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Antioxidant for subfertility
their role, highlights on generic, trade name and studies relevant

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  1. 1.
  2. 2. Presentation ByM.A.Wadood Aref
  3. 3.  Infertility or Subfertility is defined as the failure to conceive after 1 year of regular, unprotected intercourse with the same partner. 10–17% of all couples experience primary or secondary infertility at some time during their reproductive life. M.A.Wadood Aref
  4. 4.  Male factor is considered a major contributory factor to infertility in 50% of cases, with no identifiable cause in 25%. Along with the conventional causes for male infertility such as varicocele, cryptorchidism, infections, obstructive lesions, cystic fibrosis, trauma, and tumors, a new, yet important cause has been identified: oxidative stress. M.A.Wadood Aref
  5. 5.  male factor Idiopathic  Idiopathic 25%  tubal conditions male factor 40%  ovulation disorders tubal  age relatedconditions  Endometriosis 15%  Coital Disorders Coital disorders ovulation age 5% disorders related Endometriosis 15% 10% 10% Total % exceeds 100% as 15% of couples have more than one cause of Infertility.
  6. 6. Minority (of cases) MajorityKnown cause Idiopathic Specific Empiricalmedical treatment medical treatment
  7. 7. 1. Gonadotrophins2. Dopamine Agonists3. Anti-estrogens4. Aromatase Inhibitors5. Androgens M.A.Wadood Aref
  8. 8.  Includes Anti-oxidants or Combination therapy Indications 1. Idiopathic infertility: in an attempt to improve semen parameters and subsequent fertility potential. 2. Known untreatable causes of infertility, such as following surgery for cryptorchidism or torsion & some cases of testicular failure. 3. known potentially treatable causes which failed to adequately respond to specific treatments. M.A.Wadood Aref
  9. 9. Cell destruction by ROSReactive oxygen species (ROS)
  10. 10.  Cells living under aerobic conditions require oxygen to support life. Free radicals are highly reactive molecules with one or more unpaired electrons that can oxidatively modify biomolecules. M.A.Wadood Aref
  11. 11.  Reactive oxygen species (ROS) are free radicals that are derived from the metabolism of oxygen. Major ROS in seminal plasma include:  superoxide (O2).  hydrogen peroxide (H2O2).  hydroxyl radical (OH). Male germ cells generate ROS at low physiologic levels to regulate sperm capacitation, acrosome reaction and sperm–oocyte fusion M.A.Wadood Aref
  12. 12.  ROS React almost immediately with any substance in surrounding beginning a chain reaction leading to cellular damage. In healthy men, a delicate balance exists between physiological ROS and antioxidants in the male reproductive tract High levels of seminal ROS have been found in 30 - 80% of infertile men. M.A.Wadood Aref
  13. 13. Balance status between ROS and antioxidantsOxidative stress (OS)
  14. 14.  Oxidative stress is a condition that occurs when there is an imbalance between ROS production and antioxidant capacity (ROS exceed antioxidant capacity). In 1943, John MacLeod first made the observation that oxidative stress could be a significant cause of male infertility. M.A.Wadood Aref
  15. 15. High ROS level in subfertile menReduced Defective Sperm Oocyte-sperm Motility Increased fusion Cell membrane Sperm DNA Lipid Damage peroxidation
  16. 16. Oxidative stress can be measuredEvaluation of oxidative stress
  17. 17.  Quantification of the level of oxidative stress is important to determine if it is a significant contributor to sperm dysfunction in a given patient. Despite the different methods available to measure ROS, currently no standard exists for estimating oxidative stress. M.A.Wadood Aref
  18. 18.  oneof the most widely used methods to assess the level of ROS. discriminates between the production of superoxide and hydrogen peroxide by spermatozoa by the reagent used. M.A.Wadood Aref
  19. 19.  uses the principles of light scattering, light excitation, and emission of fluorochrome molecules to generate specific multiparameter data measures. M.A.Wadood Aref
  20. 20.  determines relation between total amount of ROS and the total antioxidant capacity to measure ultimate amount of oxidative stress and subsequent damage. determined by either the enhanced chemiluminescence assay or the calorimetric assay. M.A.Wadood Aref
  21. 21. Treatment of infertility caused by oxidative stress
  22. 22. 1. Behaviors and lifestyle modification may decrease endogenous ROS production.2. Antioxidant supplements increase the antioxidant capacity of semen, thereby scavenging excess ROS and decreasing OS.3. Specific laboratory techniques used to decrease ROS production (when sperm are handled in the laboratory for ART). M.A.Wadood Aref
  23. 23. Antioxidant kick out free radicals in blood Antioxidants
  24. 24. Antioxidants in seminal plasma PreventAffection of Prevent DNA Sperm fragmentation Motility Prevent Cryo-damage
  25. 25.  Human body uses 3 systems of antioxidants that constantly scavengers (inactivate) ROS: 1. Endogenous antioxidants. 2. Metal-binding proteins. 3. Dietary antioxidants. M.A.Wadood Aref
  26. 26. Enzymes Vitamins Vitamin E Superoxide Fat-soluble dismutase (SOD) Vitamin A Water Vitamin C Catalase soluble Glutathione peroxidase M.A.Wadood Aref
  27. 27.  Metal-binding proteins include: 1. Albumin. 2. Cerruloplasmin. 3. Metallo-thionein. 4. Transferrin. 5. Ferritin. 6. Myoglobulin. They inactivate the transition metal ions (e.g, iron) that catalyze the production of free radicals.
  28. 28.  present in fruits and vegetables and daily dietary supplements. The mechanism of action of the dietary antioxidants includes:  scavenging free radicals.  chain-breaking effect of lipid pero- xidase enzyme. M.A.Wadood Aref
  29. 29. 1. Carnitine 6. N-acetyl cysteine2. vitamin C 7. CoEnzyme Q103. vitamin E 8. Pentoxyfilline4. Carotenoids 9. Zinc (vitamin A) 10.Selenium5. Glutathione M.A.Wadood Aref
  30. 30. CarnitineL-Carnitine & L-acetyl carnitineDaily requirement: 200 - 500 mg Oral supplemntation dose: L-Carnitine 1 gm 1 x2 or 1x3 (3 mnths)Found in: red meat & dairy products Available in Egypt
  31. 31.  Water soluble Dietary antioxidant (75% derived from diet). decreases ROS by removing extracellular toxic acetyl-CoA that is responsible for mitochondrial ROS. Stabilizes spermatozoal membrane. M.A.Wadood Aref
  32. 32.  The highest concentration of carnitine occurs in the epididymis (2000-fold that of plasma). 50% of carnitine In seminal fluid exists as acetyl-carnitine. M.A.Wadood Aref
  33. 33.  Some studies showed beneficial effect.Study ParametersMoncada et al., 1992 Improved sperm motilityCosta et al., 1994 Improved sperm motility and countVitali et al., 1995 Improved sperm motility in 60%Lenzi et al., 2003 Improved sperm motility , no effect on morphologyLenzi et al., 2004 Improved sperm motility , no effect on morphologyCavallini et al., 2004 Improved sperm morphology
  34. 34.  Other studies showed no effect.Study Parameters improvedSigman et al., 2006 L-carnitine and L-acetyl carnitineLenzi et al., 2004 no effect on motility, morphology or count M.A.Wadood Aref
  35. 35. Vitamin EDaily requirement: 50 - 800 mg /d.Oral supplemntation dose: 400 or 600 mg /d . Found in: fats and oils (olive, and sunflower oils) Rx: R/ Vitamin E 400 mg tab 1 x 1 (available in Egypt)
  36. 36.  Vitamin E which is present within the cell membrane, is one of the major membrane protectants against ROS. It neutralizes hydrogen peroxide and protects the plasma membrane from lipid peroxidation. M.A.Wadood Aref
  37. 37. Study Parameters improvedRoss et al., 2010 decrease ROSComhaire et al, 2000 vit.E, vit.A, acetyl cysteine, decreased ROSSuleiman et al., 1996 improving motility and the probability of achieving pregnancyKessopoulou et al, decrease ROS, improved zona-binding assay1995ade Lamirande & protect spermatozoa from OS and loss of motilityGagnon, 1992 Dawson et al., 1987 protect spermatozoa from OS during cryopreservation and thawing
  38. 38. Vitamine CDaily requirement: 60 mg /dOral supplemntation dose 200-1000 mg /d Found in: citrous fruits, vegetables, fish Rx: R/ Vitamin C 500 mgcaps. 1X1 available in Egypt
  39. 39.  Vitamin C (ascorbic acid) is a water-soluble, highly potent antioxidant. concentrations 10-fold higher in seminal plasma than serum. It also has been shown to recycle vitamin E by repairing its tocopheroxyl radical, thereby allowing vitamin E to function as a free radical chain-breaking antioxidant The hydrophilicity and lipophilicity of vitamins C and E may act synergistically to protect against peroxidative attack on spermatozoa M.A.Wadood Aref
  40. 40.  Some studies showed beneficial effect.Study Parameters improvedGreco et al., 2005a reduction in DNA-fragmented spermatozoaGreco et al., 2005b improvement in pregnancy and implantation ratesKodama et al, 1997 improved concentration, decreased DNA damage M.A.Wadood Aref
  41. 41.  Other studies showed no effect.Study ParametersRolf et al, 1999 no improvement inKessopoulou et al., 1995b • concentration, • motility,Moilanen & Hovatta,1995 • morphology, orGiovenco et al., 1987 • viability M.A.Wadood Aref
  42. 42. Carotenoids(beta-carotene and lycopene) Daily requirement: 1000 mg / d Oral supplemntation dose: Lycopene 5-10 mg /d Found in: tomatoes, watermelon, guava. available in Egypt
  43. 43.  Beta-carotenes protect the plasma membrane against lipid peroxidation. Lycopene is twice as potent as beta-carotene and ten times more potent than vitamin E in scavenging singlet oxygen and inhibiting lipid peroxidation in serum plasma Astaxanthin, a newly studied carotenoid extracted from the algae Hemaococcus pluvialis.
  44. 44. Study Parameters improvedComhaire et al., 2005 improved pregnancy ratesGupta & Kumar, 2002 improved sperm concentration & motility M.A.Wadood Aref
  45. 45. Glutathione (GSH)essential nutrient synthesizedin the body (not obtained via food) Oral supplemntation dose: 600 mg /d IM IM form is not available in Egypt
  46. 46. Glutathione (GSH) one of the most common antioxidant & reducing agent in the body. It plays an important role in protecting lipids, proteins, and nucleic acids against oxidative damage. It combines with vitamin E and selenium to form glutathione peroxidase (the main enzyme involved in removing H2O2 in the epididymis). M.A.Wadood Aref
  47. 47. N-acetyl cysteine (NAC) Derived from Cysteine amino acid Oral supplemntation dose: 30 mg /d Should be given with IM Glutathione
  48. 48.  NAC is a precursor that replenishes Glutathione . scavenges free radicals and reduces ROS production in human ejaculate. NAC plays an important role in germ cell survival in human seminiferous tubules in vitro. M.A.Wadood Aref
  49. 49. Study Parameters improvedComhaire et al., 2000 NAC improved sperm concentration and acrosome reaction & reduced ROSOeda et al., 1997 improved sperm motilityLenzi et al., 1993 improved sperm motility (forward progression) M.A.Wadood Aref
  50. 50. Zinc Daily requirement: 8 - 11 mg/d Oral supplemntation dose: Zinc Gluconate 50 mg /dFound in: oysters, wheat, beansavailable in Egypt only with multivitamins
  51. 51.  Adequate zinc intake is needed to maintain the optimal functioning level of antioxidant enzymes, such as superoxide dismutase. Seminal plasma zinc concentrations is significantly lower in subfertile men Zinc deficiency is associated with abnormal flagella .
  52. 52. Study Parameters improvedRoss et al, 2010 progressive motility, sperm integrity and pregnancy ratesOmu et al., 2008 Decreased apoptosis & DNA fragmentationWong et al., 2002 Increased total sperm countOmu et al., 1999 Improved sperm concentrationTikkiwal et al., 1987 Improved sperm concentrationHartoma et al., 1977 Improved sperm concentration M.A.Wadood Aref
  53. 53. SeleniumDaily requirement: 55 mg/dOral supplemntation dose: 225 mcg /dFound in: Garlic, seeds, meat, eggs. available in Egypt
  54. 54.  Selenium is a trace element necessary for the synthesis of glutathione peroxidase. selenium acts with Vitamin E synergistically as antiperoxidants. M.A.Wadood Aref
  55. 55. Study Parameters improvedKesker-Ammar et al., 2003 improved motilityVezina et al., 1996 improved motility but not pregnancy rates M.A.Wadood Aref
  56. 56. Co-enzyme Q 10 (Ubiquinol)Daily requirement: 3 -6 mg /dOral supplemntation dose: 30 mg /dFound in: meat and fishes available in Egypt
  57. 57.  an energy-promoting agent in the mitochondria of sperm mid-piece. CoQ10 recycles vitamin E and prevents its pro-oxidant activity. The reduced form of CoQ10, ubiquinol, also acts as an antioxidant preventing lipid peroxidation. M.A.Wadood Aref
  58. 58. Study Parameters improvedThomas et al., 1997 improve fertilisation rateAlleva et al., 1997 inhibit hydrogen peroxide ROS M.A.Wadood Aref
  59. 59. Pentoxifylline Synthetic Drug Oral supplemntation dose: 400 mg 1x3 available in Egypt
  60. 60.  competitive non-selective phospho- diesterase inhibitor that raises intracellular cAMP, so improves testicular micro-circulation. decrease ROS production. preserve sperm motility in vitro improve semen parameters in vivo. M.A.Wadood Aref
  61. 61. Study Parameters improvedOkada et al., 1997 decreased ROS and preserved sperm motility in vitroPang et al., 1993 preserve sperm motility in vitroTesarik et al., 1992 Improved sperm motility but not %Gavella & Lipovac, decrease ROS1992Gavella et al., 1991 decrease ROSYovich et al., 1990 improve semen parameters in vivoMarrama et al., 1985 improve semen parameters in vivo
  62. 62. Antioxidant role in vitroIn Vitro Antioxidant supplements
  63. 63.  In vitro supplements of antioxidants used during sperm preparation and ART (assisted reproductive technique)1. Neutralizes ROS produced by leukocytes and immature spermatozoa2. Improves sperm-oocyte fusion. M.A.Wadood Aref
  64. 64.  In vitro supplementation with superoxide dismutase and catalase leads to:1. prevention of lipid peroxidation of the sperm plasma membrane caused by ROS.2. recovery of high-quality spermatozoa after freezing-thawing procedures. M.A.Wadood Aref
  65. 65. Antioxidant role in female reproductive pathologies Antioxidants for Females
  66. 66.  OS is implicated in pathological processes of the female reproductive tract that contribute to infertility and poor pregnancy outcome. Antioxidants are used in order to improve fertility and pregnancy rates. M.A.Wadood Aref
  67. 67.  PCOS: N-acetyl cysteine improve glucose control and peripheral insulin sensitivity in hyperinsulinemic patients. Endometriosis: The antioxidants catalase, RU486, curcumin, melatonin, and catechins have anti-proliferative and anti- angiogenic effects stopping disease progression. M.A.Wadood Aref
  68. 68.  Unexplained infertility: Selenium normalize patient’s RBC Mg levels and can result in clinical pregnancy after 8 months of treatment. recurrent pregnancy loss: folic acid, melatonin, and omega-3 fatty acids are now investigated (particularly in antiphospholid antibody syndrome). M.A.Wadood Aref
  69. 69. Antioxidant kick out free radicalsTake Home Message
  70. 70.  Spermatozoa are under a continuous influence of OS because of excessive generation of ROS but natural antioxidants decrease the progression of the damage. M.A.Wadood Aref
  71. 71.  However, when an imbalance exists between levels of ROS and the natural antioxidant defenses, various measures can be used to protect spermatozoa against the OS-induced injury . M.A.Wadood Aref
  72. 72.  For patients suspected to have high levels of ROS and Oxidative stress (OS), antioxidant supplements can be considered. M.A.Wadood Aref
  73. 73.  Oxidativestress can be also reduced by modifying certain lifestyle behaviors and environmental factors. M.A.Wadood Aref
  74. 74.  Another important method for decreasing OS is the use of antioxidants during various sperm processing techniques (ARTs). M.A.Wadood Aref
  75. 75.  Combined therapy is much more beneficial because antioxidants act by different mechanisms on different free radicals. M.A.Wadood Aref
  76. 76.  Although further studies are required to validate use of antioxidants, The low cost and relatively low risk of toxicity of the antioxidants is appealing to both patients and clinicians. M.A.Wadood Aref
  77. 77. M.A.Wadood Aref
  78. 78. M.A.Wadood Aref
  79. 79. M.A.Wadood Aref

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Antioxidant for subfertility their role, highlights on generic, trade name and studies relevant


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