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Role of Micronutrients in the Management of Male Infertility.

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Presentation on theme: "Role of Micronutrients in the Management of Male Infertility."— Presentation transcript:

1 Role of Micronutrients in the Management of Male Infertility

2 Final Diagnostic Categories in a Male Infertility Clinic DiagnosisNo% Varicocele Idiopathic Obstruction Normal/Female factor Cryptorchidism Immunologic Ejaculatory dysfunction Testicular failure Drug/Radiation Endocrinologic Infection Sexual dysfunction Systemic disease Sertoli -cell-only Ultrastructural defect Genetic Testis cancer 603 324 205 113 49 36 18 16 13 4 3 2 42.2 22.7 14.3 7.9 3.4 2.6 1.3 1.1 0.9 0.3 0.2 0.1 Total1,430100.0 (Stigman et al. 1997)

3 Treatment of Male Infertility 1.Medical Therapy 2. Surgical Therapy Varicocelectomy Vasovasostomy Vasoepididymostomy TUR of ejaculatory duct obstruction 3. Assisted Reproductive Technology (ART) Sperm processing, IUI, IVF 4. Artificial Insemination of Donor (AID)

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

5 Criteria for Success Duration : 3~6 months, at least one full spermatogenic cycleDuration : 3~6 months, at least one full spermatogenic cycle Parameter : Semen analysis & hormonal assayParameter : Semen analysis & hormonal assay : Criteria - count 30%, motility 20% (Lee et al. 1986) : Criteria - count 30%, motility 20% (Lee et al. 1986) Volume>2.0ml pH>7.2 Sperm concentration >20×10 6 /ml >15 million Total sperm count >40×10 6 /ejaculate Motility >50% (grade a+b) or >25% (grade a) Morphology >15% by strict criteria 10% Viability>75% WBC <1×10 6 /ml WHO criteria of normal semen, 1999


7 Specific Medical Therapy Endocrine Disorder Pyospermia Immunologic Infertility with Antisperm Ab Retrograde Ejaculation

8 Nonspecific Empirical Medical Therapy Hormonal Therapy GnRHGonadotropinTestosteroneAntiestrogen Aromatase inhibitor Growth hormone Iatrogenic oligospermia Refractory to specific medical therapy Adjuvant therapy before and after 1 st line therapeutic modality Preliminary therapy prior to ARTs Non-hormonal Therapy CarnitineKallikreinPentoxyphyllineNSAIDs α-blocker ClonidineMisellaneous

9 Difficult Cases for Empirical Medical Treatment 1. Shrunken testicle (volume < 10ml) 2. Histopathological findings of testis biopsy : Sertoli cell only syndrome : Sertoli cell only syndrome Severe maturation arrest (Johnson score 3-4) Severe maturation arrest (Johnson score 3-4) 3. Azoospermia or severe oligospermia (1.0 × 10 6 ml) : especially, Increased FSH to twice normal : especially, Increased FSH to twice normal

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

11 Newer concepts

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

13 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.

14 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 rebamipide 2) Sperm washing with culture media including antioxidant 2) Sperm washing with culture media including antioxidant to removal leukocyte to removal leukocyte

15 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. Klinefelters syndrome, Kallmans syndrome can also result in male infertility Indian J Med Res. 2008;127:124-132. J. Biosci. 2001;26(4):492-435.

16 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.

17 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

18 Nutritional Considerations Various micronutrients are associated with male fertility. Deficiency of these micronutrients may result in infertility. Nutritional Factors Free radical scavengers L-CarnitineLycopene Coenzyme Q10 Vitamin C ZincVitamin E ArginineGlutathione Vitamin B12Selenium Altern Med Rev. 2000;5(1):28-38.

19 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.

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

21 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 Co enzyme Q10

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

23 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

24 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

25 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. Coenzyme Q10: Clinical Trials

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

27 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.

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

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

30 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.

31 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.

32 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.

33 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.

34 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 10 6 /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

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

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

37 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 may improve sperm quality

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

39 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 Lycopene

40 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

41 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 Lycopene - Biological activity

42 Lycopene: Clinical Trials Int Urol Nephrol. 2002;34:369–372. 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

43 Improvement in sperm concentration

44 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

45 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. Zinc Rev Prat. 1993;43:146-151. Ann Nutr Metab. 1986;30:213-218.

46 The functions of zinc in male reproduction

47 Effects of zinc supplementation on subfertility

48 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.

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

50 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.

51 Arginine Arginine is thought to be essential for sperm motility. 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 However, the dosage of arginine is higher compared to other micronutrients. J Urol 1973;110:311-313. Minerva Urol Nefrol 1994;46:251-253.

52 Selenium Selenium and glutathione are essential to the formation of phospholipid hydroperoxide 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]

53 Methylcobalamin Vitamin B 12 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. Hinyokika Kiyo 1986;32:1177-1183. Hinyokika Kiyo. 1984;30:581-586. Hinyokika Kiyo 1988;34:1109-1132.

54 Vitamin E 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 Fertil Steril 1995;64:825-831. Biol Trace Elem Res 1996;53:65-83. Arch Androl 1992;29:65-68.

55 Nonhormonal Therapy Kallikrein · Kininogenase stimulate the release of kinins (bradykinin, kallidin, methionylkallidin) from kininogens (bradykinin, kallidin, methionylkallidin) from kininogens Increase vascular permeability, smooth m. contraction Increase vascular permeability, smooth m. contraction & membrane glucose transport & membrane glucose transport Increase sperm motility Increase sperm motility 600 units/day, po 600 units/day, po Count 0~50% (25%) Count 0~50% (25%) Motility 20~67% (43.5%) Motility 20~67% (43.5%) Pregnancy 17~25% (16.3%) Pregnancy 17~25% (16.3%)

56 Nonhormonal Therapy Penotoxifylline Universal phosphodiesterase inhibitor : Inhibit the breakdown effect of c-AMP : Inhibit the breakdown effect of c-AMP 400mg, po, tid 400mg, po, tid Count 57% Count 57% Motility 47% Motility 47% Pregnancy 17% Pregnancy 17%

57 Nonhormonal Therapy NSAIDs indomethacin, ketoprofen, diclofenac sodium indomethacin, ketoprofen, diclofenac sodium Inhibit prostaglandin with decreasing Inhibit prostaglandin with decreasing testicular steroidogenesis, spermatogenesis testicular steroidogenesis, spermatogenesis and sperm motility and sperm motility 150mg/day 150mg/day

58 Nonhormonal Therapy α-blocker Improve testicular circulation Improve testicular circulation Terazocin 2~4mg/day, po Terazocin 2~4mg/day, po doxazocin doxazocin alfuzocin alfuzocin

59 Nonhormonal Therapy Clonidine Enhance secretion of Growth Hormone Enhance secretion of Growth Hormone Clonidine 1.75mg/day Clonidine 1.75mg/day improvement 50% improvement 50%

60 Nonhormonal Therapy Miscellaneous 1.Bromocriptine mesylate, metergoline, corticosteroids, thyroxine oxytocin 2.Folic acid, adenosine triphosphate (ATP) L- glutamine 3.Serotonin

61 Clinical Effects of Nonspecific Medical Therapy DrugsnoImprovementPregnancy no%no% HCG + Amino acids Folic acid & Zinc metergoline851034267633174751518 L-arginineAlCAMINVitaminSelenium4029504510814425282811556131712 CarnitineKallikreinClonidineNSAIDs α-blocker 100631001518351530503525151351514503525 ClomipheneTamoxifen5691813211711311

62 The Quadruple of Atreya According to ancient sage Athreya, there are 4 components for a successful treatment 1. The Physician. 2. Drugs. 3. The Patient. 4. Attendants It is told that all the 4 components have to be efficient to achieve successful treatment. Charka Samhitha

63 Ideal Nutraceutical for Male Infertility Just like the Quadruple of Atreya, successful treatment of male infertility should control all the aspects of sperm dysfunction in infertile males. An combination of L-Carnitine, Coenzyme Q10, Lycopene and Zinc can provide holistic approach to male infertility

64 L-carnitine Improves sperm motility by providing energy to the sperm cell through fatty acid metabolism Zinc Promotes sperm production & maturation testosterone synthesis & improves sperm morphology Ideal Nutraceutical for Male Infertility Coenzyme Q10 Improves sperm motility by providing energy through ATP generation in mitochondrion Lycopene Increases sperm count and improves morphology by reducing oxidative damage to sperm DNA and lipids

65 Thank you What is an Ideal Choice in Male Infertility?

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