Maxoza - Neo DGM slides.pptx

ROLE OF MICRO NUTRIENTS
IN MALE INFERTILITY

Infertility
• Inability to achieve pregnancy after 1 year of
regular unprotected sexual intercourse
• Linked to several emotional, physical, and
sociocultural problems1
• WHO estimates 60–80 million couples worldwide
currently suffer from infertility2
• Estimates of infertility vary widely among Indian
states: 3.7% in UP, HP & Maharashtra, 5 to 6% in
AP, 7 and 15% in Kashmir
1. J Hum Reprod Sci 2019;12:4-18
2. J Hum Reprod Sci. 2015 Oct-Dec; 8(4): 191–196
8–12% of couples worldwide

Male infertility
• Male infertility refers to a male's inability to result pregnancy in a fertile female
• “Male factor” infertility is seen as an alteration in sperm concentration and/or
motility and/or morphology
• Data demonstrate an association between male infertility and overall health
• Adding to complexity is that men typically do not seek health care unless there
is acute medical need or, as in the case of the infertile couple, the male goes
for a reproductive examination and semen analysis
• Advanced paternal age is associated with increased risk for
– Adverse perinatal outcomes for both offspring and mother;
• In addition to age, paternal lifestyle factors, such as obesity and smoking
impact not only the male fertility but also the offspring wellness
• Various factors are involved in the pathophysiology of male infertility including
Oxidative stress
Andrology, 2019, 7, 762–768

• While male factors such as decreased semen quality are responsible for
25% of all infertility issues, the etiology of suboptimal semen quality is
poorly understood.
•. Int J Urol. 2009 May;16(5):449-57.

Percentages of infertility cases per region that are due to male factor
Agarwal et al. Reproductive Biology and Endocrinology (2015) 13:37.

India prevalence
• In a retrospective analysis of 10 years carried out in a rural tertiary care centre of Central India
from January 2005 to December 2014:
• It was found that of total 3084 cases
– 1104 (35.8%) males: Normal sperm count
– 1980 (64.2%) males: Abnormal semen analysis report
Kumar N, et al. Indian Journal of Obstetrics and Gynaecology Research 2015;2(3):132-136

Testicular Function
Testis have dual function in adult males:
• Spermatogenesis (germ cells)
• Testosterone synthesis (Leydig cells)

Sperm Morphology
50 μm in length
oval head between 4.0-5.0 μm length
2.5 to 3.5 μm width
Tail
Acrosome
Head
Nucleus
Neck
Middle
piece

Male Reproductive hormonal Axis
• LH stimulates testosterone production by
the Leydig cells
• FSH supports spermatogenesis in the
seminiferous epithelium by stimulation of
the Sertoli cells.
Cambridge University Press Surgical and Medical Management of Male Infertility Marc Goldstein and Peter N. Schlegel

Causes of Male Factor Infertility
World J Mens Health. 2019 Sep; 37(3): 296–312
Male
Infertility
Hormonal
Varicocele
Lifestyle
Idiopathic
Infertility
– 50%
Genetic

Semen Analysis: What to look for?
• Spermatozoa analysis: number, motility, morphology
• Other cells present in semen (leukocytes suggest infection)
• Seminal fluid analysis

Semen Analysis: Reference Values
Frequency of semen analysis: If the
results of semen analysis are normal
according to WHO criteria, one test is
sufficient. If the results are abnormal
in at least two tests, further
andrological investigation is indicated
European guidelines
Parameter Reference value
Semen volume (mL) 1.5 (1.4-1.7)
Sperm concentration 15 million/ml
Total motility (PR +
NP)
40%
Progressive motility 32 %
Vitality (live
spermatozoa, %)
58
Sperm morphology
(normal forms, %)
>4%
pH >7.2

Terminology to describe sperm pathology
Oligozoospermia
• Describes number abnormality
• Anything less than 15 million/ml is
oligozoospermia
Asthenozoospermia
• Describes motility abnormality
• Atleast 32% of sperm should show
progressive motility
• Asthenozoospermia: < 32% progressive
motile spermatozo
Teratozoospermia
• Condition characterized by the presence of
malformed spermatozoa in the semen
• Teratozoospermia: < 4% normal forms
Oligoasthenoteratozoospermia
• Abnormalities in all 3 variables
(number, motility and
morphology)
Azoospermia
• No sperm found in semen
sample on at least 2 tests
Aspermia
• No semen at all

Age and Declining Semen Quality
Eskenazi B, et al. Human Reproduction, 2003

Smoking and Poor Semen Quality
Ramlau-Hanen CB, et al. Human Reproduction, 2007

• exposure to cigarette smoke generates high levels of oxidative stress,
directly increasing both seminal leukocyte concentrations and seminal
ROS generation and decreasing seminal levels of the antioxidant enzyme
SOD
• Men who smoke also have decreased measures of sperm quality, including
decreased sperm counts, motility and morphologically normal sperm
International Journal of Urology (2009) 16, 449–457

• High amounts of alcohol intake have
also been shown to increase systemic
levels of oxidative stress

Oxidative Stress (OS)
• OS - Imbalance between the production of reactive oxygen species (ROS) and the scavenging
capacity of available antioxidants resulting in redox paradox
• Free radicals/oxidants (ROS):
– Highly reactive
– Steals electron from neighboring molecules
• Antioxidant: Molecules that neutralize free radicals (e.g. glutathione)
J Hum Reprod Sci 2019;12:4-18.
Free
radicals
Anti
oxidants
Normal Oxidative stress

Worldwide incidence of Male oxidative stress infertility in infertile
men
World J Mens Health. 2019 Sep; 37(3): 296–312
Oxidative stress might lead to an
impaired spermatogenesis and
therefore to infertility.

Some ROS activity in sperms is a necessity
• Sperm
capacitation
1
• Acrosomal
reaction
2
• Membrane
fusion
3

https://doi.org/10.1111/j.1442-2042.2009.02280.x
Reactive oxygen species and antioxidants
• ROS are products of normal cellular metabolism.
• The majority of energy produced by aerobic metabolism utilizes oxidative phosphorylation within
mitochondria.
• During the enzymatic reduction of oxygen to produce energy, free radicals (one or more unpaired
electrons) form as a byproduct.
• This electronic structure makes oxygen especially susceptible to radical formation. For example, the
addition of an extra electron to molecular oxygen (O2) forms a superoxide anion radical (O2
‐), the primary
form of ROS. This superoxide anion can then be directly or indirectly converted to secondary ROS such as
the hydroxyl radical (•OH), peroxyl radical (ROO•) or hydrogen peroxide (H2O2).
• Free radicals induce cellular damage when they pass this unpaired electron onto nearby cellular
structures, resulting in the oxidation of cell membrane lipids, amino acids in proteins or within nucleic acids

Where can oxidative stress strike?
• Sperm DNA
1
• Sperm mitochondria
2
• Sperm membrane
3

Why are sperms susceptible to ROS damage?
Sperm cytoplasm
contains low levels of
scavenging antioxidant
enzymes
Plasma membrane rich
in unsaturated fats
+
This combination of susceptibility to lipid peroxidation
along with a relative lack of vigorous intracellular defense
mechanisms is exacerbated by the autogenous production
of ROS by spermatozoa.

Oxidative stress–mediated damage
Oxidative stress–mediated damage to sperm
membrane may account for defective sperm
function observed
in high proportion of infertility patients1,2
Oxidative stress affects fluidity of sperm plasma
membrane and integrity of DNA3
May accelerate decline in sperm counts
associated with male infertility
1 Iwasaki A, et al. Fertil Steril 1992
2Aitken RJ, Reprod Fertil Dev 1994
3Aitken RJ, J Reprod Fertil 1999

Possible mechanism – abnormal spermatozoa causes damage
https://www.sciencedirect.com/science/article/pii/B9780128125014000067

Contradictory role of ROS in spermatogenesis

Outcome of oxidative stress

Evidence of ROS mediated effects in idiopathic MFI
• Studies have demonstrated that 25%–88% of nonselected infertile patients have high levels of
seminal ROS1,2
• Infertile males generating high levels of ROS 7x less likely to initiate pregnancy compared with
those with low levels of ROS3,4
1 Lewis SE, et al. Fertil Steril 1995
2JSharma RK, et al. Hum Reprod 1999
3Aitken RJ, et al. Am J Obstet Gynecol, 1991
4Agarwal A, et al. Fertil Steril, 2005

• State of OS can be evoked not only by intrinsic factors but also by a diversity of
environmental agents commonly encountered during modern life
• Presence of OS in the male reproductive tract is strongly and positively correlated with
reduced sperm motility and fertilizing potential, thus providing a rational target for the
development of new therapeutic interventions
Antioxidants (Basel). 2020 Feb 4;9(2). pii: E134

• OS is now considered as the main cause of male infertility
• Despite the need for low levels of ROS for the physiological function of sperm, its increased level
disturbs sperm functions, thereby leading to male infertility
• Therefore, early diagnosis of infertility is necessary to prevent its irreversible damage due to the OS in
the long term
• Besides, the lifestyle change is the primary action to balance levels of ROS and antioxidants in the
body and prevent oxidative stress
• Reduced smoking and alcohol, non-exposure to radiation, and selection of a proper diet along with
planned physical activity have significant effects
• Moreover, the use of oral antioxidants can also help to reduce OS
Cell Mol Life Sci. 2020 Jan;77(1):93-113

• Sperm DNA damage is significantly
increased in men with idiopathic
male factor infertility and in men
who failed to initiate a pregnancy
after assisted reproductive
techniques.
• Such an increase may be related to
high levels of seminal oxidative
stress.

Role of Antioxidants in
male infertility

Antioxidants in semen
• bilirubin, thiols, uric acid, and coenzyme Q10
• superoxide dismutase, catalase, glutathione peroxidase
Endogenous antioxidants
• vitamin C, vitamin E,
• beta-carotenes, carotenoids, flavonoids
Dietary antioxidants
• albumin, ceruloplasmin, metallothionein, transferrin, ferritin, myoglobulin
Metal-binding proteins

Nutritional supplements – Why???
Nutrional supplements with
antioxidant capacity
Prevents ROS-mediated damage
to sperm function
Helps improve
• Sperm parameters like
motility morphology
• DNA damage
• And further overall fertility
potential

Coenzyme Q10 (CoQ10)
• Naturally-occurring compound found in every cell of the body
• Also known as ubiquinone
• Found in foods, particularly in fish & meats
• In sperm cells
• Most CoQ10 is concentrated in mitochondria of mid piece
• And energy dependent processes in sperm cell depend on availability of CoQ101
• CoQ10 in seminal fluid >> a direct correlation with semen parameters2
Comhaire F, et al. Andrologia. 1995;27(4):217-21/ Beyer RE, et al. Chem Scripta. 1987; 27: 145-58
1. Lewin et al. Mol Aspects Med, suppl., 1997; 18: S213; 2. Mancini et al. Hormon Metab Res 2005; 37: 428.

CoQ10 role
• Deficiency >> can result into sperm damage, lower sperm motility and sperm count
• Sperm cells: CoQ10 is concentrated in mitochondria
• Responsible for energy for movement & all other energy-dependent processes in sperm cell
• Exerts an important role against oxidative damage of polyunsaturated fatty acids of the lipid
bilayer
Balercia G, et al. Andrologia. 2002; 34(2): 107-11.

Coenzyme Q10: self-nanoemulsifying delivery system (SNEDDS)
• CoQ10 is practically water insoluble and has relatively high molecular weight (863 Daltons)
• Its oral bioavailability is very low or negligible
• Self-nanoemulsifying delivery system (SNEDDS), ensures that the formulation contains Coenzyme
Q10 in dissolved state
• It is similar to patented Vesisorb technology
• Research has shown that vesisorb based CoQ10 is at least 5 times superior in providing amount
Data on File

SNEDDS – Plasma profile compared to patented technology
(vesisorb)
Data on File
A – sunpharma product; B - Vesisorb
In vivo pharmacokinetic studies
between SNEDDS and Hi-strength
CoQ10 soft capsules (manufactured
by Vesisorb technology) has
demonstrated identical plasma
profile

Melatonin
• Indoleamine produced mainly by the pineal gland
• Has a potent free radical scavenger activity with subsequent antioxidant and antiapoptotic
functions
• Can also have an indirect action as antioxidant through activation of endogenous antioxidant
enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT)
Biol Signals Recept. 2000; 9(3-4): 137-59.

Possible associations between disturbances of oxidative/antioxidative balance and
oxidative protein modification in human seminal plasma
JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2017, 68, 5, 659-668

Advanced oxidation protein products(AOPP) and male fertility
• Lower amounts of advanced oxidation protein products are associated with high melatonin
levels in the seminal plasma of fertile men
• In infertile patients diagnosed with azoospermia and teratozoospermia, significantly elevated
levels of AOPPs were associated with reduced levels of melatonin
AOPPs
Influences normal
development of
spermatozoa
infertility

Seminal gelatinases and male fertility
• The reduction of MMP-9 activity
might benefit semen quality and
fertilizing potential
• In the study by Kratz et al. the
ratios of MMP-9/TIMP-1 and
MMP-2/TIMP-2 were
significantly higher in all groups
of childless men than in
normozoospermic fertile men
TIMP – tissue inhibitor of matrix metalloproteinases
TIMP
MMP
Antioxidant
Regulation of Male Fertility
(Semen quality +
Reproductive Potential)
Melatonin

Melatonin : regulates testosterone secretion
• Melatonin directly regulates testosterone secretion , increases the
responsiveness of Sertoli cells to FSH during testicular development and
modulates cellular growth, proliferation, and the secretory activity of
several testicular cell types
Int. J. Mol. Sci. 2017, 18, 1170

Action on HPA axis
Current Molecular Medicine 2015, 15, 1-13

Action on Somatic cell of testis
• Key player in regulation of testicular pathophysiology
Int. J. Mol. Sci. 2017, 18, 1170
• Local modulator of endocrine activity
• Hence would affect testosterone production
Leydig cells
• Influences cellular growth, proliferation, energy
metabolism and oxidation state
• Consequently may regulate spermatogenesis
Sertolli cells

Action on Somatic cell of testis
Male fertility and the process of spermatogenesis
are strongly dependent on Sertoli cells function,
we can speculate that melatonin acts as an important modulator
In the progression of germ cells to spermatozoa.
Int. J. Mol. Sci. 2017, 18, 1170

Melatonin : In idiopathic infertility,
• In patients with idiopathic infertility, melatonin exerts anti-proliferative
and anti-inflammatory effects on testicular macrophages, and provides
protective effects against oxidative stress in testicular mast cells.
• Melatonin is also involved in the modulation of inflammatory and
oxidant/anti-oxidant states in testicular pathology
Int. J. Mol. Sci. 2017, 18, 1170

Int. J. Mol. Sci. 2017, 18, 1170

World J Mens Health. 2020 Jan 20. doi: 10.5534/wjmh.190145
CoQ10 dosage – 200mg/d
• 65 infertile patients with idiopathic OA and forty fertile men (control) were included
• Patients received CoQ10 for 3 months
• Seminal plasma CoQ10, total antioxidant capacity (TAC), total reactive oxygen species (ROS),
glutathione peroxidase (GPx), and SDF (sperm DNA fragmentation) levels were measured in
controls (baseline) and infertile patients pre- and post-CoQ10 treatment

SDF was significantly higher
(p<0.01) in patients with
idiopathic OA compared to
the fertile controls, and
treatment with CoQ10
significantly decreased the
percentage of SDF (p<0.01).
Results
Improved sperm concentration (p<0.05),
progressive motility (p<0.05), and total
motility (p<0.01) compared to baseline
Significantly improved seminal
CoQ10 level (p<0.001), TAC
(p<0.01), and GPx (p<0.001)
levels, whereas it decreased
the total ROS levels (p<0.05)

Conclusion
• CoQ10 can attenuate ROS effects and enhance sperm functions owing to its antioxidant
activity
• Study affirms that supplementation with CoQ10 for the duration of least three months decreases
SDF and improves semen quality and seminal antioxidant capacity in OA men

Lewin A, et al. Mol Aspects Med. 1997; 18 Suppl: S213-9
CoQ10: Lewin A, et al
• Improvement in sperm functions in asthenospermic men
0
10
20
30
40
Coenzyme
Q10
Control group
35.7
19.1
Improvement
(%)
Mean increase in motility: Coenzyme Q10 vs.
control group
Coenzyme Q10: Improvement in fertilization rate
0
5
10
15
20
25
30
Baseline Day 103
Improvement
(%)

Coenzyme Q10-Clinical Evidence: Meta-analysis R. Lafuente et al
• Three trials were included:
– 149 males in CoQ10 group and
– 147 males in placebo group
Results
• Receiving CoQ10 treatment, a statistically significant increase in:
– CoQ10 seminal concentration
– Sperm concentration
– Sperm motility
J Assist Reprod Genet (2013) 30:1147–1156

Coenzyme Q10-Clinical Evidence: Meta-analysis R. Lafuente et al
J Assist Reprod Genet (2013) 30:1147–1156

Melatonin- Clinical Evidence : Ewa Maria Kratz et al
• Teratozoospermic and azoospermic - Samples from 66 infertile men
• Control - 37 normozoospermic fertile men aged 27–46 years
• Seminal plasma melatonin levels were approx. 30% higher in normozoospermic
fertile men than in samples from infertile men (P<0.0001)
Reprod Fertil Dev. 2016 Mar;28(4):507-15.
Decreased levels of melatonin together with elevated AOPP altered the oxidative–antioxidative balance in
the ejaculate, thereby reducing fertility.

Sperm count, percentage of motile
spermatozoa and the proportions of
normally formed spermatozoa with
melatonin were significantly higher
than placebo
N = 54 patients who were mildly
oligospermic (sperm count: 5–15
million) and could not have a child for
at least 1 year were included in the
study and for whom subinguinal
varicocelectomy was planned

There was a significant increase in total
antioxidant capacity in melatonin group
compared with placebo
Results & Conclusion
Melatonin therapy adds extra benefit to varicecelectomy in terms of sperm
parameters, peripheral blood inhibin B and total antioxidant capacity

Melatonin- Clinical Evidence: Bejarano et al
• Semen was obtained from thirty men (20-50 years old)
• Males were administrated with 6 mg melatonin/day for 90 days before the follicular puncture.
• Oocytes were inseminated with sperm, and fertilization results were assessed
Bejarano I etal Exogenous melatonin supplementation prevents oxidative stress-evoked DNA damage in human spermatozoa

Results
Concentration of urinary aMT6-s was clearly
increased on patients taking melatonin and,
therefore, it is most likely that serum concentration of
melatonin was also increased
TAC assay showed significantly higher levels of
urinary antioxidants not only after 45 days but also
after 90 days of melatonin supplementation

Results
• TUNEL assay is a commonly used technique to determine DNA damage in human sperm
%
Apoptotic
Cells

Results
Couples whose males were given melatonin showed a statistically significant increase in the percentage of
grade A(top quality embryos), B (good quality embryos) and C (impaired quality embryos) embryos at the
expense of grade D embryos(not recommended for transfer) which were clearly reduced

Conclusion
Melatonin supplementation not only improves sperm quality, but also
enhances oocyte quality.
Improves human sperm quality, which is essential to achieve successful
natural and/or assisted reproduction outcome
Giving melatonin to both members of an infertile couple may be of great
assistance in determining successful pregnancies

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