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Role of Micronutrients in the Management of Male Infertility

Role of Micronutrients in the Management of Male Infertility. Final Diagnostic Categories in a Male Infertility Clinic. ( Stigman et al. 1997). Treatment of Male Infertility. Medical Therapy. According to evidence dependency Specific Medical Therapy Non-specific Empirical Medical Therapy

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Role of Micronutrients in the Management of Male Infertility

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  1. Role of Micronutrients in the Management ofMale Infertility

  2. Final Diagnostic Categories in a Male Infertility Clinic (Stigman et al. 1997)

  3. Treatment of Male Infertility

  4. Medical Therapy According to evidence dependency Specific Medical Therapy Non-specific Empirical Medical Therapy II. According to drug Hormonal therapy Non-hormonal therapy

  5. Criteria for Success • Duration : 3~6 months, at least one full spermatogenic cycle • Parameter : Semen analysis & hormonal assay : Criteria -count 30%, motility 20% (Lee et al. 1986) WHO criteria of normal semen, 1999

  6. Specific Medical Therapy Endocrine Disorder Pyospermia Immunologic Infertility with AntispermAb Retrograde Ejaculation

  7. Nonspecific Empirical Medical Therapy

  8. Difficult Cases for Empirical Medical Treatment 1. Shrunken testicle (volume < 10ml) 2. Histopathological findings of testis biopsy : Sertoli cell only syndrome Severe maturation arrest (Johnson score 3-4) 3. Azoospermia or severe oligospermia (1.0 × 106ml) : especially, Increased FSH to twice normal

  9. Pitfall in Comparison among Results of Empirical Medical Therapy No placebo controlled double blind trials Heterogenous patients population Variable dosages, treatment period and follow-up Tremendous fluctuation in an individual semen parameter Different criteria for success

  10. Newer concepts

  11. 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

  12. 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.

  13. Endogenous ROS Formation and Direct Scavenging Effect of Antioxidant in Sperm Cell antioxydant Infection Radiation Chemotherapy pollution Intrinsic antioxidant : SOD, catalase, ascorbate, tocopherol Management 1) Extrinsic antioxidant : Vit A, C, E, glutathione, selenium, rebamipide 2) Sperm washing with culture media including antioxidant to removal leukocyte

  14. 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.

  15. Environmental Causes Various environmental factors can result in male infertility. 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.

  16. Environmental Causes Occupationally Free time Sedentary lifestyle Physical activity Prolonged sitting Thermoregulation of scrotum elevation of scrotal temperature HEAT EXPOSURE Spermatogenesis Quality and quantity of sperm production (count, morphology, motility, delayed coception) http://www.gfmer.ch/Endo/Fellows_11/Pdf/Infertility_environment.pdf Human Reproduction, 2001;16(8):1768-1776.

  17. 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.

  18. Role of Micronutrients in Fertility 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 Altern Med Rev. 2000;5(1):28-38.

  19. Non hormonal Therapy : To improvement of Sperm motility Sperm fertilizing capacity Sperm metabolism Testicular microcirculation • 1. Carnitine • 2. Kallikrein • 3. Pentoxyphylline • 4. NSAIDs • 5. α-blocker • 6. Clonidine 7. Miscellaneous

  20. Co enzyme Q10 • CoQ10 is a naturally-occurring compound found in every cell in the body. • Coenzyme Q10 (CoQ10) is concentrated in the mitochondrial mid-piece • CoQ10's alternate name is ubiquinone • It is found in foods, particularly in fish and meats • Coenzyme Q10 (CoQ10) acts as an electron carrier in the mitochondrial respiratory chain.* *CLIN. CHEM. 41/2, 217-219 (1995) **Chem Scripta 1987;27:145-58

  21. Co enzyme Q10 - Mechanism Free Radical Scavenger Energizer CLIN. CHEM. 41/2, 217-219 (1995)

  22. Co enzyme Q10 - Mechanism • 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.

  23. Coenzyme Q10: Clinical Trials Sperm Morphology Sperm Motility Motility index • 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. Improvement in sperm motility, motility Index and sperm morphology Folia Med (Plovdiv).2005;47(1):26–30.

  24. Coenzyme Q10: Clinical Trials • Patients – 22 infertile men with idiopathic asthenozoospermia. • Coenzyme Q10 - 200 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.

  25. Coenzyme Q10: Clinical Trials Lewin et al. showed that Coenzyme Q10 results in improvement in sperm functions in asthenospermic men Mol Aspects Med 1997;18 S213-S219.

  26. Coenzyme Q10: Clinical Trials According to a review conducted by Langade et al. Coenzyme Q10 significantly increased sperm motility within 6 months. Bombay hospital journal. http://www.bhj.org/journal/april2005/htm/reveiw_coenzyme_145.htm

  27. Non hormonal Therapy Carnitine: ◈L- carnitine &acetylcarnitine ◈ Intracellular energy metabolism Stabilization of cell wall ◈ L-carnitine 2~3 gm/day Acetylcarnitine 4 gm/day

  28. Change of L-carnitine & Acetylcarnitine in Seminal Plasma In oligoasthenozoospermia Lower level of L-carnitine (Lewin et al, 1976) Lower level of acetylcarnitine (Kohengkul et al, 1977) Significant positive correlation between L-carnitine and sperm density & motility (Menchini-Fabrisetal, 1984) Reduction of acetylcarnitine/L-carnitine ratio : low grade sperm motility (Bartelloni et al, 1987) → Rationale for using carnitine in the Tx of male infertility

  29. L-Carnitine • 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.

  30. 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. Folia Med (Plovdiv). 2005;47(1):26–30. . Zhonghua Nan Ke Xue. 2007;13(2):143–146.

  31. 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.

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

  33. Use of Carnitine therapy in selected cases of male factor infertility: 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/mL; total motility, 10%–30%; forward motility, <15%; atypical forms, <70%; velocity, 10–30 µ/s; • Interventions : L-Carnitine therapy 2 g/day or placebo; • Duration : 4 months FERTILITY AND STERILITY VOL. 79, NO. 2, FEBRUARY 2003

  34. Total motile sperm/mL Carnitine Placebo FERTILITY AND STERILITY VOL. 79, NO. 2, FEBRUARY 2003

  35. Forward motile sperm/mL Carnitine Placebo FERTILITY AND STERILITY VOL. 79, NO. 2, FEBRUARY 2003

  36. L- Carnitine in idiopathic asthenozoospermia: a multicenter study. Italian Study Group on Carnitine and Male Infertility. • 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 may improve sperm quality Andrologia 1994;26:155-159

  37. Lycopene • 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

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

  39. 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 Lycopene has been demonstrated to be the most potent antioxidant with the ranking: lycopene > α-tocopherol > α -carotene > β- carotene > lutein.

  40. Lycopene - Biological activity • Lycopene supplementation in vivo & in vitro protects cells from induced oxidative damage Lipid peroxidation is reduced by 80% DNA oxidation is reduced by 75% Matos et al, Arch Bioch Biophys 1999 Matos et al, Arch Bioch Biophys 2000 • Oral Lycopene supplementation protects against ex vivo induced lymphocyte DNA oxidation DNA fragmentation (COMET assay) is reduced by 40% Riso et al, Am J Clin Nutr 1999

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

  42. Improvement in sperm concentration

  43. 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 infertility

  44. Zinc • 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.

  45. The functions of zinc in male reproduction

  46. Effects of zinc supplementation on subfertility

  47. 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.

  48. 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

  49. 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.

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