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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
Diagnosis No % 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 Total 1,430 100.0 (Stigman et al. 1997)

3 Treatment of Male Infertility
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 According to evidence dependency II. According to drug
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) Volume >2.0ml pH >7.2 Sperm concentration >20×106/ml >15 million Total sperm count >40×106/ejaculate Motility >50% (grade a+b) or >25% (grade a) Morphology >15% by strict criteria % Viability >75% WBC <1×106/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
Iatrogenic oligospermia Refractory to specific medical therapy Adjuvant therapy before and after 1st line therapeutic modality Preliminary therapy prior to ARTs Hormonal Therapy GnRH Gonadotropin Testosterone Antiestrogen Aromatase inhibitor Growth hormone Non-hormonal Therapy Carnitine Kallikrein Pentoxyphylline NSAIDs α-blocker Clonidine Misellaneous

9 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

10 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

11 Newer concepts

12 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 불임 남성의 40%에서 Semen내에서의 ROS가 발견됩니다. 내인성 antioxidant 방어기전에도 불구하고 정자에 대한 ROS의 해로운 action mechanism은 1. sperm membrane의 lipid peroxidation을 일으키고 2. membrane fluidity 를 감소시키며 3. sperm motility 를 감소시키며 4. sperm-oocyte fusion capability를 감소시겨 5. fertilizing capacity 의 장애를 초래합니다. 다음 슬라이드 부탁합니다.

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 2) Sperm washing with culture media including antioxidant 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. Klinefelter’s syndrome, Kallman’s syndrome can also result in male infertility Indian J Med Res. 2008;127: J. Biosci. 2001;26(4):

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):

17 Environmental Causes Sedentary lifestyle Occupationally Free time
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) Sedentary lifestyle Human Reproduction, 2001;16(8):

18 Nutritional Considerations
Various micronutrients are associated with male fertility. Deficiency of these micronutrients may result in infertility. Nutritional Factors Free radical scavengers L-Carnitine Lycopene Coenzyme Q10 Vitamin C Zinc Vitamin E Arginine Glutathione Vitamin B12 Selenium 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 metabolism Testicular microcirculation 1. Carnitine 2. Kallikrein 3. Pentoxyphylline 4. NSAIDs 5. α-blocker 6. Clonidine 7. Miscellaneous

21 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, (1995) **Chem Scripta 1987;27:145-58

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

23 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.

24 Coenzyme Q10: Clinical Trials
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 Sperm Morphology Motility index Folia Med (Plovdiv).2005;47(1):26–30.

25 Coenzyme Q10: Clinical Trials
Patients – 22 infertile men with idiopathic asthenozoospermia. Coenzyme Q 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 Jan;81(1):93-8.

26 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.

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 ◈ Intracellular energy metabolism Stabilization of cell wall L-carnitine 2~3 gm/day Acetylcarnitine 4 gm/day

29 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

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:

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:

33 L- Carnitine for asthenospermia with varicocele
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.

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 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

35 Total motile sperm/mL Carnitine Placebo

36 Forward motile sperm/mL

37 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:

38 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

39 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

40 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.

41 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

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

43 Improvement in sperm concentration

44 Results Improvement in sperm concentration - 20 patients (66%)
Improved motility – 16 patients (53%) Improvement in sperm morphology 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 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– **Curr Drug Targets 2003:4,323– ***Free Radic Biol Med 31,266–274. Rev Prat. 1993;43: Ann Nutr Metab. 1986;30:

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 Aug;79(2):

49 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

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: Minerva Urol Nefrol 1994;46:

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: Science 1999;285: Environ Mol Mutagen [Epub ahead of print]

53 Methylcobalamin 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. Hinyokika Kiyo 1986;32: Hinyokika Kiyo. 1984;30: Hinyokika Kiyo 1988;34:

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: 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 → Increase vascular permeability, smooth m. contraction & membrane glucose transport → Increase sperm motility ◈ 600 units/day, po Count ~50% (25%) Motility ~67% (43.5%) Pregnancy 17~25% (16.3%)

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

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

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

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

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

61 Clinical Effects of Nonspecific Medical Therapy
Drugs no Improvement Pregnancy % HCG + Amino acids Folic acid & Zinc metergoline 85 103 4 26 76 3 31 74 75 15 18 L-arginine AlCAMIN Vitamin Selenium 40 29 50 45 10 8 14 25 28 11 5 6 13 17 12 Carnitine Kallikrein Clonidine NSAIDs α-blocker 100 63 35 30 1 Clomiphene Tamoxifen 56 9 32 7

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

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

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