 68 non-mosaic KS Men with Azoospermia
Medical Treatment: Aromatase inhibitor, hCG, CC
Positive Response: TT increase of >100ng/dL from baseline
P = 0.03
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Life-style
Habits
Specific Medical Treatment
Overview
Novel
Excessive Oxidative Stress
Obesity-related Male Infertility
Esteves, 42
Klonoff-Cohen H. Human Reproduction Update, Vol.11, No.2 pp. 180–204, 2005
Smoking
• Live birth delivery reduced by 3.7X
Alcohol
• Live birth delivery reduced by 5.5X
• Miscarriage increased by 2.7X
Stress
• Conflicting results
Caffeine
• No effect
Common Toxicants to Male
Reproductive Health
Environmental/Nutritional Endocrine disruptors (xenoestrogens
[Polychlorinated biphenyls, bisphenol
A, Phtalates]), Heavy Metals,
Pesticides
Ilicit Drugs Anabolic Steroids,
Marijuana, Cocaine, etc.
Cell Phone
Electromagnetic
Radiation
Medication Antidepressants (SSRI), Antipsychotics
(Lithium), Antihypertensives (calcium
channel blockers),
Cimetidine, Ketoconazole, Finasteride,
Antibiotics
Licit Drugs Cigarette smoking,
Alcohol
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Subclinical infections are treated with antibiotics
and leukocyte-induced inflammation can be
alleviated by oral antioxidants administration.
Medical treatment of adult onset hypo-hypo with
hCG is highly effective.
Antioxidant prescription to subfertile men is
recommended, especially in cases of eOS.
Sperm DNA damage marker of eOS.
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Medical treatment (AI) is recommended for
obese/overweight subfertile men with aromatase
hyperactivity.
KS men with NOA are candidates to medical
treatment. AI, hCG and CC boost testosterone
production and may improve chances of SSR.
Re-evalualtion of life-style habits is of utmost
importance to optimize male reproductive health.