Dr Ajit Saxena APOLLO HOSPITALS NEW DELHI Ian

Dr. Ajit Saxena APOLLO HOSPITALS NEW DELHI Ian

Causes for male Infertility 2 Percent (%) Hum Reprod Update 1999; 5(2): 120

Idiopathic male Subfertility Ø 40 -75% of cases. Ø 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. 3

Biology of ROS Pathology stems from imbalance between production and scavenging Production Degradation 4

Oxidative stress balance 5 Idiopathic Iatrogenic Lifestyle Infection Environmental Autoimmune Testicular Chronic Disease Damage to DNA Damage to membrane

Focus Role of various micronutrients in treatment of male infertility. Coenzyme Q 10 L-Carnitine Lycopene Zinc 6

Co enzyme Q 10 • Co. Q 10 is a naturally-occuring lipid soluble compound found in every cell in the body. • Coenzyme Q 10 (Co. Q 10) is concentrated in the mitochondrial mid-piece • Coenzyme Q 10 (Co. Q 10) acts as an electron carrier in the mitochondrial respiratory chain. * • It helps in transfer of electrons in respiratory chain & prevents lipid per oxidation & generation of ROS. Thus it stabilizes cell membrane, maintains & promotes sperm motility 7 *CLIN. CHEM. 41/2, 217 -219 (1995) **Chem Scripta 1987; 27: 145 -58

Co enzyme Q 10 - Mechanism Energizer Free Radical Scavenger CLIN. CHEM. 41/2, 217 -219 (1995) 8

Co enzyme Q 10 - Mechanism • In sperm cells, coenzyme Q 10 (Co. Q 10) is concentrated in the mitochondria. • Coenzyme Q 10 is responsible for energy for movement and all other energy-dependent processes in the sperm cell. • Reduction in levels of Co. Q 10 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 Co. Q 10. *Andrologia 34 (2002), 107– 111. 9

EFFECT OF Co. Q 10 ON SPERM MOTILITY In study of 38 patients (16 -normal motility & 22 –Asthenozoo- spermia) semen samples were washed in Ham’s F-10 media, incubated with increasing concentration of Co. Q for 24 hrs. Results : Normal patients- No significant change in motility rates Asthenozoospermia - Significant increase in motility in 50 µM Co. Q 10, No significant increase in 5 µM Co. Q 10 Dept. OBGY, Hadassah-Hebrew University Medical School, Jerusalem, Israel, 97. 10

Coenzyme Q 10: Clinical Trials • Administration of Co. Q 10 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. 11 Improvement in sperm motility, motility Index and sperm morphology Sperm Motility index Sperm Morphology Folia Med (Plovdiv). 2005; 47(1): 26– 30.

Coenzyme Q 10: Clinical Trials • Patients – 22 infertile men with idiopathic asthenozoospermia. • Coenzyme Q 10 - 100 mg for 6 months • A significant increase was also found in sperm cell motility Conclusion: • The exogenous administration of Co. Q(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. 12 Fertil Steril. 2004 Jan; 81(1): 93 -8.

Coenzyme Q 10: Clinical Trials Lewin et al. showed that Coenzyme Q 10 results in improvement in sperm functions in asthenospermic men Mol Aspects Med 13 1997; 18 S 213 -S 219.

Carnitine Trimethylated aminoacid -ester Synthesized in liver, brain, and kidney from dietary amino acids-methylationof lysine Most derived from diet: red meat, fish and dairy products 14

LCarnitine 15 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 Drugs 1987; 34: 1 -24. Arch Ital Urol Nefrol Androl 1992; 64: 187 -196.

L-Carnitine Significantly high levels of free L-Carnitine is observed in the seminal plasma of the fertile men compared to the infertile men. The level of free L-Carnitine in the semen has positive correlation with sperm concentration, sperm motility and vitality of sperm cells L-Carnitine provides readily available energy for use by spermatozoa, which positively affects sperm motility, maturation and the spermatogenesis process. 16 Folia Med (Plovdiv). 2005; 47(1): 26– 30. . Zhonghua Nan Ke Xue. 2007; 13(2): 143– 146.

L-Carnitine: Clinical Trials According to a study conducted by Costa et al. L-carnitine increased the sperm parameters drastically 17 Andrologia. 1994; 26: 155 -159

L- Carnitine for asthenospermia with Zhonghua Nan Ke Xue. 2004; 10(9): 671– 672. varicocele Carnitine Placebo 18 There was significant improvement in sperm count, motility and pregnancy rates in Subfertility due to varicocele.

Use of Carnitine therapy in selected cases of male factor Subfertility: A double-blind crossover trial • Patient(s): One hundred infertile patients (ages 20– 40 years) with the following baseline sperm selection criteria: concentration, 10– 20 X 106/m. L; total motility, 10%– 30%; forward motility, <15%; atypical forms, <70%; velocity, 10– 30 µ/s; • Interventions : L-Carnitine therapy or placebo; • Duration : 4 months 19 FERTILITY AND STERILITY VOL. 79, NO. 2, FEBRUARY 2003

Total motile sperm/m. L Carnitine Placebo 20 FERTILITY AND STERILITY VOL. 79, NO. 2, FEBRUARY 2003

L- Carnitine in idiopathic asthenozoospermia: a multicenter study. Italian Study Group on Carnitine and Male Subfertility. Ø N = 100 patients Ø L-carnitine Ø Duration - 4 months. Ø Percentage of motile spermatozoa increased from 26. 9 ± 1. 1 to 37. 7 ± 1. 1 %. Ø Total number of spermatozoa per ejaculate also increased Conclusion - Oral administration of L-Carnitine may improve sperm quality 21 Andrologia 1994; 26: 155 -159

Lycopene Ø Lycopene is a bright red pigment and phytochemical found in tomatoes and other red fruits, water melon & guava. Ø Belongs to a class referred to as carotenoids which are yellow, orange, and red pigments synthesized by plants 22

Lycopene Ø Lycopene possesses superior abilities in comparison to other carotenoids. Ø It has the ability to quench singlet oxygen and prevent oxidative damage to other molecules. Ø This is because of its unique structure of: 11 conjugated double bonds and no cyclic groups 23

Lycopene – Biological activity 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 24 Lycopene has been demonstrated to be the most potent antioxidant with the ranking: lycopene > αtocopherol > α -carotene > β- carotene > lutein.

Lycopene: Clinical Trials Ø A Study evaluated the effect of oral lycopene therapy in men with idiopathic Subfertility. Ø Lycopene - 2000 mcg, twice a day for three months Ø N - 30 Patients Int Urol Nephrol. 2002; 34: 369– 372. 25

Improvement in sperm concentration 26

Results ü Improvement in sperm concentration - 20 patients (66%) ü Improved motility – 16 patients (53%) ü Improvement in sperm morphology - 14 patients (46%) ü Associated with significant improvement and resulted in six pregnancies in 26 patients (23%) 27 ü Conclusion - Lycopene therapy seems to have a role in the management of idiopathic male Subfertility

Zinc Ø 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 Ø Zinc deficiency is associated with decreased testosterone levels & sperm count. Ø Zinc levels are generally lower in infertile men with diminished sperm count Ø Furthermore, zinc finger proteins are implicated in the genetic expression of steroid hormone receptors*, and zinc also has antiapoptotic ** and antioxidant properties. *** *Endocr Rev 1992 : 13, 129– 145. **Curr Drug Targets 2003: 4, 323– 338. ***Free Radic Biol Med 31, 266– 274. 28 Rev Prat. 1993; 43: 146 -151. Ann Nutr Metab. 1986; 30: 213 -218.

Zinc – Clinical Trials Ø N - 100 men with asthenozoospermia Ø Two groups--250 mg twice daily zinc therapy for 3 months and no therapy. Ø Duration – 6 months Ø 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.

Zinc – Clinical Trials Netter et al. studied the effect of zinc supplementation on testosterone, dihydrotestosterone and sperm count. The results of the study were dramatic • 37 patients were studied • Testosterone and dihydrotestosterone levels increased significantly • Nine wives became pregnant, six within 3 months and three within 2 months 30

Zinc: Clinical Trials According to study conducted by Tikkiwal et al. zinc resulted in Significant improvement in sperm count, Number of progressively motile and normal spermatozoa Normal acid phosphates activity. Indian J Physiol Pharmacol. 1987; 31(1): 30 -34. 31

First Indian randomized, double blind, placebo-controlled clinical trial of Nutraceuticals for male subfertility Clinical Trial : Analysis & Interpretation of Results

Micronutrient • Lycopene – 2. 5 mg • Co-Q 10 – 50 mg • L-Carnitine – 500 mg • Zinc – 12. 5 mg 34

Improvement in Sperm count (Million/m. L) in each arm from baseline 35 Day 180, 1 Nutraceutical FDC + 1 Placebo BID, 31. 65 180, 2 Nutraceutical FDC Sperm Count. Day (M/m. L) BID , 33. 16 30 Mean (M/m. L) 25 Day 90, 1 Nutraceutical FDC + 1 Placebo BID, 24. 88 Day 90, 2 Nutraceutical FDC BID , 26. 35 20 Day 0, 1 Nutraceutical FDC + 1 Placebo BID, 14. 37 15 Day 0, 2 Nutraceutical FDC BID , 14. 81 Day 180, 2 Placebo BID , 15. 85 Day 90, 2 Placebo BID , 14. 89 Day 0, 2 Placebo BID , 12. 86 10 5 0 Day 90 Day 180 1 Nutraceutical FDC + 1 Placebo BID 14. 37 24. 88 31. 65 2 Nutraceutical FDC BID 14. 81 26. 35 33. 16 2 Placebo BID 12. 86 14. 89 15. 85

Improvement in Sperm Count from Baseline 25 Day 180, 2 Nutraceutical FDC BID , 19. 28 Day 180, 1 Nutraceutical FDC + Placebo BID, 17. 76 LSMean Change 20 Improvement in Sperm Count from Baseline 15 Day 90, 2 Nutraceutical FDC BID , 11. 91 Day 90, 1 Nutraceutical FDC + Placebo BID, 10. 64 10 5 Day 180, 2 Placebo BID , 1. 96 Day 90, 2 Placebo BID , 1. 48 0 Day 90 Day 180 2 Nutraceutical FDC BID 11. 91 19. 28 1 Nutraceutical FDC + Placebo BID 10. 64 17. 76 2 Placebo BID 1. 48 1. 96

Improvement in Motile Sperm (%)in each arm from baseline 70 60 Motile Sperms (%) Day 180, 1 Nutraceutical FDC + 1 Placebo BID, 55. 78 Day 90, 1 Nutraceutical FDC + 1 Placebo BID, 50. 12 Day 180, 2 Nutraceutical FDC BID , 57. 35 Day 90, 2 Nutraceutical FDC BID , 51. 62 50 Day 0, 2 Nutraceutical FDC BID , 39. 22 Day 0, 2 Placebo BID , 39. 47 Mean (%) Day 0, 1 Nutraceutical FDC + 1 Placebo BID, 38. 40 40 Day 180, 2 Placebo BID , 44. 06 Day 90, 2 Placebo BID , 42. 14 30 20 10 0 Day 90 Day 180 1 Nutraceutical FDC + 1 Placebo BID 38. 4 50. 12 55. 78 2 Nutraceutical FDC BID 39. 22 51. 62 57. 35 2 Placebo BID 39. 47 42. 14 44. 06

Improvement in Motile Sperms from Baseline 20 Improvement in Motile Sperms from Baseline Day 180, 2 Nutraceutical FDC BID , 18. 44 Day 180, 1 Nutraceutical FDC + Placebo BID, 17. 79 15 LSMean Change Day 90, 2 Nutraceutical FDC BID , 12. 54 Day 90, 1 Nutraceutical FDC + Placebo BID, 11. 76 10 Day 180, 2 Placebo BID , 4. 70 5 Day 90, 2 Placebo BID , 2. 62 0 Day 90 Day 180 2 Nutraceutical FDC BID 12. 54 18. 44 1 Nutraceutical FDC + Placebo BID 11. 76 17. 79 2 Placebo BID 2. 62 4. 70

Improvement in Sperm with rapid progression: WHO A (%) 35 30 Sperm with rapid progression (%) Day 180, 2 Nutraceutical FDC Day 180, 1 Nutraceutical FDC BID , 31. 77 + 1 Placebo BID, 31. 45 Day 90, 1 Nutraceutical FDC + 1 Placebo BID, 27. 67 Day 90, 2 Nutraceutical FDC BID , 27. 80 25 Mean (%) 20 Day 0, 2 Nutraceutical FDC BID , 16. 61 Day 0, 1 Nutraceutical FDC + 1 Placebo BID, 14. 42 15 Day 180, 2 Placebo BID , 16. 31 Day 90, 2 Placebo BID , 14. 39 Day 0, 2 Placebo BID , 12. 11 10 5 0 Day 90 Day 180 1 Nutraceutical FDC + 1 Placebo BID 14. 42 27. 67 31. 45 2 Nutraceutical FDC BID 16. 61 27. 80 31. 77 2 Placebo BID 12. 11 14. 39 16. 31

Change in Sperm with WHO Grade A motility 20 Change in Sperm with Rapid Progression Day 180, 2 Paternia BID , 15. 15 Day 180, 1 Paternia + Placebo BID, 15. 91 LSMean Change 15 Day 90, 2 Paternia BID , 10. 77 Day 90, 1 Paternia + Placebo BID, 11. 28 10 Day 180, 2 Placebo BID , 5. 52 5 Day 90, 2 Placebo BID , 2. 21 0 Day 90 Day 180 2 Paternia BID 10. 77 15. 15 1 Paternia + Placebo BID 11. 28 15. 91 2 Placebo BID 2. 21 5. 52

Improvement in Sperm with Normal Morphology 70 60 Mean (% ) 50 Sperm with Normal Morphology (%) Day 180, 1 Paternia + 1 Day 180, 2 Paternia BID , 62. 30 Placebo BID, 60. 45 Day 90, 1 Paternia + 1 Placebo BID, 55. 53 Day 90, 2 Paternia BID , 55. 33 Day 0, 2 Paternia BID , 44. 07 Day 0, 1 Paternia + 1 Placebo BID, 45. 09 Day 180, BID 2 Placebo Day 90, 2 Placebo , 51. 08 BID , 51. 51 Day 0, 2 Placebo BID , 45. 75 40 30 20 10 0 Day 90 Day 180 2 Paternia BID 44. 07 55. 33 62. 3 1 Paternia + 1 Placebo BID 45. 09 55. 53 60. 45 2 Placebo BID 45. 75 51. 08 51. 51

Reduction of Sperm with Abnormal Morphology 60 Day 0, 2 Paternia BID , 55. 93 50 Mean (%) 40 Day 90, 2 Paternia BID , 44. 67 Day 180, 37. 70 Day 0, 1 Paternia + 1 Placebo Sperm with Abnormal Morphology (%) BID, 55. 14 Day 90, 1 Paternia + 1 Placebo BID, 44. 23 Day 0, 2 Placebo BID , 53. 97 Day 90, 2 Placebo Day BID 180, , 48. 92 48. 49 Day 180, 39. 58 30 20 10 0 Day 90 Day 180 2 Paternia BID 55. 93 44. 67 37. 7 1 Paternia + 1 Placebo BID 55. 14 44. 23 39. 58 2 Placebo BID 53. 97 48. 92 48. 49

Change in Sperm with normal Morphology 20 Change in Sperm With Normal Morphology Day 180, 2 Paternia BID , 17. 55 Day 180, 1 Paternia + Placebo BID, 15. 45 LSMean Change 15 Day 90, 2 Paternia BID , 10. 88 Day 90, 1 Paternia + Placebo BID, 10. 50 10 Day 180, 2 Placebo BID , 6. 11 Day 90, 2 Placebo BID , 5. 64 5 0 Day 90 Day 180 2 Paternia BID 10. 88 17. 55 1 Paternia + Placebo BID 10. 50 15. 45 2 Placebo BID 5. 64 6. 11

Change in sperm with Abnormal Morphology 0 Change in Sperm With Abnormal Morphology LSMean Change -5 Day 90, 2 Placebo BID , Day 180, 2 Placebo BID , 5. 46 6. 14 -10 Day 90, 2 Paternia BID , 10. 89 Day 90, 1 Paternia + Placebo BID, -10. 88 -15 Day 180, 1 Paternia + Placebo BID, -15. 59 -20 Day 90 Day 180, 2 Paternia BID , 17. 59 2 Paternia BID -10. 89 -17. 59 1 Paternia + Placebo BID -10. 88 -15. 59 2 Placebo BID -5. 46 -6. 14

History taking

PDE 5 inhibitors Drugs 2004; 64 (23)

Non-Responders to PDE 5 Inhibitors Comorbidities (Diabetes, Nuropathy) Inappropriate use Misdiagnosis (Pt. Having HSDD) Psychological and partner issues World J Mens Health 2013 April 31(1): 31 -35

Mode of action of L Arginine: REVERSAL OF ENDOTHELIAL AND ERECTILE DYSFUNCTION

Role of Nitric Oxide in ED Sexual Stimulation L-Arginine n. NOS e. NOS L-Arginine Nitric Oxide Guanylate Cyclase GTP GMP c. GMP Erection PDE-5 GTP, guanosine triphosphate; GMP, guanosine monophosphate; c. GMP, cyclic GMP; n. NOS, neuronal nitric oxide synthase; e. NOS endothelial nitric oxide synthase. Burnett AL. Int J Impot Res. 2004; 16: S 15 -S 19.

Andrology. 2013 Mar; 1(2): 223 -8.

Conclusion Very few medical fields have changed as dramatically over the past decade as reproductive medicine, particularly in terms of the diagnostic and treatment strategies for male infertility. These advances include oxidative stress and male infertility. The nutraceutical theory remain the safest and most cost-effective ways of treating infertile men, and, perhaps more importantly for the couples involved, many of these techniques enable couples to conceive naturally.