Page 133 - Remedial Andrology

but maturation arrest exists at the spermatocyte or spermatid level, FSH level is usually within the normal
range [1476]. However, for patients undergoing TESE, FSH levels do not accurately predict the presence of
spermatogenesis, as men with maturation arrest on histology can have both normal FSH and testicular volume
[1477, 1478]. Furthermore men with non-obstructive azoospermia (NOA) and high levels of FSH may still
harbour focal areas of spermatogenesis at the time of TESE or microdissection TESE (mTESE) [1478, 1479].

10.3.5 Genetic testing
All urologists working in andrology must have an understanding of the genetic abnormalities most commonly
associated with infertility, so that they can provide correct advice to couples seeking fertility treatment.
Men with low sperm counts can still be offered a reasonable chance of paternity, using IVF, ICSI and sperm
extraction from the testes in cases of azoospermia. However, the spermatozoa of infertile men show an
increased rate of aneuploidy, structural chromosomal abnormalities, and DNA damage, carrying the risk
of passing genetic abnormalities to the next generation. Current routine clinical practice is based on the
screening of genomic DNA from peripheral blood samples. However, screening of chromosomal anomalies
in spermatozoa (sperm aneuploidy) is also feasible and can be performed in selected cases (e.g., recurrent
miscarriage) [1480-1482].

10.3.5.1 Chromosomal abnormalities
Chromosomal abnormalities can be numerical (e.g., trisomy) or structural (e.g., inversions or translocations).
In a survey of pooled data from 11 publications, including 9,766 infertile men, the incidence of chromosomal
abnormalities was 5.8% [1483]. Of these, sex chromosome abnormalities accounted for 4.2% and autosomal
abnormalities for 1.5%. In comparison, the incidence of abnormalities was 0.38% in pooled data from three
series, with a total of 94,465 new-born male infants, of whom 131 (0.14%) had sex chromosomal abnormalities
and 232 (0.25%) autosomal abnormalities [1483]. The frequency of chromosomal abnormalities increases as
testicular deficiency becomes more severe. Patients with sperm count < 5 million/mL already show a 10-fold
higher incidence (4%) of mainly autosomal structural abnormalities compared with the general population
[1484, 1485]. Men with NOA are at highest risk, especially for sex chromosomal anomalies (e.g., Klinefelter
syndrome) [1486, 1487].

Based on the frequencies of chromosomal aberrations in patients with different sperm concentration, karyotype
analysis is currently indicated in men with azoospermia or oligozoospermia (spermatozoa < 10 million/mL)
[1485]. This broad selection criterion has been recently externally validated, with the finding that the suggested
threshold has a low sensitivity, specificity, and discrimination (80%, 37%, and 59%, respectively) [1488]. In
this context, a novel nomogram, with a 2% probability cut-off, which allows for a more careful detection of
karyotype alterations has been developed [1488]. Notwithstanding, the clinical value of spermatozoa < 10
million/mL remains a valid threshold until further studies, evaluating the cost-effectiveness, in which costs of
adverse events due to chromosomal abnormalities (e.g., miscarriages and children with congenital anomalies)
are performed [1489]. If there is a family history of recurrent spontaneous abortions, malformations or mental
retardation, karyotype analysis should be requested, regardless of the sperm concentration.

10.3.5.1.1 Sex chromosome abnormalities (Klinefelter syndrome and variants [47,XXY; 46,XY/47,
XX mosaicism])
Klinefelter syndrome is the most common sex chromosomal abnormality [1490]. Adult men with Klinefelter
syndrome usually have small firm testes along with features of primary hypogonadism. The phenotype is the
final result of a combination between genetic, hormonal and age-related factors [15]. The phenotype varies
from that of a normally virilised male to one with the stigmata of androgen deficiency. In most cases infertility
and reduced testicular volume are the only clinical features that can be detected. Leydig cell function is also
commonly impaired in men with Klinefelter syndrome and thus testosterone deficiency is more frequently
observed than in the general population [1491], although rarely observed during the peri-pubertal period, which
usually occurs in a normal manner [15, 1492]. Rarely, more pronounced signs and symptoms of hypogonadism
can be present, along with congenital abnormalities including heart and renal problems [1493].

The presence of germ cells and sperm production are variable in men with Klinefelter syndrome and are
more frequently observed in mosaicism, 46,XY/47,XXY. Based on sperm fluorescence in situ hybridisation
(FISH) studies showing an increased frequency of sex chromosomal abnormalities and increased incidence
of autosomal aneuploidy (disomy for chromosomes 13, 18 and 21), concerns have been raised about the
chromosomal normality of the embryos generated through ICSI [1494]. The production of 24,XY sperm has
been reported in 0.9% and 7.0% of men with Klinefelter mosaicism [1495, 1496] and in 1.36-25% of men with
somatic karyotype 47,XXY [1497-1500]. In patients with azoospermia, TESE or mTESE are therapeutic options
as spermatozoa can be recovered in up to 50% of cases [1501, 1502]. Although the data are not unique

132 SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021