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%VaricoceleIdiopathicObstructionNormal/Female factorCryptorchidismImmunologicEjaculatory dysfunctionTesticular failureDrug/RadiationEndocrinologicInfectionSexual dysfunctionSystemic diseaseSertoli -cell-onlyUltrastructural defectGeneticTestis cancer603324205113493618161343242.222.7126.96.36.199.188.8.131.52.30.20.1Total1,430100.0(Stigman et al. 1997)
3 Treatment of Male Infertility Medical Therapy2. Surgical TherapyVaricocelectomyVasovasostomy VasoepididymostomyTUR of ejaculatory ductobstruction3. Assisted Reproductive Technology (ART)Sperm processing, IUI, IVF4. Artificial Inseminationof Donor (AID)
4 Medical Therapy According to evidence dependency II. According to drug Specific Medical TherapyNon-specific Empirical Medical TherapyII. According to drugHormonal therapyNon-hormonal therapy
5 Criteria for SuccessDuration : 3~6 months, at least one full spermatogenic cycleParameter : Semen analysis & hormonal assay: Criteria - count 30%, motility 20% (Lee et al. 1986)Volume>2.0mlpH>7.2Sperm concentration>20×106/ml >15 millionTotal sperm count>40×106/ejaculateMotility>50% (grade a+b) or >25% (grade a)Morphology>15% by strict criteria %Viability>75%WBC<1×106/mlWHO criteria of normal semen, 1999
7 Specific Medical Therapy Endocrine DisorderPyospermiaImmunologic Infertility with Antisperm AbRetrograde Ejaculation
8 Nonspecific Empirical Medical Therapy Iatrogenic oligospermiaRefractory to specific medical therapyAdjuvant therapy before and after 1st line therapeutic modalityPreliminary therapy prior to ARTsHormonal TherapyGnRHGonadotropinTestosteroneAntiestrogenAromatase inhibitorGrowth hormoneNon-hormonal TherapyCarnitineKallikreinPentoxyphyllineNSAIDsα-blockerClonidineMisellaneous
9 Difficult Cases for Empirical Medical Treatment 1. Shrunken testicle (volume < 10ml)2. Histopathological findings of testis biopsy: Sertoli cell only syndromeSevere 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 trialsHeterogenous patients populationVariable dosages, treatment period and follow-upTremendous fluctuation in an individualsemen parameterDifferent criteria for success
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 spermby overwhelming endogenous antioxidant defenses1. Cause sperm membrane lipid peroxidation2. Decrease membrane fluidity3. Reduce sperm motility4. Decrease sperm-oocyte fusion capability5. Impair fertilizing capacity불임 남성의 40%에서 Semen내에서의 ROS가 발견됩니다.내인성 antioxidant 방어기전에도 불구하고 정자에 대한 ROS의 해로운 action mechanism은1. sperm membrane의 lipid peroxidation을 일으키고2. membrane fluidity 를 감소시키며3. sperm motility 를 감소시키며4. sperm-oocyte fusion capability를 감소시겨5. fertilizing capacity 의 장애를 초래합니다.다음 슬라이드 부탁합니다.
13 ROS and Male Infertility Reactive Oxygen Species isone of the majorcontributors to maleInfertility & cause Damage to the spermCell membraneDNA moleculesLipidsProteinsUrology. 1996;48(6):835–850.
14 Endogenous ROS Formation and Direct Scavenging Effect of Antioxidant in Sperm Cell antioxydantInfectionRadiationChemotherapypollutionIntrinsic antioxidant : SOD, catalase, ascorbate, tocopherolManagement 1) Extrinsic antioxidant : Vit A, C, E, glutathione, selenium,rebamipide2) Sperm washing with culture media including antioxidantto removal leukocyte
15 Genetic CausesDNA 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 infertilityIndian J Med Res. 2008;127:J. Biosci. 2001;26(4):
16 Environmental CausesVarious environmental factors can result in male infertility. The factors are as follows:InfectionExcessive heatRadiation exposureHeavy metal toxicityCigarette smokingXeno-estrogen exposurePesticides and other chemicalsAltern Med Rev. 2000;5(1):28-38.Human Reproduction, 2001;16(8):
17 Environmental Causes Sedentary lifestyle Occupationally Free time Physical activityProlonged sittingThermoregulation of scrotumelevation of scrotal temperatureHEAT EXPOSURESpermatogenesisQuality and quantity of sperm production(count, morphology, motility, delayed coception)Sedentary lifestyleHuman Reproduction, 2001;16(8):
18 Nutritional Considerations Various micronutrients areassociated with malefertility.Deficiency of thesemicronutrients may resultin infertility.Nutritional FactorsFree radical scavengersL-CarnitineLycopeneCoenzyme Q10Vitamin CZincVitamin EArginineGlutathioneVitamin B12SeleniumAltern 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 spermProvides nutrition for motility of spermImprovement in sperm count and motilityHelps in production of sex hormonesPrevents sperm damageAltern Med Rev. 2000;5(1):28-38.
20 Non hormonal Therapy : To improvement of Sperm motility Sperm fertilizing capacitySperm metabolismTesticular microcirculation1. Carnitine2. Kallikrein3. Pentoxyphylline4. NSAIDs5. α-blocker6. Clonidine7. Miscellaneous
21 Co enzyme Q10CoQ10 is a naturally-occurring compound found in every cell in the body.Coenzyme Q10 (CoQ10) is concentrated in the mitochondrial mid-pieceCoQ10's alternate name is ubiquinoneIt is found in foods, particularly in fish and meatsCoenzyme Q10 (CoQ10) acts as an electron carrier in the mitochondrial respiratory chain.**CLIN. CHEM. 41/2, (1995) **Chem Scripta 1987;27:145-58
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, motilityIndex and sperm morphologySpermMorphologyMotilityindexFolia Med (Plovdiv).2005;47(1):26–30.
25 Coenzyme Q10: Clinical Trials Patients – 22 infertile men with idiopathic asthenozoospermia.Coenzyme Q mg for 6 monthsA significant increase was also found in sperm cell motilityConclusion: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 menMol 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 metabolismStabilization of cell wall◈L-carnitine 2~3 gm/dayAcetylcarnitine 4 gm/day
29 Change of L-carnitine & Acetylcarnitine in Seminal Plasma In oligoasthenozoospermiaLower 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-CarnitineThe 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 motilityDrugs 1987;34:1-24.Arch Ital Urol Nefrol Androl 1992;64:
31 L-CarnitineSignificantly 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 cellsL-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-carnitineincreased the sperm parameters drasticallyAndrologia.1994;26:
33 L- Carnitine for asthenospermia with varicocele PlaceboThere 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 trialPatient(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 monthsFERTILITY 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 CarnitinePlaceboFERTILITY 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.N = 100 patientsL-carnitine - 3 g/dayDuration - 4 months.Percentage of motile spermatozoa increased from 26.9 ± 1.1 to 37.7 ± 1.1 %.Total number of spermatozoa per ejaculate also increasedConclusion - Oral administration of L-Carnitine may improve sperm qualityAndrologia 1994;26:
38 LycopeneLycopene 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 LycopeneLycopene 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 includesDamage to the cell membraneDNA moleculesLipidsProteinsLycopene 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 damageLipid peroxidation is reduced by 80%DNA oxidation is reduced by 75%Matos et al, Arch Bioch Biophys 1999Matos et al, Arch Bioch Biophys 2000Oral Lycopene supplementation protects against ex vivo induced lymphocyte DNA oxidationDNA 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 monthsN - 30 PatientsInt Urol Nephrol. 2002;34:369–372.
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 ZincZinc 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 synthesisZinc deficiency is associated with decreased testosterone levels & sperm count.Zinc levels are generally lower in infertile men with diminished sperm countFurthermore, 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:
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 monthsThere was significant improvement in the sperm quality; sperm count, progressive motility, fertilizing capacityConclusion: Zinc therapy has a role in improving sperm parameters in men with asthenozoospermiaEur J Obstet Gynecol Reprod Biol Aug;79(2):
49 Zinc – Clinical TrialsNetter et al. studied the effect of zinc supplementation on testosterone, dihydrotestosterone and sperm count.The results of the study were dramatic37 patients were studiedTestosterone and dihydrotestosterone levels increased significantlyNine wives became pregnant, six within 3 months and three within 2 months
50 Zinc: Clinical TrialsAccording to study conducted by Tikkiwal et al. zinc resulted inSignificant improvement in sperm count,Number of progressively motile and normal spermatozoaNormal 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 infertilityHowever, the dosage of arginine is higher compared to other micronutrients.J Urol 1973;110:Minerva Urol Nefrol 1994;46:
52 SeleniumSelenium and glutathione are essential to the formation of phospholipid hydroperoxide glutathione peroxidaseDeficiencies of selenium can lead to instability of the mid-piece, resulting in defective motilityHowever, it can be toxic if consumed in excess.ArchAndrol. 1992;29: Science 1999;285:Environ Mol Mutagen [Epub ahead of print]
53 MethylcobalaminVitamin 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 parametersHowever, 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 EOral supplementation with vitamin E significantly decreases the malondialdehyde concentration and improves the sperm motilityAlthough Invitro studies have prooved the efficacy of vitamin E, human studies are lackingAlthough there are few human studies, they recruited only few patientsFertil 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, poCount ~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, tidCount %Motility %Pregnancy 17%
61 Clinical Effects of Nonspecific Medical Therapy DrugsnoImprovementPregnancy%HCG + Amino acidsFolic acid & Zincmetergoline851034267633174751518L-arginineAlCAMINVitaminSelenium402950451081425281156131712CarnitineKallikreinClonidineNSAIDsα-blocker1006335301ClomipheneTamoxifen569327
62 The Quadruple of Atreya According to ancient sage Athreya, there are 4 components for a successful treatment1. The Physician.2. Drugs.3. The Patient.4. AttendantsIt 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 ofL-Carnitine,Coenzyme Q10,Lycopene andZinccan provide holistic approach to male infertility
64 Ideal Nutraceutical for Male Infertility Coenzyme Q10Improves sperm motility by providing energy through ATP generation in mitochondrionL-carnitineImproves sperm motility by providing energy to the sperm cell through fatty acid metabolismLycopeneIncreases sperm count and improves morphology by reducing oxidative damage to sperm DNA and lipidsZincPromotes sperm production & maturation testosterone synthesis & improves sperm morphology
65 What is an Ideal Choice in Male Infertility? Thank you