Research over the past
few years has clearly demonstrated that infertile men have an increased
frequency of chromosomal abnormalities. These findings are further co-related
by increased frequency of chromosomal abnormalities found in newborns and
fetuses born from the pregnancies conceived by ICSI. As reported in literature,
in half of the couples with unsuccessful pregnancy, the cause of infertility is
male related, and of them in about 30% genetic factors with abnormal semen
parameters should be considered. Chromosomal abnormality is one of the
important cause of male infertility because it disrupts genes involved in the
genetic control of human spermatogenesis 10,11,12,13.
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 %
Table I, 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% 3,4,11,13. No chromosomal
abnormality had been found in control group (P<0.05). Sex chromosomal abnormalities (13.9%) in our study were predominant in azoospermia over autosomal abnormalities (2.9%), while autosomal abnormalities (6.5%) were predominant in oligozoospermia over sex chromosomal abnormalities (2.9%). All autosomal abnormalities (5.6%) were structural type while the sex chromosome abnormalities (5.5%) were found both structural as well as numerical types (Table I). All numerical abnormalities (3.3%) were of Klinefelter's syndrome in which 4 patients were of classical form 47,XXY and 2 were of mosaic form 47,XXY/46,XY. Klinefelter's syndrome has impaired spermatogenesis associated with severe oligozoospermia or azoospermia causing infertility. This is caused by 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. Gonosomal mosaicism leads into severe oligospermia, may be a probable cause for the failure of assisted reproduction 12,13,14. While structural abnormalities (7.7%) were translocations (3.8%), inversions (1.67%), deletions (1.2%) and marker chromosomes (1.2%) can results in a variety of sperm production phenotypes from normal spermatogenesis to an inability to produce spermatogonia (Table II). From 6 autosomal translocations, 4 were non-reciprocal and 2 were Robertsonian translocations. As the most frequent chromosomes involved in translocations of infertile men are reported acrocentric chromosomes. Acrocentric chromosomes 13, 14, 15, 21 & 22 involved in translocations are more harmful for fertility of the carriers because of high tendency of acrocentrics to associate with the X-Y body causing severe spermatogenic defects 13,14,15. Translocations can also cause the loss of genetic material at the break points of genes, which can corrupt the genetic message and leads into the infertility. 16,17. Reciprocal translocations forms quadrivalents in meiosis which causes the impairment in segregation of chromosomes leads in to infertility, birth with defects or spontaneous abortion, depending on the chromosomes involved. While the Robertsonan translocations form trivalent that influence the pairing of homologous chromosomes during the I meiotic division and cause male infertility 16,17,18. An association between inversions and infertility in the males has been reported. These inversions may cause problem at mitotic divisions which will disrupt cell division and thus reduce spermatogenesis 19. In current study, two cases of marker chromosomes (sSMC) had found in oligospemic group. Males carrying an sSMC are often phenotypically normal. It may associate with the X-Y bivalent at meiotic prophase and cause male infertility through impairment of spermatogenesis due to meiotic arrest and instability resulting in maturation arrest on spermatocyte stage 20,21. 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%) (13). It increases with the severity of spermatogenic defects. 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 heterochromatin and Yq euchromatin. In some males, the removal of this locus 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. The vast majority of deletions of Y chromosome associated with complete absence of germ cells (azoospermia) or severe oligozoospermia are cytogenetically undetectable 13,17,18,19 Heterochromatic polymorphic chromosomal variants also well studied both in the infertile men and normal population. The frequency of these variants in infertile men was higher in our study (31.2%), but remained similar to that in the control group (35%) (Table IV). It was also coincidental with the literature data in infertile males (4.7-56.8%) and in 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 22,23. A large heterochromatic block in the pericentrometric region of chromosome 1 may affect the pairing of chromosomes causing meiotic arrest, death of germ cells and infertility 15. It is suggested that 9 qh+ could be in association with repeated spontaneous miscarriages, stillbirth, multiple congenital abnormalities and chromosomal abnormalities in aborts and offspring. 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%) 24,25,26. Y chromosome polymorphisms have been preferentially seen in azoospermic and severe oligospermic (Yqh+ and Yqh-). The variation in relative length of Y chromosome is said to be associated with male infertility. Long Y chromosome has been seen to be associated with an increased risk of fetal loss. However, another study did not show any relationship between the size of Y chromosome and the risk of abortion 13,27,28. 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. In our study we found 'Y' chromosome variants in 5.5% in which all were with increased hetrochromatin ('Y' qh+) 28,29 Polymorphisms of acrocentric chromosomes of D and G-groups are found both in the normal population 5% and in infertile men 6.1%. 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 of infertility 13,21,22. In this study, the difference between infertile males and control group was significant (P<0.05) only for major chromosomal abnormalities and was insignificant for polymorphic chromosomal variants (P>0.05).
conclusion, the occurrence of major chromosomal abnormalities (11.2%) in
infertile males in our study strongly suggests the genetic testing and
counseling of infertile couples prior to the use ICSI treatment for to minimize
the risk of propagation of chromosomal abnormalities into the next generation.
It should be mandatory and included in routine investigations of infertile men,
before using assisted reproduction techniques (ARTs). 13,30.