Transcript e-Business - Nagercoil Obstetric and Gynaecological Society

Role of Micronutrients in the Management of
Male Infertility
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
1,430
100.0
Total
(Stigman et al. 1997)
Treatment of Male Infertility
1. Medical Therapy
2. Surgical Therapy
Varicocelectomy
Vasovasostomy
Vasoepididymostomy
TUR of ejaculatory duct
obstruction
3. Assisted
Reproductive
Technology (ART)
4. Artificial
Insemination
of Donor (AID)
Sperm processing, IUI, IVF
Medical Therapy
I. According to evidence
dependency


Specific Medical Therapy
Non-specific Empirical Medical
Therapy
II. According to drug


Hormonal therapy
Non-hormonal therapy
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
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
>15 million
10%
WHO criteria of normal semen, 1999
Specific Medical Therapy
Endocrine Disorder
Pyospermia
Immunologic Infertility with Antisperm Ab
Retrograde Ejaculation
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
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
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
Newer
concepts
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
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.
Endogenous ROS Formation and Direct Scavenging
Effect of Antioxidant in Sperm Cell
Infection
Radiation
Chemotherapy
pollution
antioxydant
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
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;127:124-132.
J. Biosci. 2001;26(4):492-435.
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
Altern Med Rev. 2000;5(1):28-38.
• Pesticides and other chemicals
Human Reproduction, 2001;16(8):1768-1776.
Environmental Causes
Occupationally
Free time
Sedentary lifestyle
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)
http://www.gfmer.ch/Endo/Fellows_11/Pdf/Infertility_environment.pdf
Human Reproduction, 2001;16(8):1768-1776.
Nutritional Considerations
Various micronutrients are
Nutritional
Factors
Free radical
scavengers
associated with male
L-Carnitine
Lycopene
fertility.
Coenzyme
Q10
Vitamin C
Deficiency of these
Zinc
Vitamin E
Arginine
Glutathione
Vitamin B12
Selenium
micronutrients may result
in infertility.
Altern Med Rev. 2000;5(1):28-38.
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.
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
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 1987;27:145-58
Co enzyme Q10 - Mechanism
Energizer
Free Radical
Scavenger
CLIN. CHEM. 41/2, 217-219 (1995)
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 varicoceleassociated (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.
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
Motility
Motility
index
Sperm
Morphology
Folia Med (Plovdiv).2005;47(1):26–30.
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 Jan;81(1):93-8.
Coenzyme Q10: Clinical Trials
Lewin et al. showed that Coenzyme Q10 results in
improvement in sperm functions in asthenospermic
men
Mean increase in motility: Coenzyme Q10
vs. control group
Coenzyme Q10: Improvement in fertilization rate
30
30
35.7
20
19.1
10
0
Coenzyme Q10
Improvement (%)
Improvement (%)
40
25
20
15
10
5
Control group
0
Baseline
Day 103
Mol Aspects Med 1997;18 S213-S219.
Coenzyme Q10: Clinical Trials
According to a review conducted by Langade et al.
Coenzyme Q10 significantly increased sperm motility
within 6 months.
Improvement (%)
Coenzyme Q10 and improvement in sperm
motility
18
16
14
12
10
8
6
4
2
0
Baseline
After 6 months
Bombay hospital journal.
http://www.bhj.org/journal/april2005/htm/reveiw_coenzyme_145.htm
Non hormonal Therapy
Carnitine :
◈
L- carnitine & acetylcarnitine
◈
Intracellular energy metabolism
Stabilization of cell wall
◈
L-carnitine 2~3 gm/day
Acetylcarnitine 4 gm/day
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
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.
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.
L-Carnitine: Clinical Trials
According to a study conducted by Costa et al. L-carnitine
increased the sperm parameters drastically
180
163.3
160
142.4
Motile spermatozoa (%)
140
120
Mean velocity (microns)
100
Linearity index
80
60
40
32.5
28.4
20 10.8 3.7
3.1
0
Baseline
18
20.3
4.1
Spermatozoa with rapid
linear progression (%)
Number of ejaculated
spermatozoa
At 4 months
Andrologia.1994;26:155-159.
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. 2004;10(9):671–672.
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
Total motile sperm/mL
Carnitine
Placebo
FERTILITY AND STERILITY VOL. 79, NO. 2, FEBRUARY 2003
Forward motile sperm/mL
Carnitine
Placebo
FERTILITY AND STERILITY VOL. 79, NO. 2, FEBRUARY 2003
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;26:155-159
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
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
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 > βcarotene > lutein.
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
Lycopene: Clinical Trials
 A Study evaluated the
Lycopene in infertility
twice a day for three
months
 N - 30 Patients
66
53
46
Morphology
 Lycopene - 2000 mcg,
70
60
50
40
30
20
10
0
Motility
idiopathic infertility.
Improvement
(%)
therapy in men with
Sperm
concentration
effect of oral lycopene
Int Urol Nephrol. 2002;34:369–372.
Improvement in sperm concentration
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
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 :13,129–145.
**Curr Drug Targets 2003:4,323–338.
***Free Radic Biol Med 31,266–274.
Rev Prat. 1993;43:146-151.
.
Ann Nutr Metab. 1986;30:213-218
The functions of zinc in male reproduction
Effects of zinc supplementation on subfertility
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.
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
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.
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.
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]
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;32:1177-1183.
Hinyokika Kiyo. 1984;30:581-586.
.
Hinyokika Kiyo 1988;34:1109-1132
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.
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
0~50% (25%)
Motility
20~67% (43.5%)
Pregnancy 17~25% (16.3%)
Nonhormonal Therapy
Penotoxifylline
Universal phosphodiesterase inhibitor
: Inhibit the breakdown effect of c-AMP
◈ 400mg, po, tid
Count
57%
Motility
47%
Pregnancy 17%
Nonhormonal Therapy
NSAIDs
◈ indomethacin, ketoprofen, diclofenac
sodium
◈ Inhibit prostaglandin with decreasing
testicular steroidogenesis,
spermatogenesis
and sperm motility
◈ 150mg/day
Nonhormonal Therapy
α-blocker
◈ Improve testicular circulation
◈ Terazocin 2~4mg/day , po
doxazocin
alfuzocin
Nonhormonal Therapy
Clonidine
◈ Enhance secretion of Growth Hormone
◈ Clonidine 1.75mg/day
◈ improvement 50%
Nonhormonal Therapy
Miscellaneous
1. Bromocriptine mesylate, metergoline,
corticosteroids, thyroxine oxytocin
2. Folic acid, adenosine triphosphate (ATP) Lglutamine
3. Serotonin
Clinical Effects of Nonspecific Medical Therapy
Drugs
no
Improvement
Pregnancy
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
100
63
15
18
15
15
15
30
1
14
Kallikrein
Clonidine
NSAIDs
50
100
35
α-blocker
Clomiphene
Tamoxifen
35
50
35
25
56
9
18
1
32
11
35
25
7
1
13
11
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
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
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
Zinc
Increases sperm count and
improves morphology by
reducing oxidative damage
to sperm DNA and lipids
Promotes sperm production
& maturation testosterone
synthesis & improves sperm
morphology
What is an Ideal Choice
in Male Infertility?
Thank you