Role of Micronutrients in the Management of Male Infertility

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 18 16 16 13 4 4 3 3 2 2 42.2 22.7 14.3 7.9 3.4 2.6 1.3 1.3 1.1 1.1 0.9 0.3 0.3 0.2 0.2 0.1 0.1
Total 1,430 100.0
(Stigman et al. 1997)
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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
• Specific Medical Therapy
• Non-specific Empirical Medical Therapy
• II. According to drug
• Hormonal therapy
• Non-hormonal therapy

5
Criteria for Success

• Duration 36 months, at least one full
  spermatogenic cycle
• Parameter Semen analysis hormonal assay
• Criteria - count 30,
  motility 20 (Lee et al. 1986)

Volume gt2.0ml
pH gt7.2
Sperm concentration gt20106/ml gt15 million
Total sperm count gt40106/ejaculate
Motility gt50 (grade ab) or gt25 (grade a)
Morphology gt15 by strict criteria 10
Viability gt75
WBC lt1106/ml
WHO criteria of normal semen, 1999
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(No Transcript)
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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 a-blocker Clonidine Misellaneous
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Difficult Cases for Empirical Medical Treatment

• 1. Shrunken testicle (volume lt 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

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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
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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
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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. 199648(6)835850.
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
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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. 2008127124-132. J. Biosci.
200126(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. 20005(1)28-38. Human
Reproduction, 200116(8)1768-1776.
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Environmental Causes
http//www.gfmer.ch/Endo/Fellows_11/Pdf/Infertilit
y_environment.pdf Human Reproduction,
200116(8)1768-1776.
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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. 20005(1)28-38.
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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. 20005(1)28-38.
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Non hormonal Therapy

• To improvement of Sperm motility
• Sperm
  fertilizing capacity
• Sperm
  metabolism
• 
  Testicular microcirculation

1. Carnitine 2. Kallikrein 3. Pentoxyphylline 4.
NSAIDs 5. a-blocker 6. Clonidine
7. Miscellaneous
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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 198727145-58
22
Co enzyme Q10 - Mechanism
Free Radical Scavenger
Energizer
CLIN. CHEM. 41/2, 217-219 (1995)
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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), 107111.
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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
Folia Med (Plovdiv).200547(1)2630.
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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 Jan81(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 199718 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. http//www.bhj.org/journ
al/april2005/htm/reveiw_coenzyme_145.htm
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Non hormonal Therapy Carnitine

• ? L- carnitine acetylcarnitine
• ? Intracellular energy metabolism
• Stabilization of cell
  wall
• ?
• L-carnitine 23 gm/day
• Acetylcarnitine 4 gm/day

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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

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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 1987341-24. Arch Ital Urol Nefrol Androl
199264187-196.
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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). 200547(1)2630. .
Zhonghua Nan Ke Xue. 200713(2)143146.
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L-Carnitine Clinical Trials

• According to a study conducted by Costa et al.
  L-carnitine
• increased the sperm parameters drastically

Andrologia.199426155-159.
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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. 200410(9)671672.
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Use of Carnitine therapy in selected cases of
male factor infertility A double-blind crossover
trial

• Patient(s) One hundred infertile patients
  (ages 2040 years) with the following baseline
  sperm selection criteria concentration, 1020 X
  106/mL total motility, 1030 forward
  motility, lt15 atypical forms, lt70 velocity,
  1030 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.

• 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 199426155-159
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

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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

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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 gt
a-tocopherol gt a -carotene gt ß- carotene gt lutein.
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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

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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. 200234369372.
43
Improvement in sperm concentration
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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

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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 13,129145.
Curr Drug Targets
20034,323338.
Free Radic Biol Med 31,266274.
Rev Prat. 199343146-151. Ann Nutr Metab.
198630213-218.
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The functions of zinc in male reproduction
47
Effects of zinc supplementation on subfertility
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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
Aug79(2)179-84.
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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

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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. 198731(1)30-34.
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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 1973110311-313. Minerva Urol Nefrol
199446251-253.
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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. 19922965-68. Science
19992851393-1396. Environ Mol Mutagen. 2009
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 1986321177-1183. Hinyokika Kiyo.
198430581-586. Hinyokika Kiyo 1988341109-1132.
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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 199564825-831. Biol Trace Elem
Res 19965365-83. Arch Androl 19922965-68.
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 050 (25)
• Motility 2067 (43.5)
• Pregnancy 1725 (16.3)

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Nonhormonal Therapy Penotoxifylline

• Universal phosphodiesterase inhibitor
• Inhibit the breakdown effect of c-AMP
• ? 400mg, po, tid
• Count 57
• Motility 47
• Pregnancy 17

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Nonhormonal Therapy NSAIDs

• ? indomethacin, ketoprofen, diclofenac sodium
• ? Inhibit prostaglandin with decreasing
  
• testicular steroidogenesis,
  spermatogenesis
• and sperm motility
• ? 150mg/day

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Nonhormonal Therapy a-blocker

• ? Improve testicular circulation
• ? Terazocin 24mg/day , po
• doxazocin
• alfuzocin

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Nonhormonal Therapy Clonidine

• ? Enhance secretion of Growth Hormone
• ? Clonidine 1.75mg/day
• ? improvement 50

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Nonhormonal Therapy Miscellaneous

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

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Clinical Effects of Nonspecific Medical Therapy
Drugs no Improvement Improvement Pregnancy Pregnancy
Drugs no no no
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 4 25 28 28 11 5 5 6 13 17 12
Carnitine Kallikrein Clonidine NSAIDs a-blocker 100 63 100 15 18 35 15 30 50 35 25 15 1 35 15 14 50 35 25
Clomiphene Tamoxifen 56 9 18 1 32 11 7 1 13 11
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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
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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
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Ideal Nutraceutical for Male Infertility

• L-carnitine
• Improves sperm motility by providing energy to
  the sperm cell through fatty acid metabolism

Coenzyme Q10 Improves sperm motility by
providing energy through ATP generation in
mitochondrion
Zinc Promotes sperm production maturation
testosterone synthesis improves sperm morphology
Lycopene Increases sperm count and improves
morphology by reducing oxidative damage to sperm
DNA and lipids
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What is an Ideal Choice in Male Infertility?
Thank you