Research of last few years has clearly shown that
infertile m en have higher occurrence of
chromosomal abnormalities. Obviously these findings
are further co-related with the increased incidence
of chromosomal abnormalities in newborns and
fetuses born from the pregnancies conceived by
Intracytoplasmic Sperm Injection (ICSI). As also
reported in literature, in half of the infertile couples
with unsuccessful pregnancy, the cause of infertility
is male related, in which about 30% are genetic
factors with abnormal semen parameters should be
considered. Chromosomal abnormality is one of the
important causes of male infertility because it
disrupts genes involved in the genetic control of
human spermatogenesis (10, 11).
In present study, the incidence of chromosomal
abnormalities in azoospermic group 16.3% was
higher than in oligozoospermic 9.5% with an overall
occurrence of 11.2 %. It has clearly demonstrated
an inverse correlation between chromosomal
anomalies and sperm count. Also these findings
were comparable to the literature data varying from
2.2-22.6% (12, 13). No chromosomal abnormality
had been found in control group in this study
(P<0.05).
Sex chromosomal abnormalities (13.9%) were
predominant in azoospermia over autosomal
abnorm alities (2.9%), while the autosom al
abnorm alities (6.5%) were predom inant in
oligozoospermia over sex chromosomal abnormalities
(2.3%). All autosomal abnormalities were structural
type while the sex chromosome abnormalities were
found both structural as well as numerical types.
All numerical abnormalities in 6 cases were of
Klinefelter’s syndrome in which 4 patients had of
classical form 47, XXY and 2 had of mosaic form
47,XXY/46,XY. Presences of Klinefelter’s syndrome
in males impair the spermatogenesis associated with
severe oligozoospermia or azoospermia causing
infertility. This is caused due to lethal dosage
introduced into cells by an additional ‘X’
chromosome, which does not permit the development
of Sertoli cells and survival of germ cells in the
testis, resulting in azoospermia due to the advanced
germ cell atresia and aplasia. This type of gonosomal
mosaicism leads into severe oligospermia, may
be a probable cause for the failure of assisted
reproduction (5, 14).
In structural abnormalities of 14 (7.7%) cases,
translocations had found in 7(3.8%) cases, inversions
in 3(1.67%), deletions in 2(1.2%) and marker
chromosomes in 2 (1.2%) infertile males. Such type
of anomaly can results in a variety of sperm
production phenotypes from normal spermatogenesis
to an inability to produce spermatogonia.
Out of autosomal translocations, 5 had non-reciprocal
while 2 had Robertsonian translocations. As the most
common chromosomes involved in translocations of
infertile men are acrocentric chromosomes 13, 14,
15, 21 & 22, they are more harmful for fertility of
the carriers because of high tendency of these
chromosomes to be associated with the X-Y body
causing severe spermatogenic defects (15).
Translocations can also cause the loss of genetic
material at the breakpoint of genes, which can
corrupt the genetic message and leads into infertility
(16).
Reciprocal translocations form quadrivalents during
the meiotic division which cause the impairment in
segregation of chromosomes leads to infertility, birth
with defects or spontaneous abortion, depending on
the chromosomes involved. While the Robertsonian
translocations form trivalents that influence the
pairing of homologous chromosomes during I meiotic
division and cause male infertility (5, 17, 18).
An association between inversions and infertility in
the males has been reported. These inversions
may cause a problem for mitotic divisions which
will disrupt cell division and thus reduce
spermatogenesis (19). Two cases of marker
chromosomes (sSMC) had found in oligospemic
group. Males carrying sSMC are often phenotypically
normal. But sSMC may associate with the X-Y
bivalent at meiotic prophase and cause male
infertility. In this case, the infertility is caused due
to the impairment of spermatogenesis by meiotic
arrest resulting in maturation arrest on spermatocyte
stage (20).
The incidence of deletions of Y chromosome had
found in 2 patients (1.2%) in our study was lower
than that given in literature (3-18%) (21). Y
chromosome abnormalities, particularly the deletions
involving long arm of the Y chromosome lead to
azoospermia and male infertility. This type of deletion
does not appear to impair spermatogenesis in some
males but leads to infertility in others. The simple
explanation for these observations is that there is a
key locus (or loci) close to the boundary between
genetically inert heterochrom atin and Yq
euchromatin. The removal of this locus in some
males by more extensive deletion causes infertility.
Such large structural changes to the Y chromosome
might disturb normal pairing and segregation with
the X chromosome during meiosis, is the cause of
spermatogenetic failure in these males (5, 22).
Heterochromatic polymorphic chromosomal variants
also well studied both in the infertile men and fertile
control group. The frequency of these variants in
infertile men was higher in our study (31.1%), but
remained similar to the control group (35%)
(P>0.05). It was also coincidental with the literature
data in infertile males (4.7-56.8%) and fertile males
(32.7%) (13). Polymorphic variants are usually
considered as normal variants inherited from one
generation to another with low mutation rate and
without any direct harmful phenotypic effect due to
the scarcity of protein-coding region in them.
However, the increased polymorphic variants may
have some clinical significance and associated with
clinical anomalies. The detrimental effect of variants
may be not direct to phenotype but indirect through
the disturbing spermatogenesis and causing the death
of germ cell resulting in infertility or children with congenital anomalies (23, 24).
A large heterochromatic block in the pericentromeric
heterochromatin region of chromosome 1 affects
the pairing of chromosomes leads to meiotic arrest,
death of germ cells and infertility (25). Variants of
chromosome 9 (qh+) might be associated with
spontaneous miscarriages, stillbirth, congenital
abnormalities, and chromosomal anomalies in aborts
and newborns. However, the result of our study and
some of other authors do not support this report as
of high incidence of 9qh+ found both in normal
(10%) and infertile males (7.2%) (25, 26).
Y chromosome polymorphic variants (Yqh+ and
Yqh–) have been seen more frequent in azoospermia
and severe oligozoospermia. Long Y chromosome
has seen to be associated with an increased risk of
fetal loss. The variation in relative length of Y
chromosome is said to be associated with male
infertility. However, other study did not show any
relationship between the size of Y chromosome and
the risk of abortion (27). Genest and Genest also
reported that short Y chromosome does not see to
represent an increased risk of pregnancy loss. The
contribution of Y chromosome variants to cause
infertility is still a controversial topic and further
studies are required to understand this (28,29). In
our study, we found ‘Y’ chromosome variants in 5.5%
in which all were with increased heterochromatin (‘Y’
qh+).
Polymorphisms of acrocentric chromosomes D and
G-groups are found both in the fertile 5% and in
infertile men 6.1% in this study. It is reported that
higher frequencies of satellite variants have been
found in patients with reproductive failure and
spontaneous abortions. Very large satellites of
acrocentrics have been reported in infertile males,
but other studies have not shown them as a risk
factor to infertility (5, 30).
Conclusion
The occurrence of major chromosomal abnormalities
is very high in infertile males as compare to general
population and inversely related to the sperm count.
It is one of the important causes of male infertility
because it disrupts genes which are involved in the
genetic control of spermatogenesis and leads to
infertility. W hile the polymorphic chromosomal
variants are known to occur in general population
but their effect on infertility is still a controversial
topic and further studies are required to understand
the facts.
Limitations and future perspectives
The limitations of the study are cost effective and
time consuming procedures. Also participants were
not easily agreed to give the samples particularly
for semen analyses. Based on the present results,
it would be relevant to continue this prospective
study further to the molecular level for to find out
the role of various genes involved regulation of
spermatogenesis and interference of their mutations
with man’s fertility potential. This will help us to get
the answers of most of idiopathic causes of male
infertility.
