Page 134 - Remedial Andrology

[1502], there is growing evidence that TESE or mTESE yields higher sperm recovery rates when performed at a
younger age [1486, 1503].

Numerous healthy children have been born using ICSI without pre-implantation genetic diagnosis (PGD)
although the conception of one 47,XXY foetus has been reported [1490]. Although data published so far have
not reported any difference in the prevalence of aneuploidy in children conceived using ICSI in Klinefelter
syndrome compared to the general population, men with Klinefelter syndrome undergoing fertility treatments
should be counselled regarding the potential genetic abnormalities in their offspring.

Regular medical follow-up of men with Klinefelter syndrome is recommended as testosterone therapy may
be considered if testosterone levels are in the hypogonadal range when fertility issues have been addressed
[1504]. Since this syndrome is associated with several general health problems, appropriate medical follow-up
is therefore advised [16, 1505, 1506]. In particular, men with Klinefelter syndrome are at higher risk of metabolic
and cardiovasculardiseases (CVD), including venous thromboembolism (VTE). Therefore, men with Klinefelter
syndrome should be made aware of this risk, particularly when starting testosterone therapy [1507]. In addition,
a higher risk of haematological malignancies has been reported in men with Klinefelter syndrome [16].

Testicular sperm extraction in peri-pubertal or pre-pubertal boys with Klinefelter syndrome aiming at
cryopreservation of testicular spermatogonial stem cells is still considered experimental and should only be
performed within a research setting [1508]. The same applies to sperm retrieval in older boys who have not
considered their fertility potential [1509].

10.3.5.1.2 Autosomal abnormalities
Genetic counselling should be offered to all couples seeking fertility treatment (including IVF/ICSI) when the
male partner has an autosomal karyotype abnormality. The most common autosomal karyotype abnormalities
are Robertsonian translocations, reciprocal translocations, paracentric inversions, and marker chromosomes. It
is important to look for these structural chromosomal anomalies because there is an increased associated risk
of aneuploidy or unbalanced chromosomal complements in the foetus. As with Klinefelter syndrome, sperm
FISH analysis provides a more accurate risk estimation of affected offspring. However, the use of this genetic
test is largely limited by the availability of laboratories able to perform this analysis [1510]. When IVF/ICSI is
carried out for men with translocations, PGD or amniocentesis should be performed [1511, 1512].

10.3.5.2 Cystic fibrosis gene mutations
Cystic fibrosis (CF) is an autosomal-recessive disorder [1513]. It is the most common genetic disease of
Caucasians; 4% are carriers of gene mutations involving the CF transmembrane conductance regulator
(CFTR) gene located on chromosome 7p. It encodes a membrane protein that functions as an ion channel
and influences the formation of the ejaculatory duct, seminal vesicle, vas deferens and distal two-thirds of the
epididymis. Approximately 2,000 CFTR mutations have been identified and any CFTR alteration may lead to
congenital bilateral absence of the vas deferens (CBAVD). However, only those with homozygous mutations
exhibit CF disease [1514]. Congenital bilateral absence of the vas deferens is a rare reason of male factor
infertility, which is found 1% of infertile men and in up to 6% of men with obstructive azoospermia [1515].
Clinical diagnosis of absent vasa is easy to miss and all men with azoospermia should be carefully examined to
exclude CBAVD, particularly those with a semen volume < 1.0 mL and acidic pH < 7.0 [1516-1518]. In patients
with CBAVD-only or CF, testicular sperm aspiration (TESA), microsurgical epididymal sperm aspiration (MESA)
or TESE with ICSI can be used to achieve pregnancy. However, higher sperm quality, easier sperm retrieval and
better ICSI outcomes are associated with CBAVD-only patients compared with CF patients [1514].

The most frequently found mutations are F508, R117H and W1282X, but their frequency and the presence of
other mutations largely depend on the ethnicity of the patient [1519, 1520]. Given the functional relevance of a
DNA variant (the 5T allele) in a non-coding region of CFTR [1521], it is now considered a mild CFTR mutation
rather than a polymorphism and it should be analysed in each CBAVD patient. As more mutations are defined
and tested for, almost all men with CBAVD will probably be found to have mutations. It is not practical to test
for all known mutations, because many have a low prevalence in a particular population. Routine testing is
usually restricted to the most common mutations in a particular community through the analysis of a mutation
panel. Men with CBAVD often have mild clinical stigmata of CF (e.g., history of chest infections). When a man
has CBAVD, it is important to test also his partner for CF mutations. If the female partner is found to be a
carrier of CFTR mutations, the couple must consider carefully whether to proceed with ICSI using the man’s
sperm, as the risk of having a child with CF or CBAVD will be 50%, depending on the type of mutations carried
by the parents. If the female partner is negative for known mutations, the risk of being a carrier of unknown
mutations is ~0.4% [1522].

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