Small things in life make a major difference! … SYNCHRONY Dr. B. K. Iyer
Jan 28, 2015
Small things in life make a major difference! … SYNCHRONY
Dr. B. K. Iyer
The focus of attention
Today’s focus
What we know
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.
Male fertility - approach
Causes - male infertility
When there is structural abnormality in the spermsWhen there is structural abnormality in the sperms
When there is functional abnormality in the spermsWhen there is functional abnormality in the sperms
Causes - male infertility
When Number is < 1m/ejaculateWhen Number is < 1m/ejaculate
When Progression is < 2/4When Progression is < 2/4
When Motility is < 20%When Motility is < 20%
When Abnormal forms are > 85%When Abnormal forms are > 85%
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.
Causes - inadequate amount
• http://www.clevelandclinic.org/reproductiveresearchcenter/info/innomaleinf.html
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.
Causes-inadequate progression
Grade 0 is no movementGrade 0 is no movement
Grade 2 is slow movement but not straightGrade 2 is slow movement but not straight
Grade 1 is sluggish movementGrade 1 is sluggish movement
Grade 3 is movement in a straight lineGrade 3 is movement in a straight line
Grade 4 is terrific speed.Grade 4 is terrific speed.
What we may not know
ROS – how in male infertility
ROS – how in male infertility
ROS – why in male infertility
ROS - role in male infertility
Idiopathic oxidative stress has been linked with male factor infertility as it is known to contribute to defective spermatogenesis leading to male factor infertility
Idiopathic oxidative stress has been linked with male factor infertility as it is known to contribute to defective spermatogenesis leading to male factor infertility
Seminal oxidative stress correlates negatively with sperm concentration, motility and function - adversely affecting fusion events required for fertilization.
Seminal oxidative stress correlates negatively with sperm concentration, motility and function - adversely affecting fusion events required for fertilization.
Uncontrolled & excessive production of ROS overwhelms the limited antioxidant defenses in semen resulting in seminal oxidative stress
Uncontrolled & excessive production of ROS overwhelms the limited antioxidant defenses in semen resulting in seminal oxidative stress
Superoxide anion, hydroxyl radical and hydrogen peroxide are major reactive oxygen species (ROS) present in seminal plasma.
Superoxide anion, hydroxyl radical and hydrogen peroxide are major reactive oxygen species (ROS) present in seminal plasma.
ROS - role in male infertility
ROS are produced by the spermatozoa (especially damaged spermatozoa) & seminal leucocytes - most notably granulocytes.ROS are produced by the spermatozoa (especially damaged spermatozoa) & seminal leucocytes - most notably granulocytes.
ROS directly damage sperm DNA, compromising the
paternal genomic contribution to the embryo
ROS directly damage sperm DNA, compromising the
paternal genomic contribution to the embryo
This, in turn, reduces the sperm’s motility and ability to fuse with the oocyte.
This, in turn, reduces the sperm’s motility and ability to fuse with the oocyte.
Reports have indicated that high levels of ROS are detected in semen samples of 25-40% of infertile men & seems to be
the leading cause infertility by 2 principal mechanisms:
Reports have indicated that high levels of ROS are detected in semen samples of 25-40% of infertile men & seems to be
the leading cause infertility by 2 principal mechanisms:
ROS damage the sperm membrane by causing lipid
peroxidation of sperm membrane
ROS damage the sperm membrane by causing lipid
peroxidation of sperm membrane
Body's defence against ROS
To maintain normal cell function
To maintain normal cell function
Excess ROS is continuously inactivated by seminal plasma antioxidants
Excess ROS is continuously inactivated by seminal plasma antioxidants
Glutathione peroxidase Glutathione peroxidase
The seminal plasma antioxidants block the formation of new ROS or act as scavengers and remove ROS already generated
The seminal plasma antioxidants block the formation of new ROS or act as scavengers and remove ROS already generated
Natural antioxidant enzyme systems include Natural antioxidant enzyme systems include
CatalaseCatalase Superoxide dismutase Superoxide dismutase
Body's defence against ROS
In healthy men, a delicate balance exists between physiological ROS and
antioxidants in the male reproductive tract
Underlying facts on anti-oxidants
However in conditions of oxidative stress, production of ROS overwhelms antioxidant defence.
However in conditions of oxidative stress, production of ROS overwhelms antioxidant defence.
Hence, there is a pressing need for external antioxidant support!
Hence, there is a pressing need for external antioxidant support!
Antioxidants are the most important defence against free radical induced infertility
Antioxidants are the most important defence against free radical induced infertility
The several antioxidant strategies produced by the human body protect itself from ROS damage
The several antioxidant strategies produced by the human body protect itself from ROS damage
This permits normal oxidative metabolism to occur without damaging the cells, while still allowing for normal ROS-mediated cellular responses such as destruction of infectious pathogens and intracellular signalling
This permits normal oxidative metabolism to occur without damaging the cells, while still allowing for normal ROS-mediated cellular responses such as destruction of infectious pathogens and intracellular signalling
The need of the day
• Levels of ROS within semen can be ↓ by augmenting the scavenging capacity of seminal plasma, by antioxidant supplement.
Antioxidant supplements boost sperm count, morphology and sperm motility and prevent DNA damage to sperm
Antioxidant supplements boost sperm count, morphology and sperm motility and prevent DNA damage to sperm
But, what can antioxidant do to the problem of male infertility?
But, what can antioxidant do to the problem of male infertility?
What we need to know
The therapeutic supplementation in male infertility
Clomiphene – Role in male fertility
• Clomiphene citrate influences spermatogenesis and also improves semen quality
Clomiphene – Role in male fertility
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.
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
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
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 oxidized form
Enables it to function in the electron transport chain
To exist in a reduced form
Enables it to function as an antioxidant
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
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 men
suffering from infertility.
Lycopene - Role in male fertility
• Studies suggest efficacy of lycopene in male infertility as it improves.– Sperm Concentration– Sperm Motility– Sperm Morphology
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
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.
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
Omega-3 fatty acids - Role in male fertility
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.
Wheat germ oil - Role in male fertility
• Vitamin E enhances sperm performance• Vitamin E protects spermatozoa from:
1. Oxidative damage2. Loss of motility
• Male factor infertility: Effects of ROS and vitamin E on sperm by Melanie Clyne, Nature Reviews Urology 9, 62 (February 2012)
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. Hydroxyl2. Superoxide, & 3. Hydrogen peroxide radicals
Calcium ascorbate – Role in male fertility
• Vitamin C Prevents sperm agglutination.• Vitamins C and E act synergistically to
protect against peroxidative attack on spermatozoa.
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.
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
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
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.
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
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
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.
Summary