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.
Causes - male infertilityWhen there is structural abnormality in the spermsWhen there is structural abnormality in the spermsWhen there is functional abnormality in the spermsWhen there is functional abnormality in the sperms
Causes - male infertilityWhen Number is < 1m/ejaculateWhen Number is < 1m/ejaculateWhen Motility is < 20%When Motility is < 20%When Progression is < 2/4When Progression is < 2/4When 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 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 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.
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.
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.
Bodys 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
Bodys 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 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!
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
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
Antioxidants in the therapy ofmale 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 ofmale 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 ofmale 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 Enables it to function in the electron oxidized form transport chain To exist in a reduced Enables it to function as an antioxidant form
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
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 malefertility• 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 malefertility• 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 malefertility• 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 dont work – DHA plays a major role in regulating membrane fluidity in sperm + regulation of spermatogenesis
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 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)
Calcium ascorbate – Role in malefertility• 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
Calcium ascorbate – Role in malefertility• 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.