1. Dr. Shashwat Jani. M. S. ( Obs – Gyn ) Diploma in Advance Laparoscopy. Consultant Assistant Professor, Smt. N.H.L. Municipal Medical College. Sheth V. S. General Hospital, Ahmedabad. Mobile : +91 99099 44160. E-mail : drshashwatjani@gmail.com

2. Many studies and researches have proved that there is a strong positive relationship between Micronutrients & Male fertility. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 2

3. In order to examine the association between micronutrients and infertility, articles with case-control, descriptive, cohort, and interventional (clinical trials) design, published between 1984 and 2014, were accessed through PubMed and Embase databases, using keywords such as “micronutrients “, "oxidative stress", "antioxidant", "vitamins", "minerals", and "infertility“…. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 3

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5.  Infertility affects about 15 – 20 % of married couples half of which attributed to male infertility.  Defective sperm function considered to be most common cause of male infertility.  Apart from all the conventional causes of male infertility, a new & important cause has been identified as being responsible for Idiopathic male infertility : Reactive Oxygen Species ( ROS ). 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 5

6. Causes for Male Infertility Hum Reprod Update 1999; 5(2): 120 Percent (%) 65-Dec-16 Dr Shashwat Jani +91 99099 44160.

7. Idiopathic male Subfertility  40-75% of cases.  Most common pathological cause of Idiopathic Subfertility is – ‘ free radical induced damage to the sperm. ‘ Free radical is defined as… ‘ Oxygen molecule containing one or more unpaired electrons in atomic or molecular orbitals.’ 75-Dec-16 Dr Shashwat Jani +91 99099 44160.

8. R.O.S. In a healthy man, a delicate balance exists between physiological ROS & Antioxidants in the male reproductive tract. High level of seminal ROS have been found in 30 – 80 % of infertile men. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 8

9. Biology of ROS Pathology stems from imbalance between production and scavenging Production Degradation 95-Dec-16 Dr Shashwat Jani +91 99099 44160.

10. Reactive Oxygen Species in Male Infertility I. ROS generation in semen : About 40% in infertile men (Iwasaki & Gagnon, 1992) II. Harmful action mechanism of ROS on sperm by overwhelming endogenous antioxidant defenses 1. Cause sperm membrane lipid peroxidation 2. Decrease membrane fluidity 3. Reduce sperm motility 4. Decrease sperm-oocyte fusion capability 5. Impair fertilizing capacity 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 10

11. ROS and Male Infertility Reactive Oxygen Species is one of the major contributors to male Infertility & cause Damage to the sperm Cell membrane DNA molecules Lipids Proteins Urology. 1996;48(6):835–850. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 11

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13. Genetic Causes  DNA damage and mutations in mitochondrial DNA have been linked to poor sperm motility and male subfertility.  A genetic factor located at Yq11 has been established to be important for male germ cell development and Yq11 damage may lead to male infertility.  Deletions of AZFa, AZFb and AZFc (Microdeletions in the Y- chromosome) can result in male infertility.  Klinefelter’s syndrome, Kallman’s syndrome can also result in male infertility Indian J Med Res. 2008;127:124-132. J. Biosci. 2001;26(4):492-435. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 13

14. Environmental Causes The factors are as follows: Infection Excessive heat Radiation exposure Heavy metal toxicity Cigarette smoking Xeno-estrogen exposure Pesticides and other chemicals Altern Med Rev. 2000;5(1):28-38. Human Reproduction, 2001;16(8):1768-1776. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 14

15. http://www.gfmer.ch/Endo/Fellows_11/Pdf/Infertility_environment.pdf Human Reproduction, 2001;16(8):1768-1776. OccupationallyFree time Physical activityProlonged sitting Thermoregulation of scrotum elevation of scrotal temperature HEAT EXPOSURE Spermatogenesis Quality and quantity of sperm production (count, morphology, motility, delayed coception) Sedentary lifestyle Environmental Causes 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 15

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17. 1) Poor sperm motility 2) Teratozoospermia 3) high number of round cells in semen 4) increased semen viscosity 5) poor sperm membrane integrity on hypo osmoler swelling test 6)Poor fertilization on routine IVF. 7)Poor sperm motility after overnight oocyte incubation 8) poor blastocyst development in absence of a clear female factor. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 17

18. Male Infertility 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 18

19. Nutritional Considerations Various micronutrients are associated with male fertility. Deficiency of these micronutrients may result in infertility. Altern Med Rev. 2000;5(1):28-38. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 19

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21. Nutrition plays vital role in maintaining male fertility: Involved in the successful maturation of sperm Provides nutrition for motility of sperm Improvement in sperm count and motility Helps in production of sex hormones Prevents sperm damage Reduction in sperm DNA fragmentation Suppression of ROS production Altern Med Rev. 2000;5(1):28-38. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 21

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24. L - Carnitine 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 24

25. Three compartments of the male genital tract : Epididymal tissue, Seminal plasma, and Spermatozoa Maintain the highest free L-carnitine concentrations in the body. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 25

26. The main function of L-Carnitine in the epididymis is to provide an energetic substrate for spermatozoa. May be involved in the successful maturation of sperm. L-Carnitine is necessary for transport of fatty acids into the mitochondria to produce energy. Low levels of L-Carnitine reduces fatty acid concentrations within the mitochondria, leading to decreased sperm motility 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 26

27. L-Carnitine: Clinical Trials According to a study conducted by Costa et al. L-carnitine increased the sperm parameters drastically Andrologia.1994;26:155-159. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 27

28. L- Carnitine for asthenospermia with varicocele Carnitine Placebo Zhonghua Nan Ke Xue. 2004;10(9):671–672. There was significant improvement in sperm count,motility and pregnancy rates in infertility due to varicocele. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 28

29. L- Carnitine in idiopathic asthenozoospermia: a multicenter study. Italian Study Group on Carnitine and Male Infertility. Andrologia 1994;26:155-159  N = 100 patients  L-carnitine - 3 g/day  Duration - 4 months.  Percentage of motile spermatozoa increased from 26.9 ± 1.1 to 37.7 ± 1.1 %.  Total number of spermatozoa per ejaculate also increased Conclusion - Oral administration of L-Carnitine improves sperm quality 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 29

30. Mazzilli et al, established strict correlation between intrasperm L-carnitine content and sperm motility survival in bovine cervical mucus. This is possibly due to the fact that lipids are an important energy source for sperm in cervical mucus and to metabolize these lipids intrasperm Lcarnitine is essential. L-carnitine not only helps in lipid metabolism but also it modulates the reserves of free CoA, essential for tricarboxylic acid ( TCA ) cycle regulation. Therefore, L carnitine content can be considered as an indicator of sperm motility life span in cervical mucus. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 30

31. Anti Oxidant Property It is also proposed that carnitine exerts antioxidant properties as a result of repairing mechanism by which elevated intracellular toxic acetyl-CoA is removed and fatty acids in membrane phospholipids are replaced. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 31

32. Co Enzyme Q 10 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 32

33. In sperm cells, coenzyme Q10 (CoQ10) is concentrated in the mitochondria. Coenzyme Q10 is responsible for energy for movement and all other energy-dependent processes in the sperm cell. Reduction in levels of CoQ10 is observed in sperm cells and seminal plasma of idiopathic (IDA) and varicocele- associated (VARA) asthenozoospermic patients.* It is observed that sperm cells, characterized by low motility and abnormal morphology, have low levels of CoQ10. *Andrologia 34 (2002), 107–111. Co enzyme Q10 - Mechanism 335-Dec-16 Dr Shashwat Jani +91 99099 44160.

34. Administration of CoQ10 increased the pregnancy rate by 36% and with improvement of sperm count and functional sperm concentration in 70% and 60% individuals, respectively. Sperm motility and sperm motility index improved in 54% and 46 % while 38 % showed improvement in sperm morphology. Folia Med (Plovdiv).2005;47(1):26–30. Coenzyme Q10: Clinical Trials Improvement in sperm motility, motility Index and sperm morphology Sperm Morphology Motility index Sperm Motility 345-Dec-16 Dr Shashwat Jani +91 99099 44160.

35. Patients – 22 infertile men with idiopathic asthenozoospermia. Coenzyme Q10 - 100 mg for 6 months A significant increase was also found in sperm cell motility Conclusion: The exogenous administration of CoQ(10) may play a positive role in the treatment of asthenozoospermia. This is probably the result of its role in mitochondrial bioenergetics and its antioxidant properties. Fertil Steril. 2004 Jan;81(1):93-8. Coenzyme Q10: Clinical Trials 355-Dec-16 Dr Shashwat Jani +91 99099 44160.

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37. Lycopene 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 37

38.  Lycopene is a bright red pigment and phytochemical found in tomatoes and other red fruits, water melon & guava.  Belongs to a class referred to as carotenoids which are yellow, orange, and red pigments synthesized by plants. Lycopene 385-Dec-16 Dr Shashwat Jani +91 99099 44160.

39. The general mechanism by which Lycopene works is by preventing oxidative damage to sperms, which includes Damage to the cell membrane DNA molecules Lipids Proteins Lycopene has been demonstrated to be the most potent antioxidant with the ranking: lycopene > α- tocopherol > α -carotene > β- carotene > lutein. Lycopene – Biological activity 395-Dec-16 Dr Shashwat Jani +91 99099 44160.

40. Lycopene: Clinical Trials Int Urol Nephrol. 2002;34:369–372.  A Study evaluated the effect of oral lycopene therapy in men with idiopathic Subfertility.  Lycopene - 2000 mcg, twice a day for three months  N - 30 Patients 405-Dec-16 Dr Shashwat Jani +91 99099 44160.

41. Results : Improvement in sperm concentration - 20 patients (66%) Improved motility – 16 patients (53%) Improvement in sperm morphology - 14 patients (46%) Associated with significant improvement and resulted in six pregnancies in 26 patients (23%) Conclusion - Lycopene therapy seems to have a role in the management of idiopathic male Subfertility 415-Dec-16 Dr Shashwat Jani +91 99099 44160.

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43. Zinc 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 43

44.  Zinc is a micronutrient abundantly present in meat and seafood and serves as a cofactor for more than 80 enzymes involved in DNA multiplication and protein synthesis  Zinc deficiency is associated with decreased testosterone levels & sperm count.  Zinc levels are generally lower in infertile men with diminished sperm count.  Furthermore, zinc finger proteins are implicated in the genetic expression of steroid hormone receptors*, and zinc also has anti-apoptotic ** and antioxidant properties.*** *Endocr Rev 1992 :13,129–145. **Curr Drug Targets 2003:4,323–338. ***Free Radic Biol Med 31,266–274. Rev Prat. 1993;43:146-151. Ann Nutr Metab. 1986;30:213-218. 445-Dec-16 Dr Shashwat Jani +91 99099 44160.

45. Effects of zinc supplementation on subfertility 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 45

46. Zinc – Clinical Trials  N - 100 men with asthenozoospermia  Two groups--250 mg twice daily zinc therapy for 3 months and no therapy.  Duration – 6 months  There was significant improvement in the sperm quality; sperm count, progressive motility, fertilizing capacity Conclusion: Zinc therapy has a role in improving sperm parameters in men with asthenozoospermia Eur J Obstet Gynecol Reprod Biol. 1998 Aug;79(2):179-84. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 46

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48. ARGININE 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 48

49.  Arginine is essential for sperm motility, metabolism, capacitation, acrosome reaction, and is a precursor for producing petruscine, spermine, and spermidine.  According to a study by Schachter et al. Arginine significant improved sperm count and motility after taking 4 g/day for three months.  A recent study conducted in Italia also showed that arginine is effective in male infertility  The recommended daily allowance (RDA) is 20 g, with an upper limit of 30 g. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 49

50. FOLATE 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 50

51.  Adequate folic acid intake is associated with a decreased frequency of sperm DNA abnormalities.  Still its role is controversial.  The RDA is 400 mg. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 51

52. SELENIUM 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 52

53. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 53  Selenium and glutathione are essential to the formation of phospholipid hydro peroxide glutathione peroxidase.  Deficiencies of selenium can lead to instability of the mid-piece, resulting in defective motility  However, it can be toxic if consumed in excess. ArchAndrol. 1992;29:65-68. Science 1999;285:1393-1396. Environ Mol Mutagen. 2009 [Epub ahead of print]

54. METHYL COBALAMINE 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 54

55. Vitamin B12 is important in cellular replication, especially for the synthesis of RNA and DNA, and deficiency states have been associated with decreased sperm count and motility. Various studies have shown that Methylcobalamine improves the sperm parameters However, studies show that Methylcobalamine is effective in only just over 20% of infertile men. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 55

56. Vit - E 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 56

57. Oral supplementation with vitamin E significantly decreases the malondialdehyde concentration and improves the sperm motility Although Invitro studies have prooved the efficacy of vitamin E, human studies are lacking Although there are few human studies, they recruited only few patients. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 57

58. To conclude Infertile couples are likely to try multiple Micronutrients hoping to improve their chances of conception with minimal risk and cost before proceeding with ART. A recent Cochrane review in 2011 did demonstrate improved pregnancy and live birth rates with adequate dosages of Micronutrients. 5-Dec-16 Dr Shashwat Jani +91 99099 44160. 58

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60. 5-Dec-1660 Dr Shashwat Jani +91 99099 44160.