Approximately 15% of couples attempting their first pregnancy meet with failure. Reproductive centres define these patients as primarily infertile if they have been unable to achieve a pregnancy after one year of unprotected intercourse. Conception normally is achieved within twelve months in 80-85% of couples who use no contraceptive measures, and persons presenting after this time should therefore be regarded as possibly infertile and should be evaluated. Data available over the past twenty years reveal that in approximately 30% of cases pathology is found in the man alone, and in another 20% both the man and woman are abnormal. Therefore, the male factor is at least partly responsible in about 50% of infertile couples.

Male infertility affects approximately 2-7% of couples around the world.  Over one in ten men who seek help at infertility clinics are diagnosed as severely oligozoospermic and azoospermic.

Microdeletions of the Y chromosome are a recently discovered cause of spermatogenetic failure resulting in male infertility.  After the Klinefelter syndrome, Y-chromosomal microdeletions are the second most frequent genetic cause of male infertility 

1. Chromosome Abnormalities

 Chromosomes are compact structures of DNA carrying genetic information in all the cells of the body. Each cell, except reproductive cells should contain 46 chromosomes that can be arranged into 23 pairs. The chromosome pairs are divided into 22 pairs of autosomes and the sex chromosomes (2) nl. the  X and Y chromosomes. Males should have an X and a Y (46,XY), while females should have two X chromosomes  (46,XX). Approximately 5-10% of men with oligospermia and 10-15% of men with azoospermia carry a chromosome abnormality, most commonly of the sex chromosomes.

The most common numeric chromosome abnormality associated with male infertility is Klinefelter syndrome.  Men with Klinefelter syndrome have an an additional X chromosome giving a 47,XXY chromosome constitution. Klinefelter syndrome is characterized by an increased risk for learning disabilities, minor physical abnormalities and infertility. Most men with Klinefelter syndrome are only diagnosed late when experiencing fertility problems and an evaluation for infertility is performed. With the assistance of ICSI, men with Klinefelter syndrome can often overcome these problems and have children. Although these men can have healthy children, there is an increased chance to have a child with a sex chromosome abnormality and prenatal studies should always be offered to these couples.

Other chromosome abnormalities may also cause infertility in the otherwise healthy male. Carriers of translocations increase the risk for their partner having miscarriages and for children born with birth defects and mental retardation.

Balanced translocation between chromosomes 4 and 20

Carriers can also have healthy offspring with normal chromosome or a normal offspring that are carriers like the parent.

A chromosome analysis should be routinely offered to all men with infertility before proceeding with ICSI.

2.    Y-CHROMOSOME MICRODELETIONS

About 10-18% of men requesting ICSI who have severe oligospermia or azoospermia have small deletions (microdeletions) within one of the AZF (azoospermia factor) regions or certain other regions (AMELY, SRY, ZFY) of their Y chromosomes. Several genes on the Y chromosome are required for normal spermatogenesis (the process of making the sperm). The absence of one or more of these genes causes infertility.

Micro deletions of the Y chromosome are a recently discovered cause of spermatogenetic failure resulting in male infertility.  After the Klinefelter syndrome, Y-chromosomal micro deletions are the second most frequent genetic cause of male infertility (Vogt et al., 1996).

Extensive molecular studies have revealed that deletions in the azoospermia factor region of the long arm of the Y chromosome are associated with severe spermatogenic impairment.  The portion of the male-specific region of the Y chromosome (MSY), comprising 95% of the Y chromosome and flanked by pseudoautosomal regions (Skaletsky et al.,2003), which is affected by deletions, has been classically subdivided into three regions called AZFa, AZFb and AZFc, respectively (Vogt et al., 1996).

Using current screening methods, such as PCR screening , Yq deletions are detected in 5-10% of infertile men.

                                                           

Men with Y microdeletions who undergo ICSI are at risk for producing sons with the same deletions. These sons could also experience infertility.  Y chromosome microdeletion analysis should routinely be offered to all men with severe oligospermia or azoospermia.

3.  CYSTIC FIBROSIS  GENE MUTATIONS

Cystic Fibrosis (CF) is a genetic disorder typically characterized by complications of the lung and pancreas. CF is inherited as an autosomal recessive disorder. Certain mutations within the cystic fibrosis gene are known to cause congenital bilateral absence of the vas deferens (CBAVD); congenital unilateral absence of the vas deferens (CUAVD) or obstructed vas deferens. Abnormalities of the vas deferens cause oligospermia and azoospermia, which consequently results in infertility in men carrying the associated mutations. Approximately 40% of men with CUAVD and 50-80% of men with CBAVD have at least one mutation within the CF gene.

Men with CBAVD or CUAVD who carry CF mutation(s) are at an increased risk for having children with infertility, or classical Cystic Fibrosis if the mother is also a carrier of a CF mutation. All men with CBAVD and CUAVD should routinely be offered CF testing before undergoing ICSI.

4.  SAMPLE REQUIREMENTS

?         Chromosome analysis -  Specimen: 10 ml whole blood in a green top Li Heparin tube.   Results available: 7 working days

?         Y-Chromosome Microdeletion Testing - Specimen: 10 ml whole blood in a lavender top EDTA tube.  Results Available: 1 week

?         Cystic Fibrosis Gene Testing - Specimen: 10 ml whole blood in a lavender top EDTA tube.  Results Available: 1 week