Page 135 - Remedial Andrology

10.3.5.2.1 Unilateral or bilateral absence/abnormality of the vas and renal anomalies
Congenital unilateral absence of the vas deferens (CUAVD) is usually associated with ipsilateral absence
of the kidney and probably has a different genetic causation [1523]. Consequently, in these subjects CFTR
mutation screening is not indicated. Men with CUAVD are usually fertile, and the condition is most commonly
encountered as an incidental finding in the vasectomy clinic. Cystic fibrosis transmembrane conductance
regulator gene mutation screening is indicated in men with unilateral absence of the vas deferens with normal
kidneys. The prevalence of renal anomalies is rare for patients who have CBAVD and CFTR mutations [1524].
Abdominal US should be undertaken both in unilateral and bilateral absence of vas deferens without CFTR
mutations. Findings may range from CUAVD with ipsilateral absence of the kidney, to bilateral vessel and renal
abnormalities, such as pelvic kidney [1525].

10.3.5.3 Y microdeletions - partial and complete
Microdeletions on the Y-chromosome are termed AZFa, AZFb and AZFc deletions [1526]. Clinically relevant
deletions remove partially, or in most cases completely, one or more of the AZF regions, and are the most
frequent molecular genetic cause of severe oligozoospermia and azoospermia [1527]. In each AZF region,
there are several spermatogenesis candidate genes [1528]. Deletions occur en bloc (i.e., removing more than
one gene), it is not possible to determine the role of a single AZF gene from the AZF deletion phenotype and
it is unclear if they all participate in spermatogenesis. Gene-specific deletions, which remove a single gene,
have been reported only in the AZFa region and concern the USP9Y gene. These studies have suggested
that USP9Y is most likely to be a “fine tuner” of sperm production, and its specific screening is not advised
[1529]. It has been observed that a number of commercial laboratories can use a limited number of primer sets
over the AZF a, b and c regions in their Y chromosome microdeletion assay. This can eventually miss smaller
microdeletions and clinicians should be aware over the managing work-up of patients scheduled for testicular
surgery [1530, 1531].

10.3.5.3.1 Clinical implications of Y microdeletions
The clinical significance of Yq microdeletions can be summarised as follows:
• They are not found in normozoospermic men, proving there is a clear cut cause-and-effect relationship
between Y-deletions and spermatogenic failure [1532].
• The highest frequency of Y-deletions is found in azoospermic men (8-12%), followed by oligozoospermic
(3-7%) men [1533, 1534].
• Deletions are extremely rare with a sperm concentration > 5 million/mL (~0.7%) [1535].
• AZFc deletions are most common (65-70%), followed by Y-deletions of the AZFb and AZFb+c or
AZFa+b+c regions (25-30%). AZFa region deletions are rare (5%) [1536].
• Complete deletion of the AZFa region is associated with severe testicular phenotype (Sertoli cell only
syndrome), while complete deletions of the AZFb region is associated with spermatogenic arrest.
Complete deletions that include the AZFa and AZFb regions are of poor prognostic significance for
retrieving sperm at the time of TESE and sperm is not found in these patients. Therefore, TESE should not
be attempted in these patients [1537, 1538].
• Deletions of the AZFc region causes a variable phenotype ranging from azoospermia to oligozoospermia.
• Sperm can be found in 50-75% of men with AZFc microdeletions [1537-1539].
• Men with AZFc microdeletions who are oligo-zoospermic or in whom sperm is found at the time of TESE
must be counselled that any male offspring will inherit the deletion.
• Classical (complete) AZF deletions do not confer a risk for cryptorchidism or testicular cancer [1535,
1540].

The specificity and genotype/phenotype correlation reported above means that Y-deletion analysis has both a
diagnostic and prognostic value for testicular sperm retrieval [1540].

10.3.5.3.1.1 Testing for Y microdeletions
Historically, indications for AZF deletion screening are based on sperm count and include azoospermia and
severe oligozoospermia (spermatozoa count < 5 million/mL). A recent single meta-analysis assessing the
prevalence of microdeletions on the Y chromosome in oligo-zoospermic men in 37 European and North
American studies (n = 12,492 oligo-zoospermic men) showed that the majority of microdeletions occurred in
men with sperm concentrations < 1 million sperm/mL, with < 1% identified in men with > 1 million sperm/mL
[1535]. In this context, while an absolute threshold for clinical testing cannot be universally given, patients may
be offered testing if sperm counts are < 5 million sperm/mL, but must be tested if <1 million sperm/mL.

With the efforts of the European Academy of Andrology (EAA) guidelines and the European Molecular Genetics
Quality Network external quality control programme (http://www.emqn.org/emqn/), Yq testing has become

134 SEXUAL AND REPRODUCTIVE HEALTH - MARCH 2021