1. ANTIOXIDANTS
AND
MALE
INFERTILITY
DR. ABHISHEK SINGH PARIHAR
M.S.( OBS & GYNAE), FELLOW REPRODUCTIVE
MEDICINE.
CONSULTANT : LIFECARE I.V.F

2.  In 40- 60% Of Infertile
Couples A Male Related
Problem Is A Cause Of
Infertility .
 Sperm production cycle
occurs in a mean 64 ± 8
days (range: 42–76
days)—(by stable
isotope and gas
spectrometric analysis)

3.  Several reports
describe reduction in
male fertility over
recent decades.
 Estimates that
sperms counts in U.S
males decreasing by
1.5% each year

4.  30%-80% of infertile men have
elevated markers of OS
 Agarwal et al., Urology 2006
Reactive Oxygen Species (ROS)
(Log ROS + 1; cpm)
OXIDATIVE STRESS
An emerging
explanation
for several
cases of male
infertility
2,5
2
1,5
1
0,5
0

5. REACTIVE OXYGEN SPECIES
(ROS)
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 in mitochondria.
Sources:
Leukocytes (extrinsic)
Spermatozoa (intrinsic)
Sperm and Seminal Plasma Antioxidants:
Enzymatic (SOD, catalase, GPX): inactivate ROS
(conversion into other substances)
Non-enzymatic (ascorbic acid, alpha-tocopherol, carnitine,
etc.): neutralize ROS
Lampiao et al., Oxidative stress. In: Male Infertility. Parekattil & Agarwal (eds) 2012, pp.225-35

6. REACTIVE OXYGEN SPECIES
THE NEGATIVE EFFECTS OF ROS ON SPERM QUALITY HAVE
GAINED LOT OF ATTENTION

7. OXYGEN & ROS PARADOX

13. STRESS

14. SPERM DNA FRAGMENTATION AND
ASSISTED CONCEPTION
Live Birth Rates by
Intrauterine Insemination
OR = 0.07
[95% CI: 0.01-0.48]
Normal Elevated
Pregnancy by Method in Cases
of Elevated Sperm DNA
Fragmentation
42%
26%
P <0.05
Adapted from Bungum et al., Hum Reprod 2007
ICSI
1.5%
IVF
19%19%
19%

15. SPERM DNA FRAGMENTATION AND
MISCARRIAGE
Population: Meta-analysis of 16 cohort studies (2,969
couples), 14 prospective.
Techniques for DNA integrity:
Acridine orange-based assays, TUNEL and COMET.
Findings:
Significant increase in miscarriage rates in patients
undergoing IVF/ICSI with high sperm DNA damage compared
with those with low DNA damage.
Risk ratio (RR) = 2.16 (1.54, 3.03), P < 0.00001).
Miscarriage rates are positively
correlated with sperm DNA
damage
levels

16. SIGNS OF OXIDATIVE
STRESS IN SEMEN ANALYSIS
 Reduction of sperm parameters ( Asthenozoospermia is the
best surrogate marker of OS ( Kesks et al. , Ammar et al. )
 DNA fragmentation ( Kao et al. 2007)
 Hyperviscosity– (ureaplasma infection ? )
 Semen leukocytes ( round cells ) count using peroxidase
or seminal elastase test ( Kopa et al. 2003)
Testing Malondialdehyde level in sperm/seminal plasma
Or
Chemoluminescence assays using luminol/lucigenin are expensive,
complicated and highly sensitive.

17. MANAGEMENT OF OS –
RELATED
INFERTILITY
In >80% of males medical treatment is ineffective .
General measures
1 –Lifestyle modification ( smoking , poor diet , alcohol ,obesity,
stress)
2–Avoid activities heating the scrotum
3–Proper ventilation /use of personal protective equipment to
reduce exposure to chemicals /metals linked with OS
4–Treatment of infections / variecocele
5–ANTIOXIDANTS ,VITAMINS AND FOOD
SUPPLEMENTATION.

18. ROLE OF
MICRONUTRIENTS IN
FERTILITY
Nutrition plays vital role in maintaining male fertility:
 Involved in the successful maturation of sperm
 Provides nutrition for motility of sperm
 Improvement in sperm count and motility
 Helps in production of sex hormones
 Prevents sperm damage

19. NUTRITIONAL
CONSIDERATIONS
Various micronutrients are
associated with male
fertility.
Deficiency of these
Micronutrients &
ANTIOXIDANTS may result
in infertility.
 Nutritional Factors
 Free radical scavengers
 L-Carnitine
 Lycopene
 Coenzyme Q10
 Vitamin C
 Zinc
 Vitamin E
 Arginine
 Glutathione
 Vitamin B12
 Selenium

20. IDEAL NUTRACEUTICAL FOR MALE
INFERTILITY
 Coenzyme
Q10
 Improves sperm
motility by
providing energy
through ATP
generation in
mitochondrion
L-carnitine
Improves sperm motility by providing
energy to the sperm cell through fatty
acid metabolism
Lycopene
Increases sperm count and improves
morphology by reducing oxidative damage
to sperm DNA and lipids
Zinc
Promotes sperm production & maturation
testosterone synthesis & improves sperm
morphology

21. VITAMINS , MINERALS AND HERBS
USED FOR INFERTILITY
TREATMENT
 Vitamins B complex combat the effect of oxidative stress.
B5 –for hormone production
Folic acid – Arole in RNA and DNA synthesis during spermatogenesis and
has antioxidative properties.
 Vitamin C: Helps carry oxygen to sex organs
Necessary for balanced hormone / sperm production
 Selenium is related to significantly a higher concentration of sperm per
ejaculate .
 Herbs: Red clover / rich in every trace element, vitamins and proteins .
Red raspberry – high in essential minerals .
Damiana–potent aphrodisiac

23. ORAL ANTIOXIDANT
THERAPY
Methodological weakness of antioxidants trials make it difficult to
determine “who”,“how” and “for how long??
 Patient selection and controls
 Associated pathology
 Single or combination antioxidants
 Dosage & formulation
 Outcome measures
 Varying duration of treatment
 Lack of diagnostic markers for oxidative stress
 Presence of molecular and genetic differences
Controversies

24. ORAL ANTIOXIDANTS
IN MALE INFERTILITY
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
Detrimen
tal
long-
term use and
high
doses;
No Consensus Yet.
Short-term use
appear to be safe.
Caution against
indiscriminate use
of high dosages for
long periods.

25. Who are the candidates for Oral
Antioxidant Therapy?
 Infertile men with OS
 Diagnosis

26. HOW TO USE ANTIOXIDANT THERAPY
TREATMENT STRATEGY
Once OS is diagnosed,
focus on identifying and
controlling source of
increased ROS
Varicocele
Genital Infection
Smoking
Medication
Drug abuse
Systemic disease
Pollution
Radiation
Differentiate
between
sperm and
leukocyte
source of ROS
Testing for
Leukocytes in
Semen
Select antioxidant
formulation and dosage
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

27. ORAL ANTIOXIDANTS IN MALE
INFERTILITYOUR FORMULA MAXOLA -L
 Co Enzyme Q 10-20mcg Vitamin B12 2.5 mcg
 Folic acid 500 mcg Zinc Sulfate 10mg
 Selenium 50 mcg Lycopene 2500mcg
 Fructose 1g L-Carnitine fumarate -1g
 Acetyl-L-Carnitine 0.5g Citric Acid 50mcg
 PLAIN MAXOLA does not contain LYCOPENE.
 How long: minimum 2 months
 From initiation of sperm production to ejaculation
Old concept ~80 days
New concept 60 days

28. Oral Antioxidants
Cochrane Review 2011
Outcome
Live birth
Pregnancy rate
DNA fragmentation
Miscarriage, sperm
count, sperm motility
Adverse effects
N
studies
3
15
1
6-16
6
participants
214
964
64
242-700
426
Effect size
(OR; 95% CI)
4.85 [1.92, 12.24]
4.18 [2.65, 6.59]
-13.80 [-17.50, -10.10]
No effect
No effect
Improve the outcomes of live birth and pregnancy rate for
subfertile couples undergoing ART cycles

29. ALTERNATIVE
TREATMENT
 Testicular (not epididymal) sperm extraction in
men with poor sperm DNA quality if
conservative treatment ( AO and lifestyle
modification) have failed. ( Greco2005,
O΄Connell 2002 ).
 Reduce centrifugation time prior to IUI /IVF
 Use of non–centrifuge separation techniques
(swim–up etc…)
 Limit the sperm culture time in media away
from seminal plasma

30. ALTERNATIVE
TREATMENT
 Culturing sperm under low oxygen tension
( 5% O2) reduces seminal leukocyte ROS.
 Avoid using frozen sperm (if possible ) since
ROS are produced during freezing /thawing
( Watson 2000)
 Supplement sperm separation media with a
variety of AO ( catalase—Rossi et al
2001,vit.C — Zheng and Zhang, EDTA,
glutathione/hypotaurine , albumin, N–
acetyl–cysteine.

31. SUMMARY
 Oxidative stress impairs sperm function and is a risk
factor for male infertility and miscarriage .
current evidence suggest that OA supplementation for
subfertile males improve the chances for pregnancy and live
birth for couples undergoing ART.
Well-designed studies are needed to determine the best
candidate for AO therapy and which formulation and
dosages yield better results.

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