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