Dr. Ajit Saxena
APOLLO HOSPITALS
NEW DELHI
Ian
Causes for male Infertility
6.5
Other
1.5
2.3
Obstruction
Tumor
4.2
5
5.8
Immunologic
Systemic
Malformation
8.5
8.9
9
Cryptorchidism
Hypogonadism
Infection
16.6
Varicocele
31.7
Idiopathic
0
2
5
10
15
Percent (%)
20
25
30
35
Hum Reprod Update 1999; 5(2): 120
Idiopathic male Subfertility
 40-75% of cases.
 Most common pathological cause of Idiopathic Subfertility is – free
radical induced damage to the sperm.
Free radical is defined as oxygen molecule containing one or more
unpaired electrons in atomic or molecular orbitals.
3
Biology of ROS
Pathology stems from imbalance between production
and scavenging
Production
Degradation
4
Oxidative stress balance
5
Idiopathic
Iatrogenic
Lifestyle
Infection
Environmental
Autoimmune
Testicular
Chronic Disease
Damage to DNA
Damage to membrane
Focus
Role of various micronutrients in treatment of male infertility.
 Coenzyme Q10
 L-Carnitine
 Lycopene
 Zinc
6
Co enzyme Q10
• CoQ10 is a naturally-occuring lipid soluble compound found
in every cell in the body.
• Coenzyme Q10 (CoQ10) is concentrated in the
mitochondrial mid-piece
• Coenzyme Q10 (CoQ10) acts as an electron carrier in the
mitochondrial respiratory chain.*
• It helps in transfer of electrons in respiratory chain & prevents
lipid per oxidation & generation of ROS. Thus it stabilizes cell
membrane, maintains & promotes sperm motility
7
*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)
8
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.
9
EFFECT OF CoQ 10 ON SPERM MOTILITY
 In study of 38 patients (16 -normal motility & 22 –Asthenozoo-spermia)
semen samples were washed in Ham’s F-10 media, incubated with increasing
concentration of CoQ for 24 hrs.
Results :
 Normal patients- No significant change in motility rates
Asthenozoospermia - Significant increase in motility in 50 µM CoQ10, No
significant increase in 5 µM CoQ10 Dept. OBGY, Hadassah-Hebrew
University Medical School, Jerusalem, Israel, 97.
1
0
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.
1
1
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 - 100 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.
1
2
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
Coenzyme Q10: Improvement in fertilization rate
Mean increase in motility: Coenzyme Q10
vs. control group
Improvement (%)
Improvement (%)
40
30
30
35.7
20
19.1
10
25
20
15
10
5
0
Baseline
Day 103
0
Coenzyme Q10
Control group
Mol Aspects Med
13
1997;18 S213-S219.
Carnitine
 Trimethylated aminoacid -ester
 Synthesized in liver, brain, and kidney from dietary amino
acids-methylationof lysine
 Most derived from diet: red meat, fish and dairy products
14
LCarnitine
1
5
 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.
1
6
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
20
32.5
28.4
10.8
3.73.1
18
20.3
4.1
Spermatozoa with rapid
linear progression (%)
Number of ejaculated
spermatozoa
0
Baseline
At 4 months
17
Andrologia.1994;26:155-159
L- Carnitine for asthenospermia with
Zhonghua Nan Ke Xue. 2004;10(9):671–672.
varicocele
Carnitine
Placebo
1
8
There was significant improvement in sperm count,motility
and pregnancy rates in Subfertility due to varicocele.
Use of Carnitine therapy in selected cases of male
factor Subfertility: 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 or placebo;
• Duration : 4 months
1
9
FERTILITY AND STERILITY VOL. 79, NO. 2, FEBRUARY 2003
Total motile sperm/mL
Carnitine
Placebo
2
0
FERTILITY AND STERILITY VOL. 79, NO. 2, FEBRUARY 2003
L- Carnitine in idiopathic asthenozoospermia: a
multicenter study. Italian Study Group on Carnitine
and Male Subfertility.
 N = 100 patients
 L-carnitine
 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
2
1
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
2
2
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
2
3
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
2
4
Lycopene has been demonstrated to be the most
potent antioxidant with the ranking: lycopene > αtocopherol > α -carotene > β- carotene > lutein.
Lycopene: Clinical Trials
66
53
46
Morphology
Motility
70
60
50
40
30
20
10
0
Sperm
concentration
 Lycopene - 2000 mcg,
twice a day for three
months
Lycopene in infertility
Improvement
(%)
 A Study evaluated the
effect of oral lycopene
therapy in men with
idiopathic Subfertility.
 N - 30 Patients
Int Urol Nephrol. 2002;34:369–372.
25
Improvement in sperm concentration
2
6
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%)
2
7
 Conclusion - Lycopene therapy seems to
have a role in the management of idiopathic
male Subfertility
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 antiapoptotic ** and antioxidant properties.***
2
8
*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.
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
3
0
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.
3
1
Indian J Physiol Pharmacol. 1987;31(1):30-34.
First Indian randomized, double blind, placebocontrolled clinical trial of Nutraceuticals for
male subfertility
Clinical Trial : Analysis & Interpretation of
Results
Micronutrient
• Lycopene – 2.5 mg
• Co-Q10 – 50 mg
• L-Carnitine – 500 mg
• Zinc – 12.5 mg
3
4
Improvement in Sperm count (Million/mL) in each arm from baseline
Sperm Count (M/mL)
35
Day 180, 1 Nutraceutical FDC +
1 Placebo BID, 31.65
Day 180, 2 Nutraceutical FDC
BID , 33.16
30
Mean (M/mL)
25
Day 90, 1 Nutraceutical FDC +
1 Placebo BID, 24.88
Day 90, 2 Nutraceutical FDC
BID , 26.35
20
Day 0, 1 Nutraceutical FDC + 1
Placebo BID, 14.37
15
Day 0, 2 Nutraceutical FDC
BID , 14.81
Day 180, 2 Placebo BID , 15.85
Day 90, 2 Placebo BID , 14.89
Day 0, 2 Placebo BID , 12.86
10
5
0
Day 0
Day 90
Day 180
1 Nutraceutical FDC + 1 Placebo BID
14.37
24.88
31.65
2 Nutraceutical FDC BID
14.81
26.35
33.16
2 Placebo BID
12.86
14.89
15.85
Improvement in Sperm Count from Baseline
Improvement in Sperm Count from Baseline
20
LSMean Change
25
Day 180, 2 Nutraceutical FDC
BID , 19.28
Day 180, 1 Nutraceutical FDC
+ Placebo BID, 17.76
15
Day 90, 2 Nutraceutical FDC
BID , 11.91
Day 90, 1 Nutraceutical FDC
+ Placebo BID, 10.64
10
5
Day 180, 2 Placebo BID , 1.96
Day 90, 2 Placebo BID , 1.48
0
Day 90
Day 180
2 Nutraceutical FDC BID
11.91
19.28
1 Nutraceutical FDC + Placebo BID
10.64
17.76
2 Placebo BID
1.48
1.96
Improvement in Motile Sperm (%)in each arm from baseline
Motile Sperms (%)
70
60
Day 180, 1 Nutraceutical FDC +
1 Placebo BID, 55.78
Day 90, 1 Nutraceutical FDC +
1 Placebo BID, 50.12
Day 180, 2 Nutraceutical FDC
BID , 57.35
Day 90, 2 Nutraceutical FDC
BID , 51.62
50
Day 0, 2 Nutraceutical FDC
BID , 39.22
Mean (%)
Day 0, 1 Nutraceutical FDC + 1
Placebo BID, 38.40
40
Day 180, 2 Placebo BID , 44.06
Day 90, 2 Placebo BID , 42.14
Day 0, 2 Placebo BID , 39.47
30
20
10
0
Day 0
Day 90
Day 180
1 Nutraceutical FDC + 1 Placebo BID
38.40
50.12
55.78
2 Nutraceutical FDC BID
39.22
51.62
57.35
2 Placebo BID
39.47
42.14
44.06
Improvement in Motile Sperms from Baseline
Improvement in Motile Sperms from Baseline
20
Day 180, 2 Nutraceutical FDC
BID , 18.44
Day 180, 1 Nutraceutical FDC +
Placebo BID, 17.79
15
LSMean Change
Day 90, 2 Nutraceutical FDC
BID , 12.54
Day 90, 1 Nutraceutical FDC +
Placebo BID, 11.76
10
Day 180, 2 Placebo BID , 4.70
5
Day 90, 2 Placebo BID , 2.62
0
Day 90
Day 180
2 Nutraceutical FDC BID
12.54
18.44
1 Nutraceutical FDC + Placebo BID
11.76
17.79
2 Placebo BID
2.62
4.70
Improvement in Sperm with rapid progression: WHO A (%)
Sperm with rapid progression (%)
35
Day 180, 1 Nutraceutical FDC +
1 Placebo BID, 31.45
30
Day 90, 1 Nutraceutical FDC +
1 Placebo BID, 27.67
Day 180, 2 Nutraceutical FDC
BID , 31.77
Day 90, 2 Nutraceutical FDC
BID , 27.80
25
Mean (%)
20
Day 0, 2 Nutraceutical FDC
BID , 16.61
Day 0, 1 Nutraceutical FDC + 1
Placebo BID, 14.42
15
Day 180, 2 Placebo BID , 16.31
Day 90, 2 Placebo BID , 14.39
Day 0, 2 Placebo BID , 12.11
10
5
0
Day 0
Day 90
Day 180
1 Nutraceutical FDC + 1 Placebo BID
14.42
27.67
31.45
2 Nutraceutical FDC BID
16.61
27.80
31.77
2 Placebo BID
12.11
14.39
16.31
Change in Sperm with WHO Grade A
motility
Change in Sperm with Rapid Progression
20
Day 180, 1 Paternia + Placebo
BID, 15.91
Day 180, 2 Paternia BID , 15.15
LSMean Change
15
Day 90, 2 Paternia BID , 10.77
Day 90, 1 Paternia + Placebo
BID, 11.28
10
Day 180, 2 Placebo BID , 5.52
5
Day 90, 2 Placebo BID , 2.21
0
Day 90
Day 180
2 Paternia BID
10.77
15.15
1 Paternia + Placebo BID
11.28
15.91
2 Placebo BID
2.21
5.52
Improvement in Sperm with Normal
Morphology
Sperm with Normal Morphology (%)
70
Day 180, 2 Paternia BID , 62.30
60
Day 90, 2 Paternia BID , 55.33
50
Mean (% )
Day 0, 2 Paternia BID , 44.07
Day 180, 1 Paternia + 1 Placebo
60.45
Day 90, 1 Paternia + 1BID,
Placebo
BID, 55.53
Day 0, 1 Paternia + 1 Placebo
BID, 45.09
Day 180,BID
2 Placebo
Day 90, 2 Placebo
, 51.08 BID , 51.51
Day 0, 2 Placebo BID , 45.75
40
30
20
10
0
Day 0
Day 90
Day 180
2 Paternia BID
44.07
55.33
62.30
1 Paternia + 1 Placebo BID
45.09
55.53
60.45
2 Placebo BID
45.75
51.08
51.51
Reduction of Sperm with Abnormal
Morphology
60 Day 0, 2 Paternia BID , 55.93
50
Day 90, 2 Paternia BID , 44.67
Mean (%)
40
Day 180, 37.70
Sperm with Abnormal Morphology (%)
Day 0, 1 Paternia + 1 Placebo
BID, 55.14
Day 90, 1 Paternia + 1 Placebo
BID, 44.23
Day 0, 2 Placebo BID , 53.97
Day 90, 2 Placebo Day
BID 180,
, 48.92
48.49
Day 180, 39.58
30
20
10
0
Day 0
Day 90
Day 180
2 Paternia BID
55.93
44.67
37.70
1 Paternia + 1 Placebo BID
55.14
44.23
39.58
2 Placebo BID
53.97
48.92
48.49
Change in Sperm with normal
Morphology
Change in Sperm With Normal Morphology
20
Day 180, 2 Paternia BID ,
17.55
Day 180, 1 Paternia +
Placebo BID, 15.45
LSMean Change
15
Day 90, 2 Paternia BID ,
10.88
Day 90, 1 Paternia + Placebo
BID, 10.50
10
Day 180, 2 Placebo BID ,
6.11
Day 90, 2 Placebo BID , 5.64
5
0
Day 90
Day 180
2 Paternia BID
10.88
17.55
1 Paternia + Placebo BID
10.50
15.45
2 Placebo BID
5.64
6.11
Change in sperm with Abnormal Morphology
Change in Sperm With Abnormal Morphology
0
LSMean Change
-5
Day 90, 2 Placebo BID , -5.46
Day 180, 2 Placebo BID , 6.14
-10
Day 90, 2 Paternia BID , 10.89
Day 90, 1 Paternia + Placebo
BID, -10.88
-15
Day 180, 1 Paternia +
Placebo BID, -15.59
Day 180, 2 Paternia BID , 17.59
-20
Day 90
Day 180
2 Paternia BID
-10.89
-17.59
1 Paternia + Placebo BID
-10.88
-15.59
2 Placebo BID
-5.46
-6.14
History taking
PDE5 inhibitors
Drugs 2004; 64 (23)
Non-Responders to PDE5 Inhibitors
 Comorbidities (Diabetes, Nuropathy)
 Inappropriate use
 Misdiagnosis (Pt. Having HSDD)
 Psychological and partner issues
World J Mens Health 2013 April 31(1): 31-35
Mode of action of L Arginine:
REVERSAL OF ENDOTHELIAL AND ERECTILE DYSFUNCTION
12
10
8
Column 1
Column 2
Column 3
6
4
2
0
Row 1
Row 2
Row 3
Row 4
Role of Nitric Oxide in ED
Sexual
Stimulation
L-Arginine
nNOS
eNOS
L-Arginine
Nitric
Oxide
Guanylate Cyclase
GTP
cGMP
GMP
Erection
PDE-5
GTP, guanosine triphosphate; GMP, guanosine monophosphate;
cGMP, cyclic GMP; nNOS, neuronal nitric oxide synthase;
eNOS endothelial nitric oxide synthase.
Burnett AL. Int J Impot Res. 2004;16:S15-S19.
Andrology. 2013 Mar;1(2):223-8.
Conclusion
 Very few medical fields have changed as dramatically over the
past decade as reproductive medicine, particularly in terms
of the diagnostic and treatment strategies for male infertility.
 These advances include oxidative stress and male infertility.
 The nutraceutical theory remain the safest and most costeffective ways of treating infertile men, and, perhaps more
importantly for the couples involved, many of these
techniques enable couples to conceive naturally.