1. Small things in life make a major
difference! … SYNCHRONY
Dr. B. K. Iyer

2. The focus of attention
Today’s focus

3. What we know

4. Male infertility
• Male infertility of unknown origin is a
condition in which fertility impairment occurs
spontaneously or due to an obscure or
unknown cause
• It includes 2 categories,
1. Unexplained male infertility, &
2. Idiopathic male infertility.
• The dividing line between them is semen
analysis, which is normal in the unexplained
category and abnormal in idiopathic infertility.

5. Male fertility - approach

6. Causes - male infertility
When there is structural abnormality in the sperms
When there is structural abnormality in the sperms
When there is functional abnormality in the sperms
When there is functional abnormality in the sperms

7. Causes - male infertility
When Number is < 1m/ejaculate
When Number is < 1m/ejaculate
When Motility is < 20%
When Motility is < 20%
When Progression is < 2/4
When Progression is < 2/4
When Abnormal forms are > 85%
When Abnormal forms are > 85%

8. Causes - oxidative stress
• Oxidative stress (OS) is the imbalance
between the production of reactive oxygen
species (ROS) by the spermatozoa and
leukocytes & the antioxidant capacity of the
seminal plasma.
1. The primary source of ROS production in
infertile patients is the immature spermatozoa.
2. Oxidative stress can damage the DNA of the
spermatozoa & prevent them fertilizing an egg.
3. Reactive oxygen species (ROS) includes
oxygen ions, free radicals and peroxides.

9. Causes - inadequate amount
• http://www.clevelandclinic.org/reproductiveresearchcenter/info/innomaleinf.html

10. Causes - inadequate sperm motility
• Semen parameters, reactive oxygen species
(ROS) levels & DNA fragmentation index
(DFI) in normozoospermic infertile men and
controls
– Indian J Med Res. 2011 September; 134(3):
396–398.

11. Causes-inadequate progression
Grade 0 is no movement
Grade 0 is no movement
Grade 1 is sluggish movement
Grade 1 is sluggish movement
Grade 2 is slow movement but not straight
Grade 2 is slow movement but not straight
Grade 3 is movement in a straight line
Grade 3 is movement in a straight line
Grade 4 is terrific speed.
Grade 4 is terrific speed.

12. What we may not know

13. ROS – how in male infertility

14. ROS – how in male infertility

15. ROS – why in male infertility

16. ROS - role in male infertility
Idiopathic oxidative stress has been linked with male factor
Idiopathic oxidative stress has been linked with male factor
infertility as it is known to contribute to defective
infertility as it is known to contribute to defective
spermatogenesis leading to male factor infertility
spermatogenesis leading to male factor infertility
Uncontrolled & excessive production of ROS overwhelms the
Uncontrolled & excessive production of ROS overwhelms the
limited antioxidant defenses in semen resulting in seminal
limited antioxidant defenses in semen resulting in seminal
oxidative stress
oxidative stress
Seminal oxidative stress correlates negatively with sperm
Seminal oxidative stress correlates negatively with sperm
concentration, motility and function -- adversely affecting fusion
concentration, motility and function adversely affecting fusion
events required for fertilization.
events required for fertilization.
Superoxide anion, hydroxyl radical and hydrogen peroxide
Superoxide anion, hydroxyl radical and hydrogen peroxide
are major reactive oxygen species (ROS) present in seminal
are major reactive oxygen species (ROS) present in seminal
plasma.
plasma.

17. ROS - role in male infertility
ROS are produced by the spermatozoa (especially damaged
ROS are produced by the spermatozoa (especially damaged
spermatozoa) & seminal leucocytes --most notably granulocytes.
spermatozoa) & seminal leucocytes most notably granulocytes.
Reports have indicated that high levels of ROS are detected
Reports have indicated that high levels of ROS are detected
in semen samples of 25-40% of infertile men & seems to be
in semen samples of 25-40% of infertile men & seems to be
the leading cause infertility by 2 principal mechanisms:
the leading cause infertility by 2 principal mechanisms:
ROS damage the sperm
ROS damage the sperm ROS directly damage sperm
ROS directly damage sperm
membrane by causing lipid
membrane by causing lipid DNA, compromising the
DNA, compromising the
peroxidation of sperm
peroxidation of sperm paternal genomic
paternal genomic
membrane
membrane contribution to the embryo
contribution to the embryo
This, in turn, reduces the sperm’s motility and ability to fuse with
This, in turn, reduces the sperm’s motility and ability to fuse with
the oocyte.
the oocyte.

18. Body's defence against ROS
To maintain normal
To maintain normal Excess ROS is continuously inactivated
Excess ROS is continuously inactivated
cell function
cell function by seminal plasma antioxidants
by seminal plasma antioxidants
The seminal plasma antioxidants block the formation of new ROS or act
The seminal plasma antioxidants block the formation of new ROS or act
as scavengers and remove ROS already generated
as scavengers and remove ROS already generated
Natural antioxidant enzyme systems include
Natural antioxidant enzyme systems include
Glutathione
Glutathione Superoxide
Superoxide
Catalase
Catalase
peroxidase
peroxidase dismutase
dismutase

19. Body's defence against ROS
In healthy men, a delicate balance exists
between physiological ROS and
antioxidants in the male reproductive
tract

20. Underlying facts on anti-oxidants
Antioxidants are the most important defence against free radical induced
Antioxidants are the most important defence against free radical induced
infertility
infertility
The several antioxidant strategies produced by the human body protect
The several antioxidant strategies produced by the human body protect
itself from ROS damage
itself from ROS damage
This permits normal oxidative metabolism to occur without damaging the
This permits normal oxidative metabolism to occur without damaging the
cells, while still allowing for normal ROS-mediated cellular responses
cells, while still allowing for normal ROS-mediated cellular responses
such as destruction of infectious pathogens and intracellular signalling
such as destruction of infectious pathogens and intracellular signalling
However in conditions of oxidative stress, production of ROS
However in conditions of oxidative stress, production of ROS
overwhelms antioxidant defence.
overwhelms antioxidant defence.
Hence, there is a pressing need for external
Hence, there is a pressing need for external
antioxidant support!
antioxidant support!

21. The need of the day
• Levels of ROS within semen can be ↓ by
augmenting the scavenging capacity of
seminal plasma, by antioxidant supplement.
But, what can antioxidant do to the
But, what can antioxidant do to the
problem of male infertility?
problem of male infertility?
Antioxidant supplements boost sperm count, morphology and sperm
Antioxidant supplements boost sperm count, morphology and sperm
motility and prevent DNA damage to sperm
motility and prevent DNA damage to sperm

22. What we need to know
The therapeutic supplementation
in male infertility

23. Clomiphene – Role in male fertility
• Clomiphene citrate influences spermatogenesis
and also improves semen quality

24. Clomiphene – Role in male fertility

25. Antioxidants in the therapy of
male infertility

Because ROS have been associated with
sperm DNA damage, investigators have
studied possible protective roles of
antioxidants in preventing or treating sperm
DNA damage.

Sperm DNA damage in male infertility: etiologies, assays,
and outcomes by Ryan Tet al, J Assist Reprod Genet. 2010
January; 27(1): 3–12.

26. Antioxidants in the therapy of
male infertility

82% trials showed an improvement in either
sperm quality or pregnancy rate after
antioxidant therapy.

10 trials examined pregnancy rate and 6 showed
a significant improvement after antioxidant
therapy.

The use of oral antioxidants in infertile men could
improve sperm quality and pregnancy rates.

A systematic review of the effect of oral antioxidants on male
infertility by C. Ross et al, Reproductive BioMedicine Online,
Volume 20, Issue 6, Pages 711-723, June 2010

27. Antioxidants in the therapy of
male infertility

Ubidecarenone

Carotenoids
(Lycopene)

Omega 3 fatty acids

Carnitine

Vitamin E & Vitamin C

Selenium

Glutathione

N-acetyl cysteine

Pentoxifylline

Trace Metals like Zinc

Vitamin B12

28. Ubidecarenone
• Also known as Coenzyme Q10,
ubiquinone, coenzyme Q, and abbreviated
at times to CoQ10 , CoQ, Q10, or Q
• Component of the electron transport chain
and participates in aerobic cellular
respiration, generating energy as ATP.
• Unique capacity of this molecule:
To exist in a completely Enables it to function in the electron
oxidized form transport chain
To exist in a reduced Enables it to function as an antioxidant
form

29. Ubidecarenone - Role in male fertility
• In sperm cells, Co Q10 is concentrated in the
mitochondrial mid-piece, where it is involved
in energy production.
• It also functions as an antioxidant, preventing
lipid peroxidation of sperm membranes.
• According to studies, Ubidecarenone shows
significant increase in:
sperm motility
sperm density
improvement in fertilization rate

30. Lycopene - Role in male fertility
• Bright red carotenoid pigment,
phytochemical and powerful antioxidant with
a major role in the management of idiopathic
male infertility.
– Most efficient oxygen & free radical quencher
and prime carotenoid in plasma / other tissues
– It is a component of human redox defence
mechanism against free radicals
• Found in high concentrations in the testes
and seminal plasma
– Decreased levels have been demonstrated in

31. Lycopene - Role in male fertility
• Studies suggest efficacy of lycopene in male
infertility as it improves.
– Sperm Concentration
– Sperm Motility
– Sperm Morphology

32. Mixed caretenoids - Role in male
fertility
• Carotenoids work synergistically with Se and
vitaminE
• Mixed carotenoids, taken with vitamins C
and E, may help protect sperm from damage
by free radicals as it improves -
– Sperm Motility
– Sperm Morphology
– Sperm Concentration and
– Improved Fertility rates

33. Omega-3 fatty acids - Role in male
fertility
• Omega−3 fatty acids includes
eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA).
• DHA (Docosahexaenoic acid) is essential for
male fertility.
– Omega-3 fatty acids are abundant in the sperm
with DHA being abundant in the sperm tail to
have significant effect in sperm motility.
• Its deficiency is linked to low sperm count
and infertility.

34. Omega-3 fatty acids - Role in male
fertility
• Normal sperm cells contain an arc-like
structure called the acrosome. Acrosome is
critical in fertilization because it houses,
organizes, and concentrates a variety of
enzymes that sperms use to penetrate egg.
– DHA is essential in fusing the building blocks of
the acrosome together.
– Without DHA, this vital structure does not form
and sperm cells don't work
– DHA plays a major role in regulating membrane
fluidity in sperm + regulation of spermatogenesis

35. Omega-3 fatty acids - Role in male
fertility

36. Wheat germ oil - Role in male fertility
• Source of Vitamin E and primary function is
as an Antioxidant
• It is a major chain-breaking antioxidant in
the sperm membranes
– Protects the sperm membrane from oxidative
damage and increased levels are associated
with low levels of reactive oxygen species.
• It scavenges all 3 types of free radicals, viz.
– Superoxide,
– Hydrogen peroxide and
– hydroxyl radicals.

37. Wheat germ oil - Role in male fertility
• Vitamin E enhances sperm performance
• Vitamin E protects spermatozoa from:
1. Oxidative damage
2. Loss of motility
• Male factor infertility: Effects of ROS and
vitamin E on sperm by Melanie Clyne,
Nature Reviews Urology 9, 62 (February
2012)

38. Calcium ascorbate – Role in male
fertility
• Natural form of Vitamin C that is a water-
soluble ROS scavenger with high potency.
• Readily absorbed in the blood stream than
the other forms of calcium.
• It is a strong antioxidant destroying free
radicals in the body and protects human
spermatozoa against endogenous oxidative
damage by neutralising :
1. Hydroxyl
2. Superoxide, &
3. Hydrogen peroxide radicals

39. Calcium ascorbate – Role in male
fertility
• Vitamin C Prevents sperm agglutination.
• Vitamins C and E act synergistically to
protect against peroxidative attack on
spermatozoa.

40. Vitamin B 12 - Role in Male Fertility
• Vitamin B12 is important in cellular
replication, especially for the synthesis of
RNA and DNA
• Deficiency states have been associated with
decreased sperm count and motility
• B12 supplementation improves sperm
parameters such as:
1. Sperm concentration,
2. Sperm count and
3. Sperm motility.

41. Selenium - Role in Male Fertility
• Selenium is a nonmetal & a trace mineral
that is essential to good health but required
only in small amounts.
• Its antioxidant properties helps prevent
cellular damage from free radicals
• Protects against oxidative sperm DNA
damage and is required for:
1. Normal testicular development
2. Spermatogenesis
3. Motility and function

42. Selenium - Role in Male Fertility
• Essential for formation of phospholipid
hydroperoxide glutathione peroxidase - an
enzyme present in spermatids which
becomes a structural protein comprising over
50 % of the mitochondrial capsule in the mid-
piece of mature spermatozoa.
– Deficiency leads to instability of the mid-piece,
resulting in
• Defective motility
• Breakage of the spermatozoal mid-piece and
• Increased morphological abnormalities, mostly
affecting the sperm head

43. Zinc - Role in male fertility
• Zinc is a trace mineral essential for normal
functioning of the male reproductive
system.
• Zinc levels are generally lower in infertile
men with diminished sperm count
– Zinc supplementation shows improvement in
sperm quality, sperm motility, fertilisation
capacity and a reduction in the incidence of
anti-sperm antibodies.

44. Zinc - Role in male fertility
• Zinc is found in high concentration in sperm,
and is vital in making the outer layer of the
sperm, as well as the tail.
– Zinc deficiency is associated with decreased
testosterone levels and sperm count
• Administration of exogenous systemic zinc to
males with zinc deficiency can improve
sperm production and sperm motility.
– Supplementing zinc in the diet can re-establish
testosterone and sperm count levels to
acceptable levels

45. Zinc - Role in male fertility
• Omu et al. have demonstrated that zinc
therapy results in significant improvement in
sperm quality with increase in sperm density,
progressive motility and improve conception
and pregnancy outcome
– Oxidative stress adversely affects spermatogenesis in
male infertility by Z.G. Badade et al, Biomedical
Research 2011, 22 (3): 323-328

46. Piperine
• Piperine is an alkaloid - a standardized
extract from the fruits of Piper nigrum L.
(black pepper) or Piper longum L. (long
pepper)
• Piperine may be co-administered with
various nutrients for human health.
– It has antioxidant activity
– It lowers lipid peroxidation
– It increases the plasma levels of Coenzyme Q10
following oral supplementation.

47. Summary