Chapter

Insights of Sperm Pathology and

Its Association with Infertility
Mohd Sajad and Sonu Chand Thakur

Abstract

This section considers the structural characteristics of spermatozoon, its assem-

bly, composition, and mechanism behind regulation of their peculiar function.
The spermatozoon is tremendously peculiar cell with an arrangement of structural
characteristics which furnish it with remarkable capability of carrying the genome
of male to the egg. A variety of genes are only expressed in spermatids and result in
the formation of proteins that are very crucial and distinctive to spermatozoa. These
proteins package the DNA, form the head of sperm, account the component of
matrix and enzymes of acrosome, construct the flagellar structure, and work as ion
channels that are associated in modulating the motility of sperm and also become
adenylyl cyclase which yields cyclic adenosine monophosphate (cAMP) to induce
signaling effect which regulates the function of spermatozoon. These proteins are
critical essential to sperm and, sometimes, mutation inhibits their synthesis or
disrupts their function which leads to male infertility. Researchers are trying to
identify those proteins that are significant for proper function of sperm through
gene knockout approach in mice that are probable to be necessary in humans as
well. However, various questions still persist regarding the spermatozoon composi-
tion, organization, and function and need to be answered.

Keywords: sperm, spermatogenesis, ROS, infertility, oxidative stress, motility

1. Introduction

Male reproductive function can be divided into three subdivision: (i) hormonal
balance of male reproductive function (ii) spermatogenesis, development of sperm;
and (iii) fulfill of male sexual act.
Spermatogenesis begins within the seminiferous tubules of testis through the
successive mitotic, meiotic and post meiotic phases which results in the formation
of spermatozoon, the end product of this process. To expand the spermatogonial
population, the germ line stem cell during the mitotic phase undergo a series of
division which culminates into two meiotic division and formation of haploid
spermatids without the replication of DNA. For the development of male gam-
etes these two phases are very significant. During this phase the remodeling of
spermatids occurs extensively into sperm by acrosome formation, condensation
of nucleus, development of flagella and loss of cytoplasm. The head and flagel-
lum are the two-substantial component of sperm. These two components are
joined together by a connective piece. The head carries the nucleus, cytoskeleton
element and cytoplasm. It comprises various types of enzymes homogeneous to

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lysosomes of a typical cell, including hyaluronidase (having the ability to digest

proteoglycan filaments of tissue) and powerful proteolytic enzymes which can
digest proteins having an important role in the process of oocyte fertilization.
The flagellum is divided into three regions: mid piece, principle piece and termi-
nal piece. A central complex of microtubules covered by outer dense forms the
axoneme. Mitochondria are present in the mid piece which surrounds the outer
dense fibers and neighboring axoneme. The principle part of the flagellum is
mostly comprised by the existence of fibrous sheath which surrounds the dense
fibers and axoneme. In higher vertebrates these dense fibers and fibrous sheath are
developed due to internal fertilization and these are cytoskeletal material of sperm
flagellum [1]. The plasma membrane as in sperm head surrounds the flagellum
tightly and contains scattered cytoplasm. Invertebrate’s sperm usually have an
acrosome in the head region and mitochondria and an axoneme in the flagellar
region but the accessory or additional cytoskeletal elements are absent [2]. To
achieve the fertilization the acrosome, have an enzyme which plays a key role to
penetrate into egg. The flagellum of the sperm contains the source of energy that
generates sperm motility required to reach the egg. All these characteristics of
sperm are necessary to deliver the genetic material exists in sperm nucleus to egg.
After that, zygote is formed by the fusion of haploid pronuclei of male and female,
and thus development initiates. In most mammals, the nucleus of haploid sperm
carries the sex chromosome decides the sex of resulting animals [3]. The genome
of both maternal and paternal parents is essentially required to proceed the normal
development, generally due to distinctive genes imprinting in males and females
during gametogenesis [4, 5].
This chapter gives center of attention on the unique features of mammalian sper-
matozoa with especial consideration to molecules presently known that enrich to the
structure and function of sperm. The main topics contemplated are; physiology of
male sexual organ, spermatogenesis, sperm count, heritable effect on human sperm
structure, regulation of sperm motility, effect of oxidative stress on male reproduc-
tive system, sources of reactive oxygen species in seminal plasma, physiological role
of ROS in seminal plasma, consequence of Oxidative Stress on male Reproductive
System, management and prevention of oxidative stress, correlation between biol-
ogy of male reproduction and sleep and role of inflammation in infertility.

2. Physiology of male sexual organ

The favorable outcome of male reproductive system depends mainly upon the
cohesive function of vast array of tissues. It comprises of assembly of sperm in the
testes, sperm maturation in epididymis, secretion of seminal fluid by addition sex
glands, deliver sperm into the reproductive tract of female, erection of penis, emis-
sion and final ejaculation. Fertilization of the egg requires the motility of sperm,
successful capacitation and acrosomal reaction. These entire needs are dependent
directly or indirectly on the secretion of testosterone hormone by the Leydig cells.
The testis of male is comprised of up to 900 coiled seminiferous tubules, in which
the sperm is formed and each seminiferous tubule exceeds up to 1 meter long in
average. The sperm then discharged into one more coiled tube which is about
6-meter long known as epididymis. The epididymis enlarges into vasa deferens
that infiltrates into prostate gland. There are two seminal vesicles and the material
(Is secreted) from both the ampulla and seminal vesicles. The excretion from both
the prostate gland and seminal vesicles enters into the ejaculatory duct through the
body of prostate gland and then vacant into the internal urethra. Mucus released

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from urethral gland and more from bilateral bulbourethral glands which is located
near to urethra is supplied to urethra [6].

3. Spermatogenesis

The process of spermatogenesis takes place in each of the testis tubules. In

this process the spermatozoa are produced by the population of germ cells (sper-
matogonia) through process of mitosis and meiosis. This entire spermatogenesis
process starts during the onset of puberty and last till the old age. This process
involved various stages starting with germ cells formation in the germinal epithe-
lium and followed by continuous development into primary and secondary sper-
matocytes. These spermatocytes finally developed into functional spermatozoa.
Spermatogenesis is extremely well-ordered process; male germ cells proliferate and
differentiate rapidly and the modulation of spermatogenesis occurs at the extra
testicular and intra testicular level and can be dispersed ubiquitously. As aforemen-
tioned, spermatogonia originated from the primordial germ cells that migrate into
the genital ridge of the indifferent gonads, during embryo development and are
present in two to three layers in seminiferous tubules. At puberty, the spermatogo-
nia starts mitotic division, proliferate and differentiate continuously to form mature
sperm cells [7] (Figure 1).

Figure 1.
General characteristics of germ.

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3.1 Steps of spermatogenesis

The process of spermatogenesis starts at an average age of 12–13 years, continues

throughout the remaining life, and markedly decreases during the older age. During
the initial stage of spermatogenesis, the spermatogonia shift toward the central

Figure 2.
Steps of spermatogenesis.

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lumen of seminiferous tubules. The Sertoli cells are part of a seminiferous tubule
and support the process of spermatogenesis. Its main function is to nourish the
developing sperm cells throughout the stages of spermatogenesis. Sertoli cells con-
trol the entry and exit of nutrients, hormones and other substances into the tubules
of the testis. The Sertoli cells are also responsible for establishing and maintaining
the spermatogonial stem cell niche, which ensures the renewal of stem cells and
the differentiation of spermatogonia into mature germ cells, that progress stepwise
through the long process of spermatogenesis, ending in the release of spermatozoa.

3.2 Meiosis

Spermatogonia which are able to pass across Sertoli cell layer change and grow
in size progressively into primary spermatocytes. The two secondary spermatocytes
are formed by meiotic division from the primary spermatocytes. These secondary
spermatocytes, also divide to produce spermatids that transform into sperm after
a period of time. During the process of spermatocyte to spermatid stage trans-
formation, the 23 pair of chromosomes (46 chromosome total) of spermatocytes
also divides, and as a result, 23 chromosomes go to one spermatid and the rest 23
chromosomes to the other spermatid. It takes about 74 days to complete the entire
process of spermatogenesis, from spermatogonia to spermatozoa [6] Figure 2.
Suggested: Round and elongated spermatids will differentiate into mature sperma-
tozoa, by the process of spermiogenesis.

4. Sperm motility

Motility of sperm cells is provided by the back-and-forth movement of tail

and it results from rhythmic longitudinal sliding motion between the anterior and
posterior tubules [8]. Different molecular markers of sperm, such as mitochon-
drial membrane potential (MMP), DNA fragmentations and ROS have presently
concluded as reliable estimators of sperm function that can be used to evaluate the
quality of the sperm [9]. Due to the overloading of ROS, osmatic stress is increased
which in turn decreases the MMP and increases the fragmentation of DNA, affect-
ing the viability of sperm [10]. It is broadly accepted that motility of sperm mainly
depends upon ATP which is produced by the mitochondria. The latest is located
in mid piece of spermatozoa, which explains the correlation between motility and
mitochondrial membrane potential [11, 12].

4.1 Sperm count: how much is considered normal?

The spermatozoon is the cell of male reproductive system. Sperm count, also
known as sperm concentration, is the parameter to measure the number of sperm
cells in the ejaculate. During each coitus the quantity of ejaculated semen in aver-
age, is about 3.5 milliliters, and 120 million sperm might be present in average in
each milliliter of semen. However, in normal males this count can vary from 35 to
200 million. In several milliliters of each ejaculated semen, an average of total of
400 million sperms might be present. When the sperm count is less than 20 million
in 1 milliliter (ml), it might point to infertility. A relatively high sperm count might
elevate the chances of conception [6].
There are several causes of infertility in males such as genetic factors like crypt-
orchidism, congenital absence of vas deferens, karyotype abnormalities and some
acquired factors like trauma, varicocele, medication, urogenital infection, inflam-
mation, testicular torsion and idiopathic factors.

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Semen deficiencies are termed as

a. Oligospermia or oligozoospermia—lower than normal number of spermatozoa

in semen.

b. Aspermia—complete lack of semen.

c. Azoospermia—absence of sperm cells in semen.

d.Hypospermia—reduction in the seminal volume.

e. Teratospermia—abnormal morphology of sperm cells.

f. Asthenozoospermia—reduced motility of sperm.

4.1.1 Oligospermia

Oligospermia, is one of male infertility causes, defined as low concentration

of sperm cells in the ejaculate. Semen with decreased concentration of sperm
may often depict considerable abnormalities in morphology and motility of sper-
matozoa. Low sperm count may be due to an endocrinopathy such as varicocele,
prolactinoma or it may be a genetic cause. In about 6 and 15% of patients with
severe low sperm count or azoospermia (respectively), microdelitions can be found
in azoospermic factor (AZF) region of Y chromosome. AZF refers to one of several
proteins or their genes, which are coded from the AZF region located in the human
male Y chromosome. Deletions in this region are associated with inability to pro-
duce sperm. Subregions within the AZF region are AZFa, AZFb and AZFc, located
in the long arm of Y chromosome [13]. By cytogenetic analysis, chromosomal
abnormalities were detected in 2% of men having low sperm count and 15–20%
with no sperm count. These abnormalities include translocation of nonsex chromo-
some and Klinefelter syndrome [14].

4.1.2 Asthenozoospermia

Asthenozoospermia, low sperm motility, could be derived due to:

A. Inborn metabolic deficiency (such as Kartagener’s syndrome or immotile cilia

syndrome—ICS).

B. Abnormal ultrastructure of the sperm flagellum: as primary ciliary dys-

kinesia; spermatozoa consist of altered peri-axonemal structure but have
normal axoneme. Densed individual fibers are extended abnormally along
the axoneme, location and number of longitudinal columns of fibrous
sheath are modified and change in the order of termination of these
structures [15].

Sperm with the following syndromes: abnormal axoneme, partial or complete

lacking of dynein (a family of cytoskeletal motor proteins that move along microtu-
bules in cells and convert the chemical energy stored in ATP to mechanical work),
lack of central sheath and lack of inner arms might be unable to show motility;

C. Necroozospermia—binding of antisperm antibodies or an increase in

white blood cell concentration in the ejaculate, which later results in the

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overproduction of reactive oxygen species, might lead to damages in the

spermatozoa [16].

D. Dysplasia of fibrous sheath spermatozoa: spermatozoa with very short, thick,

rigid and immotile tail, mainly due to disorganized and hyperplastic fibrous
sheath [17, 18].

5. Heritable effect on human sperm structure

The hereditary condition which causes the defects in the flagella of sperm is
termed as Kartagener’s syndrome, immotile cilia syndrome (ICS), or primary ciliary
dyskinesia (PCD). It often leads to chronic respiratory problems, male sterility and
situs inversus [19]. These states are linked directly or indirectly with the autosomal
recessive traits. The aforementioned conditions make the flagella unable to show
normal movement. Sperm with these syndromes have abnormal axoneme lacking
dynein arm partially or completely, lack of central sheath, lack of inner arms [20].
Due to variety of defects presented in sperm and cilia, many genes are mutated and
contribute to the syndrome [21]. Another flagellar defect characterized by severe
asthenozoospermia is familiar as dysplasia of fibrous sheath. In this type of disor-
der, the sperm have disorganized and hyperplastic fibrous sheath, and very short,
thick, rigid and immotile tail [17, 18]. Another flagellar defect which appears in
sperm cells of infertile men is known as flagellar dyskinesia [15]. This type of defect
was observed in brothers and has been suggested that it arises due to the genetic
abbreviation [22]. The sperm consist of altered peri-axonemal structure but have
normal axoneme. Densed individual fibers are extended abnormally along the axo-
neme location and number of longitudinal columns of fibrous sheath are modified
and else, there are changes in the order of termination of these structures [15].

6. Regulation of sperm motility

Sperm depicts two kinds of motility:

a. Progressive motility—typical for newly ejaculated sperm.

Spermatozoa acquire the ability of progressive motility in the epididymis.

Relatively symmetrical motion of flagella which leads to forward movement has
been shown in this type of motility [23].

b. Hyperactivated motility—after sometimes either in reproductive tract of

female or in culture, sperm achieves the hyperactivated motility that is char-
acterized by whip like beating of flagellum, asymmetrical flagellar bends and
circular swimming [24].

6.1 Activation of motility

It is broadly acquired that precious motility of sperm is the chief component of

fertility of male. During the beginning of progressive motility and origin of hyper
activation of sperm, key factors are involved. These key factors are calcium (Ca2+),
cyclic adenosine monophosphate (cAMP) and bicarbonate (HCO3−). Olfactory
and GABA receptors are the possible candidates which trigger the progressive and
hyperactivated motility of sperm.

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6.2 Role of calcium in motility

Calcium plays a key role in sperm function by different aspects. Recent studies
have been demonstrated that in knockout mice there are at least four components
participate in the intracellular regulation of calcium level and initiation of sperm
motility. These are CatSper1, CatSper2, Cav2.3 and PMCA4. CatSper1 are localized
in the principle piece of sperm and it is a voltage gated Ca2+ channels of the testis.
Lacking or any mutation in CatSper1 gene reduces the progressive motility and
causes infertility. A sperm cell that lacks the CatSper1 showed progressive motility
but failed to develop hyperactivated motility [25]. CatSper2 present in flagellum
shows similarity to CatSper1 and it is also a voltage-gated ion channel. Sperm of
mice having knockout CatSper2 gene depict decreased flagellar amplitude and also
failed to develop hyperactivated motility [26]. Disruption of gene for PMCA4, that
have Ca2+/calmodulin dependent ATPase activity involve in efflux of Ca2+, also
causes infertility in men. In developing sperm cells and sperm flagellum the cyclic
nucleotide gated Ca2+ channels are present. The role of these channels is to regulate
the influx of calcium in various micro domains of the flagella [26].

6.3 cAMP and motility

During sperm motility regulation, cAMP is the second key messenger. Adenylate
cyclase converts the ATP into cAMP. Thus, the level of cAMP increases and in turn
activates the cAMP dependent kinase A (PKA) which phosphorylates the serine
and threonine residues in the flagellum, which ultimately causes the phosphoryla-
tion of tyrosine residues in the proteins [27, 28]. In most cells the adenylyl cyclase is
activated by G protein in response to external stimuli. In mouse sperm the plasma
membrane bounds (mACs) activated by G protein take a part in the acrosome
reaction, and in chemotaxis and hyperactivation in human sperm [29]. It was

Figure 3.
Signalling pathway showing regulation of motility of sperm in mammals.

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demonstrated that HCO3− and Ca2+ are inculpated in cAMP regulated activation of
sperm motility. The activity of soluble adenylyl cyclase is augmented by HCO3− with
increased activation of enzymes (adenylyl cyclase) and by reducing the substrate
inhibition that happens at higher concentration of ATP-Mg2+. Due to low level of
HCO3−, activity of soluble adenylyl cyclase would be reduced in sperm by substrate
inhibition stored in epididymis [30].

6.4 PKA and motility

PKA causes the phosphorylation of tyrosine residue of flagellar proteins. The pro-
teins anchoring with PKA site (AKAP3, AKAP4 and TAKAP-80) in the fibrous sheath,
point out that the main role of this structure is to bind PKA in the principle piece of
flagellum [31]. Regulatory and catalytic subunits are present in PKA holoenzyme.
Four genes (RIα, RIβ, RIIα and RIIβ) are present in regulatory subunits (R subunit) in
human and mouse; three catalytic (C subunit) Cα, Cβ and Cγ in human, and two C
subunit Cα and Cβ in mice. The cAMP binding site are present in R and C subunits. C
subunits is released when cAMP binds to R subunits and their catalytic site is activated
by cAMP. The R and C subunits are involved in the motility of sperm (Figure 3).

7. Effect of oxidative stress on male reproductive system

Oxidative stress is a state which causes disproportion between systemic reac-

tive oxygen species and detoxifying capability of biological system to neutralize
the reactive intermediates, also called antioxidant defenses. Spermatozoa have
antioxidant defense mechanism that quench the ROS and therefore protects the
cells of gonads and mature spermatozoa from oxidative damage [32]. Statistics from
United States depicted that the major cause of male infertility is ROS. In 30–40%
of infertile men’s seminal plasma, there is an increase in the level of ROS [33]. In
spermatozoa ROS are generated by two methods.

1. At the level of sperm plasma membrane—by nicotinamide adenine dinucleo-

tide phosphate oxidase system.

2. At the level of mitochondria—by nicotinamide adenine dinucleotide-­

dependent oxidoreductase reaction [34].

The production of ROS at the level of mitochondria is the chief source. Large
concentration of mitochondria is present in spermatozoa because of a constant need
of energy to spermatozoa for motility. In semen, presence of nonfunctional sper-
matozoa considerably increases the level of ROS that in turn impair the function of
mitochondria and motility of sperm. In human spermatozoa, ROS which is produced
in large concentration is O2−. It reacts with itself to generate H2O2 by dismutation.
H2O2 and O2− generates most destructive and reactive OH− by Haber-Weiss reaction
in the presence of iron and copper. OH− affects the function of sperm by disrupting
the fluidity of membrane [35, 36]. Recent studies depicting that O2 production in
spermatozoa showed the presence of calcium dependent NADPH oxidase also called
NOX5 has been residing in acrosomal and midpiece region of spermatozoa [37].
Initially the NOX5 resides in human testis. It is activated upon binding of calcium to
its cytosolic domain and causes conformational changes in cells [35]. ROS is generated
during the normal metabolism of cells. Under physiological conditions the mitochon-
drial respiration is the chief source of superoxide anion radicals. Quality of sperm and
function is affected by the high concentration of ROS and is potentially toxic.

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8. Sources of reactive oxygen species in seminal plasma

The production of ROS in the seminal plasma originated from different endoge-
nous and exogenous pathways. Ejaculate of human contains varieties of mature and
immature cells, epithelial cells, leukocytes and round cells. Of these, leukocytes,
immature spermatozoa, macrophages and neutrophils are considered to be the main
endogenous source. Others life style practices as: excessive alcohol consumption,
smoking and environmental factors (e.g., toxins and radiations) may contribute to
exogenous ROS production [38–40].

8.1 Endogenous sources of ROS

8.1.1 Leukocytes

Peroxidase-positive leukocytes include polymorphonuclear leukocytes in about

50–60% and macrophages 20–30%. Peroxidase-positive leukocytes originates in
large proportion from prostrate and seminal vesicles of male. These main sources
of ROS are activated by different intracellular and extracellular responses such as
inflammation and infection. The latest can produce 100 times reactive oxygen spe-
cies than normal and also increase the secretion of NADPH through hexose mono-
phosphate shunt [41, 42]. There is a decrease in the level of antioxidant superoxide
dismutase and an increase in the concentration of proinflammatory cytokines,
which can lead to the increased level of ROS and respiratory burst ultimately lead-
ing to formation of oxidative species OS. OS will than cause the damage of sperm
if the concentration of seminal leukocytes is abnormally high [43]. Although in
phagocytic clearance and immuno surveillance of unhealthy (abnormal) sperm,
leukocytes and ROS play a decisive role. Inflammatory changes are depicted in
the testes of smokers due to increased concentration of leukocyte activated free
radicals. These leukocytes overcome the protective action of antioxidants and lead
to oxidative stress. OS causes severe single and double stranded breaks in DNA by
changing sperm chromatin integrity, modification of bases, deletions and rear-
rangement of chromosome [7].

8.1.2 Immature spermatozoa

During the process of spermatogenesis, the developing spermatozoa expel their

cytoplasmic content to prepare itself for the process of fertilization. Due to the
arrest in spermiogenesis, the abnormal spermatozoa retained excess of cytoplasm
around the midpiece. This condition is referred as excess residual cytoplasm (ERC).
By virtue of hexose monophosphate shunt the ERC activates the NADPH system,
which is used as a source of electron by spermatozoa for production of ROS and OS
[30]. Therefore, ERC affects the morphology, motility and fertilization potential of
sperm which can lead to infertility [44].

8.1.3 Varicocele

Varicocele is a condition of abnormal enlargement of vein in scrotum, i.e., in the

plexus pampiniformis situated throughout the spermatic cord. It is considered to be
an etiology of male infertility, because varicocele is found in 19–40% of male part-
ners in infertile couples. Current evidence suggested that oxidative stress is the cen-
tral element contributing to infertility in men with varicocele [45]. Varicocele arises
when damage occurs in valves into the spermatic vein(s) resulting in dysfunction
and retrograde blood flow into scrotum from abdomen creating an inappropriate

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environment for development of sperm. Several studies reveal that oxidative stress
also leads to varicocele in male, which occurs due to decrease in the concentration
of antioxidants. It results in the deterioration of structure of cell membrane and
in the DNA integrity. Nitric oxide is a lipophilic molecule which is presented in the
spermatic vein of varicocele patient. Both NO and superoxide might cause a damage
in spermatozoa [46].

8.2 Exogenous sources of ROS

8.2.1 Radiation

Radiation, a natural source of energy, has a considerable effect on humans.

Several studies have been depicted that radiation emitted from mobile phone
increases the concentration of ROS in human semen resulting in impaired sperm
quality [47, 48]. In vitro studies showed that in human, spermatozoa electromagnet
radiation urges the production of ROS and damages of DNA. These changes fur-
ther diminish the vitality and motility of sperm cells [49]. Due to the presence of
varieties of charged molecules in the cytosol the flow of electron along the internal
membrane of cells can be negatively affected by these radio frequency electro-
magnet radiations, and therefore interferes with the functions of the cell and the
organelles [50].

8.2.2 Toxins

Toxins which are discharged from industrial products and structural materi-
als accumulates in the body of human and increases the production of ROS in the
testes. This might result in the negative impact on the structure and function of
sperm [51]. Phthalates which are found in the plastics objects used for industrial
and domestic’s purpose have been found to impair the spermatogenesis process
and causes DNA damages in spermatozoa. Moreover, it has been studied that those
laborers who were continuously exposed to metal toxins such as chromium, mer-
cury, manganese and cadmium were more probable to have diminished quality of
sperm, sperm count, density and volume [50].

8.2.3 Smoking

Tobacco is familiar to be one of the major causes of worldwide death. It has been
reported that more than 4000 toxic chemical compounds have been present in
cigarettes which includes nitrosamines, alkaloids and inorganic molecules. In the
semen of smokers some of those chemicals were depicted to be the source of imbal-
ance between antioxidant and ROS [41]. This disproportion between the ROS level
and antioxidant adversely affects the overall quality of semen. It has been depicted
that smoking increases by 48% the concentration of seminal leukocytes and 107%
the ROS level in semen [52]. Due to the substantial increase in the level of 8-OHdG
which is also a biomarker of oxidative damage, a decrease of the antioxidant level
in seminal plasma, like vitamin C and vitamin E occurs, thus causing more risk of
oxidative damage [40]. A study performed on smokers found an increased con-
centration of lead and cadmium in their semen and blood, which led to increase
the production of ROS with a decrease in the motility of the sperm [53]. Moreover,
the spermatozoa of smoker were substantially more prone to acid mediated dena-
turation as compare to nonsmoker spermatozoa which led to DNA strand break
[54]. Furthermore, it was shown that prolonged smoking damages sperm DNA and
apoptosis which results in male infertility.

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Figure 4.
Demonstration of various factors responsible for male infertility (origin).

8.2.4 Alcohol consumption

Alcohol is widely known as the inducer of ROS and it interferes with the antioxi-
dant defense mechanism of the body, mainly in the liver. Acetaldehyde which is the
byproduct of ethanol metabolism, may react with protein and lipids forming the
ROS, and may lead to damages in DNA, protein and lipids at the molecular level.
The excessive consumption of alcohol is linked with a decrease in the concentration
of normal sperm in asthenozoospermia patients [55] (Figure 4).

9. Physiological role of ROS in seminal plasma

Physiological level of ROS plays a significant task in the physiological process

such as capacitation, hyperactivation, acrosomal reaction, fusion of sperm and
oocyte in order to assure the proper fertilization [56].

9.1 Capacitation

When spermatozoa pass the epididymis, it is supposed to be mature and

their activity is checked by different inhibitory factors which are produced by
genital duct epithelia. However, at that time sperm is unable to fertilize the ova.
Ejaculated mammalian spermatozoa should reside in the female genital tract
for several hours before gaining their fertilizability. In humans however, sperm
must move out of the seminal plasma immediately after ejaculation and appear

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in the fallopian tube within minutes. As soon as sperm cells are moving out of
the ejaculate and passing the cervical mucus, they undergo several biochemical
changes collectively called capacitation. These changes involve molecules absorb-
ing on, or integrating into, the sperm plasma membrane during epididymal
maturation. The removal or alteration of these molecules prepares the sperm
toward successful binding, penetration and fertilization with the egg [57]. During
the process of capacitation a production of ROS occurs in spermatozoa that
initiates various molecular modifications. Firstly, there is an increase in cAMP; in
various organisms and varieties of life processes, this cAMP pathway is necessary
because it might activate various enzymes and might regulate the expression of
genes [58]. cAMP activates the protein kinase A and causes the phosphorylation
of PKA substrate like arginine, serine and threonine. This successively leads to the
phosphorylation of MEK, threonine-glutamate-tyrosine, and tyrosine phosphory-
lation of fibrous sheath proteins. This cAMP increase makes the hyperactivation
of sperm. Only the hyperactivated spermatozoa undergo acrosomal reaction due
to increased motility and acquired all those properties which are necessary for
fertilization [59, 60].

9.2 Hyperactivation

Hyperactivation is the peculiar condition of sperm motility. The hyperactiva-

tion process is significant for lucrative fertilization and it regarded a subcategory
of capacitation. Hyperactivated sperm have characteristics of asymmetric flagellar
movement, high amplitude, side to side head displacement and also a nonlinear
motility [61].

9.3 Acrosome reaction

Hyperactivated spermatozoon binds to zona pellucida after passing the cumu-

lus oophorus, starting the exocytotic discharge of hyaluronidase and proteolytic
enzymes, sperm acrosome reaction (AR) induced by oocyte investment, is a
prerequisite event for the spermatozoa. It is obligatory for the sperm cell to enable
to penetrate the zona pellucida (ZP) and to fuse with the oocyte. Progesterone
(P4), secreted by cumulus cells, is an important cofactor for the occurrence of this
exocytosis event. The AR results from the fusion between outer acrosomal and
plasma membranes leading to inner acrosomal membrane exposure. Binding of
agonists, P4 or ZP3 glycoprotein, to plasma membrane sperm receptors activates
intraspermatic signals and enzymatic pathways involved in the AR. Among
the proteins or glycoproteins described as potential sperm receptors for ZP, Gi/
Go protein-coupled and tyrosine kinase receptors have been described. ZP- and
P4-promoted AR is mediated by an obligatory intracellular calcium increase,
appearing first at the acrosome equatorial segment and spreading throughout
the head. The plasma membrane channels involved in calcium entry are operated
by a plasma membrane depolarization and protein phosphorylation mediated by
protein kinase C and tyrosine kinase protein. Part of the calcium increase could
also be due to intracellular store release through nucleotide (cAMP)-gated chan-
nels. Besides adenylate cyclase and phospholipase C activations, intracellular
calcium increase also stimulates phospholipase A2 and actin depolymerization,
leading to membrane fusion [62]. The sperm cell crosses the physical barrier of
zona pellucida and within few minutes it fuses with the oocytes. ROS is involved
in the action of the spermatozoa by phosphorylating three plasma membrane
proteins [63].

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Innovations in Assisted Reproduction Technology

9.4 Sperm-oocyte fusion

High concentration of docosahexaenoic acid (DHA) plays a considerable part

in maintaining the fluidity of the membrane of spermatozoa. ROS enhances the
fluidity of membrane and sperm-oocyte fusion rate, during the process of capaci-
tation and acrosomal reaction. Throughout the entire capacitation process, ROS
hinder the protein tyrosine phosphate activity and arrest the dephosphorylation
and turnoff the phospholipase A2. PLA2 increases the fluidity of the membrane
by cleaving the secondary fatty acid from the triglycerol backbone of membrane
phospholipid [64, 65].

10. Management and prevention of oxidative stress

Sperm DNA of healthy males is protected from osmotic stress by two

mechanisms;

1. Tightly packed and coiled DNA so that the genetic material is less exposed to
ROS [66].

2. Production of ROS is minimized by natural antioxidant present in seminal

plasma and spermatozoa.

Enzymatic and nonenzymatic antioxidant like superoxide dismutase (SOD),

Catalase, Vitamin C, Vitamin E and Carotenoids react with ROS and neutralize it,
thus prevent the onset of osmatic stress and also preserves the function of sperm
[67] (Table 1).

Antioxidant Mechanism of action Effect

Superoxide Neutralizes the superoxide anions Prevents lipid peroxidation.

dismutase

GSH/GPX Scavenges the free radicals Prevents the lipid peroxidation

and enhance the sperm membrane
characteristics.

Catalase Splits down the H2O2 into H2O and O2. Also arrests the lipid peroxidation.

Vitamin C Counteracts free radicals Protects the viability and motility of

sperm.
Vitamin E Counteracts free radicals Blocks the lipid peroxidation
and enhance the activity of other
antioxidant.

Carotenoids Suppresses the singlet molecular O2. Blocks the lipid peroxidation.

Carnitine Acts as energy source and neutralize the Prevents the damage of DNA and
free radical. lipid peroxidation.

Cysteines Elevates the concentration of GSH Inhibits lipid peroxidation.

synthesized.

Pentoxifylline Prevents the breakdown of cAMP and Inhibits lipid peroxidation.

quench the formation of proinflammatory
factors.

Table 1.
Procedure of action and consequences of different antioxidants.

14
Insights of Sperm Pathology and Its Association with Infertility
DOI: http://dx.doi.org/10.5772/intechopen.90950

11. Correlation between biology of male reproduction and sleep

The whole process of spermatogenesis is controlled by hypothalamic pituitary

gonadal axis. Hypothalamus secretes GnRH that stimulates the anterior pituitary to
secrete LH and FSH. FSH act on the testicular tissue and LH triggers the secretion
of testosterone in the testis by Leydig cells. Maximum level of testosterone secre-
tion occurs during sleep. This nocturnal rise in testosterone secretion appears at the
same time with the beginning of resting eye movement sleep and it is not concerned
with the change in the level of melatonin [68]. In male reproductive system,
prolactin hormone secreted by anterior pituitary o has also a key role. Prolactin
increases in Leydig cells the utterance of LH receptors at physiological level. The
latest leads to increased secretion of testosterone promoting spermatogenesis. The
increasing pervasiveness of 24/7 constant distribution of entertainment, disrupts
the circadian rhythm and impair the duration and quality of sleep on population
level. The schedule of sleep and wake is delayed by the use of electronic devices at
night time. More over blue light emitted by LED reduces the secretion of melatonin
and thus decreases the prolonged, objective and subjective sleepiness. Sleep restric-
tion disrupts the level of gonadal hormone. The level of testosterone is reduced in
10 volunteer’s healthy males in 1 week of restricted sleep. While in another exami-
nation of sleep restriction of 4–5 hours in 15 men is also associated with reduction
in the level of testosterone. Effect of sleep restriction and resting eye movement
deprivation was analyzed by Alvarenga et al. on parameter of sperm and expression
of testis specific genes in male rat. Both sleep restriction (SR) and rapid eye move-
ment sleep deprivation (RSD) group has decreased viability of sperm [69].

12. Inflammation and infertility

Inflammation is a complexed process of response to tissue damage and injury. It

starts with the aggregation of leukocytes and more plasma molecules to infection
site. Several factors may be responsible for inflammation in reproductive tract of
male. (i) Blockage of ejaculatory duct (ii) epididymitis that causing pain, swelling
in scrotal area, penile leakage and presence of blood in urine (iii) sexual transmit-
ted diseases by several agents like E. coli (iv) Urethritis (v) testicular torsion is
another pathology affects the fertility in male. It occurs due to abnormality in
supportive tissue of testis and causing the testis to pervert inside the scrotum which
result in severe swelling and pain [70]. During the process of inflammation, the
quality of semen is reduced due to abnormal function of accessory glands, sperm
transport hindrance and spermatogenesis dysregulation [71, 72]. Cytokines which
are either secreted by activated cells or secreted after receiving stimulus might assist
help in normal function of reproductive system [73, 74]. Testicular macrophage is
the chief source of cytokine in male but Leydig and Sertoli cells are also depicted
to secrete cytokines. Two types of changes are seen due to inflammation in male
genitalia; an increase in secretion of seminal fluid leads to redness, local heat and
depletion in velocity of seminal flow. Cytokines (TNF-α, IL-6, and IL-1) induce the
oxidative damages that impair the quality of semen and have bad impact on fertil-
ity of male. Raised level of few cytokines in male semen also disrupts the quality,
density and morphology of sperm. The increased level of TNF-α is linked with low
sperm count, motility and morphology of sperm. In semen raised level of TNF-α
induced apoptosis due to proliferation and differentiation of B-cell, T- cell and
NK cells. At the site of inflammation, the blood vessels are dilated permitting the
leukocytes in high concentration to migrate out of blood and bind with vascular

15
Innovations in Assisted Reproduction Technology

endothelium. Accumulation of local fluid due to increased permeability causes pain

and swelling. So different types of disorders either due to hormonal imbalance,
physical or physiological problems lead to infertility in male [7].

13. Summary

Vast array of knowledge about the structural and functional characteristics of

spermatozoa has been obtained in last few decades. This study provides an infor-
mation about the molecular composition and mechanism of function responsible
behind the unique features of spermatozoa. No doubt that the function of sperma-
tozoa is to carry the haploid genome of male and deliver it to the oocyte, so that it
can fuse with haploid genome of female to begin the development of future genera-
tion. In the last decade the most substantial approaches in knowledge regarding
spermatozoa have come by using many tools of molecular biology and proteomics to
recognize the gene and protein controlling composition of spermatozoa and using
gene targeting method for ascertaining the function of particular gene in sperm. A
few of these advances are;

a. Determination of calcium channels that helps in motility of sperm.

b. Identification of activated adenylyl cyclase.

c. Phosphorylation of tyrosine flagellar proteins during capacitation.

d.Finding the role of heredity on the structure and function of sperm.

About 15% of couples are diagnosed as infertile and in these cases, male contrib-
utes 40%. Osmatic stress has been recognized as the inducer of male fertility due
to dysfunction of sperm. It has been depicted that antioxidant defense mechanism
is disrupted by the production of ROS in large concentration, while only a little
concentration of ROS is demanded for normal function of sperm. This augmented
production of ROS has negative impact on spermatozoa quality and damage their
capacity of fertilizing the egg. ROS itself and their metabolites can cause the death
of cells by attacking DNA, proteins and lipids, impair the function of the enzymes,
creating irreparable damage and ultimately results to diminish in semen parameter
concerned with infertility of male. So, an enhanced knowledge is also needed about
the composition, organization and function of spermatozoon so that highly specific
approaches are to be developed to regulate the function of sperm and essential for
determining the environmental effect on male fertility.

16
Insights of Sperm Pathology and Its Association with Infertility
DOI: http://dx.doi.org/10.5772/intechopen.90950

Author details

Mohd Sajad and Sonu Chand Thakur*

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia
University, New Delhi, India

*Address all correspondence to: [email protected]

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License (http://creativecommons.org/licenses/
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.

17
Innovations in Assisted Reproduction Technology

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