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more reliable in different routine genetic laboratories. The EAA guidelines provide a set of primers capable of
detecting > 95% of clinically relevant deletions [1541].

10.3.5.3.1.2 Genetic counselling for AZF deletions
After conception, any Y-deletions are transmitted to the male offspring, and genetic counselling is therefore
mandatory. In most cases, father and son will have the same microdeletion [1541], but occasionally the son
may have a more extensive deletion [1542]. The extent of spermatogenic failure (still in the range of azoo-/
oligo-zoospermia) cannot be predicted entirely in the son, due to the different genetic background and the
presence or absence of environmental factors with potential toxicity on reproductive function. A significant
proportion of spermatozoa from men with complete AZFc deletion are nullisomic for sex chromosomes [1543,
1544], indicating a potential risk for any offspring to develop 45,X0 Turner’s syndrome and other phenotypic
anomalies associated with sex chromosome mosaicism, including ambiguous genitalia [1545]. Despite this
theoretical risk, babies born from fathers affected by Yq microdeletions are phenotypically normal [1540, 1541].
This could be due to the reduced implantation rate and a likely higher risk of spontaneous abortion of embryos
bearing a 45,X0 karyotype.

10.3.5.3.1.3 Y-chromosome: ‘gr/gr’ deletion
A new type of Yq deletion, known as the gr/gr deletion, has been described in the AZFc region [1546]. This
deletion removes half of the gene content of the AZFc region, affecting the dosage of multicopy genes
mapping inside this region. This type of deletion confers a 2.5-8 fold increased risk for oligozoospermia [1541,
1547-1549]. The frequency of gr/gr deletion in oligozoospermic patients is ~5% [1550].

According to four meta-analyses, gr/gr deletion is a significant risk factor for impaired sperm production [1548-
1550]. It is worth noting that both the frequency of gr/gr deletion and its phenotypic expression vary among
different ethnic groups, depending on the Y-chromosome background. For example, in some Y haplo-groups,
the deletion is fixed and appears to have no negative effect on spermatogenesis. Consequently, the routine
screening for gr/gr deletion is still a debated issue, especially in those laboratories serving diverse ethnic and
geographic populations. A large multi-centre study has shown that gr/gr deletion is a potential risk factor for
testicular germ cell tumours [1521]. However, these data need confirmation in an ethnically and geographically
matched case-control study setting. For genetic counselling it is worth noting that partial AZFc deletions, gr/gr
and b2/b3, may predispose to complete AZFc deletion in the next generation [1551].

10.3.5.3.1.4 Autosomal defects with severe phenotypic abnormalities and infertility
Several inherited disorders are associated with severe or considerable generalised abnormalities and infertility
(e.g., Prader-Willi syndrome [1552], Bardet-Biedl syndrome [1553], Noonan’s syndrome, Myotonic dystrophy,
dominant polycystic kidney disease [1554, 1555], and 5 α-reductase deficiency [1556-1559], etc.). Pre-
implantation genetic screening may be necessary in order to improve the ART outcomes among men with
autosomal chromosomal defects [1560, 1561].

10.3.5.4 Sperm chromosomal abnormalities
Sperm can be examined for their chromosomal constitution using FISH both in men with normal karyotype and
with anomalies. Aneuploidy in sperm, particularly sex chromosome aneuploidy, is associated with severe damage
to spermatogenesis [1483, 1562-1564] and with translocations and may lead to recurrent pregnancy loss (RPL) or
recurrent implantation failure [1565]. In a large retrospective series, couples with normal sperm FISH had similar
outcomes from IVF and ICSI on pre-implantation genetic screening (PGS). However, couples with abnormal FISH
had better clinical outcomes after PGS, suggesting a potential contribution of sperm to aneuploidic abnormalities
in the embryo [1566]. In men with sperm aneuploidy, PGS combined with IVF and ICSI can increase chances of
live births [1482].

10.3.5.5 Measurement of Oxidative Stress
Oxidative stress is considered to be central in male infertility by affecting sperm quality, function, as well as the
integrity of sperm [1567]. Oxidative stress may lead to sperm DNA damage and poorer DNA integrity, which are
associated with poor embryo development, miscarriage and infertility [1568, 1569]. Spermatozoa are vulnerable
to oxidative stress and have limited capacity to repair damaged DNA. Oxidative stress is generally associated
with poor lifestyle (e.g., smoking) and environmental exposure, and therefore antioxidant regimens and
lifestyle interventions may reduce the risk of DNA fragmentation and improve sperm quality [1570]. However,
these data have not been supported by RCTs. Furthermore, there are no standardised testing methods for
ROS and the duration of antioxidant treatments. Although ROS can be measured by various assays (e.g.,
chemiluminescence), routine measurement of ROS testing should remain experimental until these tests are
validated in RCTs [1571].

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