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Subclinical Infections and Male Infertility
1. Sandro C. Esteves, MD., PhD.
Director, ANDROFERT
Andrology& Human Reproduction Clinic
Campinas, BRAZIL
Subclinical Infections and Male Infertility
ISO 9001:2008
Reproductive Andrology Surgery Workshop II
Reproductive Medicine Unit -JahraHospital -Kuwait 2014
2. Subclinical Male Genital Tract Infection (MAGI)
ANDROFERT
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC -REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 2
2014 December
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Urethritis, prostatitis
3. Macrophage
Neutrophils
ROS production by leukocytes is 100x higher than defective sperm
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC -REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 3
2014 December
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4. Chemical species with unpaired electron capable to oxidize lipids, proteins and nucleic acids:
Superoxide anion (•O-2)
Hydroxyl radical (•OH); Hydrogen peroxide(H2O2)
Peroxylradical (ROO•); Hypochlorite ion (OCl-)
Generated from sperm aerobic metabolism and leukocytes
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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ANDROLOGY AND HUMAN REPRODUCTION CLINIC -REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 4
2014 December
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5. Yanushpolskyet al 1996, Saleh& Agarwal2002, Aziz et al 2004
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC -REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 5
2014 APRIL
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25%
34%
39%
% DNA Damage (SCSA)
6. Anti-bacterial properties (Zinc)
Semen Culture Unreliable
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC -REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 6
2014 December
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7. Leukocytospermia>1.0 x 106leukocytesper mLofsemenmarker of reproductive tract inflammation
Spontaneous resolution in 50% of cases
Braniganet al 1995, Erelet al 1997, Lackneret al 2008
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC -REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 7
2014 December
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granulocyte
macrophage
lymphocyte
8. ANDROFERT
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC -REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 8
2014 December
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Round cells Neubauerchamber
15 minutes
Peroxidase Positive
Peroxidase Negative
20 μlsemen + 20μl PBS + 40 μlbenzidine+ H2O2solution
9. •Yanushpolskyet al, 1995; Erelet al., 1997
•Braniganet al., 1995
Antibiotics
•Lackneret al., 2006
•Gamberaet al., 2007
Cicloxigenase-2
Inhibitors
•Oliva& Mutigner, 2006
Antihistamines
•Tremellenet al., 2007
•Piombiniet al., 2008
Antioxidants
Treatment of Subclinical MAGI and Associated Inflammatory Changes
ANDROFERT
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC -REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 9
2014 December
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10. Subclinical MAGI
Azitromycin1.0g single dose (couple) + frequent ejaculation (every 2-3 days) + Antioxidants
42% leukocytospermiaresolution (N=278; Androfert)
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC -REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 10
2014 December
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Neisseria gonorrheae
Chlamydia pneumoniae
Chlamydia trachomatis
Mycoplasma pneumoniae
Ureaplasmaurealyticum
11. 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)
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ANDROLOGY AND HUMAN REPRODUCTION C LINIC - REFERRAL C ENTER FOR MALE REPRODUCTION
S ESTEVES, 11
2014 December
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12. MAGI -Clinical Management
Ascorbic acid (Vit. C)
-tocopherol(Vit. E)
Glutathione
N-acetyl-cysteine
Carnitine, Coenzyme Q10
Lycopene. Picnogenol
Pentoxifylline. Selenium
Shao-Fu-Zhu-Yu-Tang
Astaxanthin
Lepidiummeyenii
-linolenicacid and lignans
Folic acid, Zinc
Combine OA
Antibiotics
First line therapy
Varicocele
Genital Infection
Smoking
Medication
Drug abuse
Systemic diseases
Pollution
Radiation
Focus on identifying source of increased ROS
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC -REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 12
2014 December
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13. 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
MisellLM et al. J Urol. 2006
Esteves& Agarwal. Novel concepts in male infertility. IntBrazJ Urol2011
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC -REFERRAL CENTER FOR MALE REPRODUCTION
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2014 December
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14. 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
ShowellMG et al. CochraneDatabase Syst Rev 2011
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2014 December
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15. MAGI may decreases fertility mainly via oxidative stress effects
Antibiotic therapy is suggested, but effect on fertility is still unclear (GR-B)
EAU guidelines in male infertility 2014
MAGI
Key Messages
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC -REFERRAL CENTER FOR MALE REPRODUCTION
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2014 December
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OS is defined as the imbalance between prooxidative and antioxidative molecules in a biological system which arises as a consequence of excessive production of free radicals and impaired antioxidant defense mechanisms.
It is common to find leukocytes in the semen. Leukocytospermia is defined as the presence of > 1 million leukocytes per mililiter of semen. Among the leukocytes, neutrophils are the most important category and usually arise from the epididymis and prostate. Neutrophils are also named “granulocytes” as they have granules containing peroxidase enzyme.
Leukocytospermia prevalence in subfertile males: 10-20% (Wolff, 1995)
It is common to find leukocytes in the semen. Leukocytospermia is defined as the presence of > 1 million leukocytes per mililiter of semen. Among the leukocytes, neutrophils are the most important category and usually arise from the epididymis and prostate. Neutrophils are also named “granulocytes” as they have granules containing peroxidase enzyme.
Leukocytospermia prevalence in subfertile males: 10-20% (Wolff, 1995)
Neurophils can be easily detected in the semen based on the capacity of peroxidase to react with hydrogen peroxide. In this test, an aliquot of semen is incubated with hydrogen peroxide and a substrate to facilitate the reaction to occur. The final result is the oxidation of the substrate in the presence of granulocytes and hydrogen peroxidase. Neutrophils granules containing peroxidase show a brown color.
12
Based on several studies, our center has derived an empiric regimen of synthetic vit C and E, folate, zinc and selenium for men demonstrating elevated oxidative stress levels in their semen profile.
Cochrane review analyzed 34 randomized controlled trials ( RCT) involving 2876 couples.
The study evaluated the effect of oral antioxidant supplementation for male partners of couples undergoing assisted reproduction techniques (ART).
A recent Cochrane meta-analysis on the use of oral antioxidants in male infertility found that these agents significantly improved pregnancy rates and live births and decreased sperm DNA damage [101]. An associated statistically significant increase in live birth rate [pooled odds ratio (OR) = 4.85; 95% CI 1.92–12.24; P = 0.0008; I (2) = 0%] has been obtained when men taking antioxidants were compared to controls. No studies reported harmful side effects from the antioxidant therapy used. Nevertheless, improvements in semen parameters were not well evident. The evidence suggests that antioxidant supplementation in subfertile males may improve the outcomes of live birth and pregnancy rate for subfertile couples undergoing fertility treatment. However, clinical
trials are still necessary to identify the superiority of one antioxidant over the other in different subpopulations of infertile males, as well as other important aspects such as dose and duration of therapy.
