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
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 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