Full text of DOI:10.1007/BF03343793

J. Endocrinol. Invest. 23: 677-683, 2000
Chromosomal alterations and male infertility
A. Antonelli*, L. Gandini**, P. Petrinelli*, L. Marcucci*, R. Elli*, F. Lombardo**,
F. Dondero**, and A. Lenzi**
*Laboratory of Human Cytogenetics, Section of Molecular Genetics, Department of Cellular
Biotechnology and Hematology; **Laboratory of Seminology and Reproductive Immunology,
Section of the Training Center in Andrology of the European Academy of Andrology, Department
of Pathophysiology, “La Sapienza” University, Rome, Italy
ABSTRACT. Reduced male fertility can be caused
by genetic factors affecting gamete formation or
function; in particular, chromosome abnormalities
are a possible cause of male subfertility as shown
by their higher frequency in infertile men than in
the general male population. Meiotic studies in a
number of these males have shown spermatoge-
nesis breakdown, often related to alterations in
the process of chromosome synapsis. Indeed, any
condition that can interfere with X-Y bivalent for-
mation and X-chromosome inactivation is critical
to the meiotic process; furthermore, asynapsed
regions may themselves represent a signal for the
meiotic checkpoint that eliminates spermatocytes
with synaptic errors. We performed cytogenetic,
hormonal and seminal studies in 333 infertile pa-
tients selected because azoospermic, severely
oligozoospermic or normozoospermic with failure
to fertilize the partner’s oocytes in an in vitro fer-
tilization (IVF) program. Our findings: 1) confirm
the high incidence of chromosomal anomalies
among infertile males; 2) highlight the relevance in
male infertility of quantitative/positional modifi-
cations of the constitutive heterochromatin; and
3) underline the relevance of cooperation be-
tween andrologists and cytogenetists prior to ev-
ery kind of assisted reproduction, above all prior
to intracytoplasmic sperm injection, in which se-
lective hurdles eliminating abnormal germ cells
are bypassed.
(J. Endocrinol. Invest. 23: 677-683, 2000)
©2000, Editrice Kurtis
STATE OF ART
these cases (3). In particular, chromosome abnor-
malities have been known for some time to be a
possible cause of male subfertility (4, 5). Indeed,
the overall incidence of chromosome anomalies in
infertile men is higher than in the general male pop-
ulation, ranging between 2.2% and 8.6%. This val-
ue increases to about 16% in azoospermic males
due to the presence of patients with Klinefelter syn-
drome (47,XXY) in this group. Besides sex chromo-
some abnormalities, a variety of structural chromo-
some anomalies, such as Robertsonian transloca-
tions, reciprocal translocations, accessory marker
chromosomes and inversions, are found in the kary-
otype of infertile males. Meiotic studies in a number
of these males have shown spermatogenesis break-
down, often related to alterations in the process of
chromosome synapsis. Indeed, as suggested by
Lifschytz and Lindsley (6), any condition that can in-
terfere with X-Y bivalent formation and X-chromo-
some inactivation is critical to the meiotic process.
Presumably, the transcriptionally inactive status of
the X-chromosome during male meiotic prophase
may constitute a control mechanism for normal
spermatogenesis. Furthermore, asynapsed regions,
The relationship between male infertility and
anomalies of the constitutional karyotype has be-
come even more relevant since the development
of the intracytoplasmic sperm injection (ICSI) as the
most advanced therapy in male infertility. In fact,
one of the debates on the widespread use of ICSI
is that this technology could lead to the production
of abnormal fetuses through the use of chromoso-
mally unbalanced spermatozoa that have avoided
all the steps of the natural selection pathway (1).
Reduced fertility affects approximately 15% of cou-
ples worldwide and in about 40% of these a male
factor can be identified as the cause of childless-
ness (2). Genetic factors affecting gamete forma-
tion or function are responsible for a proportion of
Key-words: Male infertility, semen analysis, chromosome, heterochro-
matine.
Correspondence: Prof. Andrea Lenzi, Dipartimento di Fisiopatologia
Medica, Servizio di Seminologia e Immunologia della Riproduzione,
Policlinico Umberto I, 00161 Roma, Italy.
E-mail: lenzia@uniroma1.it
677

A. Antonelli, L. Gandini, P. Petrinelli, et al.
even if they do not interfere with X-Y bivalent, may
in themselves represent a signal for the meiotic
checkpoint that eliminates spermatocytes with
synaptic errors via p53-independent apoptosis, as
shown in mice (7).
erochromatic short arm has a high probability of be-
ing asynapsed, remains transcriptionally active dur-
ing meiosis and shows contacts with the X-Y bivalent
in a high proportion of the translocation carriers sper-
matocytes (13-15). Also the accessory marker chro-
mosomes formed by acrocentric short arms − 5-fold
more frequent in infertile males than in newborns (4)
− presumably affect spermatogenesis during pa-
chytene by interfering with X-chromosome inactiva-
tion through contacts between the sex vescicle and
NOR-carrying short arms (16). Finally, autosomal in-
versions − 8-fold more frequent in infertile males than
in newborns (4) − can be correlated to spermatogenic
impairment taking into account the meiotic behavior
of the inversion bivalent. In fact, small inverted seg-
ments may be asynapsed because of the difficulty in
loop-forming, whereas large inverted segments may
form loops that are not properly synapsed. In addi-
tion, the heterochromatic blocks possibly present in
the inverted segment are usually delayed in their pair-
ing, and this may have a particular disruptive effect
on the alignment and synapsis of adjacent euchro-
matic segments (17). In this respect, pericentric in-
version involving only the heterochromatin of chro-
mosomes 1 and 9 can represent a particular risk for
male infertility. This is true for chromosome 1 inver-
sions, regardless of the breakpoint positions (8, 18),
but not for chromosome 9 inversions. 9ph is common
in the general population and is considered a “normal
variant”, although contradictory data are reported
about its effect on reproductive fitness in males (19-
21). One explanation could be that inverted chro-
mosome 9 is likely to have different breakpoints
and/or heterochromatic blocks of different size (22).
In this respect, chromosomal regions made of con-
stitutive heterochromatin may play a relevant role.
As recently pointed out by investigations in other
species, such as Drosophila melanogaster, hete-
rochromatin has a wide range of actions influenc-
ing chromosome pairing and segregation, togeth-
er with gene expression and nuclear organization
(23). Therefore, variations in amount/position of het-
erochromatin play a role in disturbing synapsis of
the adjacent regions (17).
Regarding the numerical abnormalities of sex chro-
mosomes, the most common chromosome constitu-
tion is 47,XXY, mostly associated with azoospermia.
Indeed, the possibility of XXY cells producing ga-
metes seems so unlikely that the rare non-azoosper-
mic Klinefelter patients seen are possibly undetect-
ed XXY/XY mosaics (5). It is not yet known why XXY
cells cannot carry out meiosis (8). The considerable
overlap between the testicular pathologies in tri-
somies caused either by an additional X chromosome
or by an extra 21 suggests that this may be conse-
quent to pairing problems in pachytene of a super-
numerary chromosome rather than specific for X-chro-
mosome disomy (9). Thus, the excess of disomic XY
spermatozoa observed in XXY men (10) and in XXY
mice (11) may be the result of mis-segregation in XY
spermatocytes or of selection against XXY sperma-
tocytes bearing the XX bivalent.
On the other hand, patients with a supernumerary
Y chromosome, although more frequently observed
among infertile men than in newborn males (4),
have a spermatogenic profile ranging from severe
impairment to apparent normality as in the gener-
al population (5). Different explanations for “nor-
mal variability” were put forward. As suggested by
early meiotic studies (12, 13), XYY spermatogonia
tend to lose the supernumerary Y chromosome be-
fore or during meiosis thus ensuring the correct
continuation of the meiotic process. Alternatively,
XYY cells enter meiosis preferentially forming a YY
bivalent plus an X univalent or forming an XY biva-
lent plus a Y univalent (10); both conditions, by not
interfering with sex vescicle formation and X inacti-
vation, allow meiosis to proceed normally.
With regard to the different anomalies of chromo-
some structure correlated to spermatogenic impair-
ment, the data available show that they share the abil-
ity to cause disturbance in the spermatogenic pro-
cess. This possibly occurs through contacts between
asynapsed active autosomal material and sex chro-
mosomal chromatin; as a result, interference in (mei-
otic? X chromosome?) function should determine
spermatogenesis breakdown (6). Rearranged chro-
mosomes that can form a meiotic asymmetrical mul-
tivalent have a high probability of being asynapsed;
Robertsonian translocations are rearrangements at
special risk − 8.5 fold more frequent in infertile males
than in newborns (4) − and reciprocal translocations
involving one acrocentric chromosome. In the latter,
the nucleolus organizing region (NOR)-carrying het-
OUR EXPERIENCE
In order to investigate the role of chromosomal ab-
normalities in male infertility, we performed a study in
a selected group of 333 infertile patients, male part-
ners of infertile couples living in Rome and sur-
rounding areas, attending the Outpatients Depart-
ment of our Seminology Unit. Patients underwent
clinical andrological examination, seminal analysis and
laboratory screening for hormones (FSH, LH, PRL and
678

Chromosomes in male infertility
Table 1. Karyotypes, mean SD of age and sperm parameters of the 269 infertile non-azoospermic patients.
Karyotypes
Patients
(no.)
Age
(years)
Conc./ml
(no.x106)
Forward
motility
(%)
Atypical
forms
(%)
Normal
Abnormal
Variant
231
26
33.3 6.1
30.3 4.3
32.4 7.2
17.7 18.6
10.5 12.6
26.9 27.1
16.0 14.0
13.3 15.0
22.5 20.5
75.0 16.8
81.7 16.7
67.3 23.6
12
T). The selection criteria for cytogenetic studies based
upon seminal analyses were the presence of at least
one of the following conditions: azoospermia; severe
oligozoospermia (sperm concentration <5x106/ml);
oligozoospermia (sperm concentration 5-20x106/ml)
and normozoospermia (sperm concentration >20x-
106/ml) with failure to fertilize the partner’s oocytes
in an IVF program (at least 4 oocytes, all classified as
mature, unsuccessfully inseminated).
males were cultured in RPMI 1640 supplemented
with 10% fetal calf serum, penicillin, streptomycin
and 0.1 ml of phytohemagglutinin (PHA) M (Murex
Biotech). Metaphase chromosomes were prepared
from PHA-stimulated lymphocyte cultures. Chro-
mosome preparations were carried out according
to standard protocols. Three cultures were set up
for each patient. Chromosome identification was
performed by R banding. For this purpose bro-
modeoxyuridine (Budr) (final concentration 10-3 M)
was added to cultures 6 hours before harvesting
and chromosome preparations were stained with
Giemsa (RBG) or Acridine Orange (RBA).
Semen analysis
Semen analyses were carried out according to the
World Health Organization standards (24). All the se-
men samples were analyzed by the same biologists
without any knowledge of the karyotype. The follow-
ing variables were used for this study: sperm concen-
tration (no.x106/ml), total and forward sperm motility
(%), sperm morphology (% atypical forms). Several
sub-classes were identified on the basis of the sperm
parameters; 5 sub-classes for sperm concentration: a)
azoospermia; b) <5x106/ml; c) 5-10x106/ml; d) 11-
19x106/ml; e) ꢀ20x106/ml; 4 subclasses for sperm for-
ward motility: a) <10%; b) 10-24%; c) 25-50%; d)
>50%; and 4 subclasses for atypical forms: a) 100-
91%; b) 90-81%; c) 80-70%; d) <70%.
Differential stainings for active NORs was per-
formed by Ag-I. CBG banding was used when vari-
ations of amount/position of constitutive hete-
rochromatin were suspected. The heteromorphism
extent of the constitutive heterochromatin of chro-
mosomes 1, 9, 16 and Y were evaluated according
to Hsu et al. (25).
Statistical analysis of data was performed by
Student t test or by χ2 test (RxC Table).
Results and comments
In our group of 333 patients 42 had an abnormal
karyotype and 17 had a “variant” karyotype, i.e.
karyotype showing variations of chromosome struc-
ture usually referred to as “normal” in the literature,
Cytogenetic studies
Peripheral lymphocytes obtained from infertile
Table 2. Hormonal data of the infertile males studied.
Normal
karyotype
Abnormal
karyotype
Variant
karyotype
Sperm
FSH
LH
T
PRL
ng/ml
FSH
LH
T
PRL
FSH
LH
T
PRL
conc./ml mU/ml
mU/ml mg/ml
mU/ml mU/ml mg/ml ng/ml
mU/ml mU/ml ng/ml ng/ml
no.x106
0
18.2 10.8 13.2 8.8 5.6 1.9 9.3 9.5
11.3 6.1 7.5 4.8 6.7 3.7 10.2 4.3
9.0 4.5 6.7 4.1 6.6 2.5 6.9 6.2
6.0 2.8 4.7 1.9 6.4 3.2 6.5 2.9
5.5 2.7 4.6 2.2 6.5 15.7 9.3 22.1
25.8 11.5 15.6 9.0 3.0 3.0 9.7 3.8 12.6 11.5 7.1 4.9 5.0 2.5 11.7 3.8
<5
10.2 4.2 8.9 4.6 5.4 1.3 8.9 4.9
6.7 0.8 6.7 1.1 7.1 2.4 5.7 2.7
10.6 8.0 6.6 1.9 6.9 329 8.5 3.0
5.3 1.7 5.5 1.6 5.3 2.4 7.1 2.4
8.6 8.1 7.3 8.1 4.9 1.7 6.3 1.1
5-10
11-19
ꢀ20
-
-
-
-
17.0*
14.0*
4.2*
7.9*
5.9 1.6 6.1 1.9 4.8 1.5 9.4 2.6
Values are mean SD; *class represented by a single subject.
679

A. Antonelli, L. Gandini, P. Petrinelli, et al.
Table 3 - Seminal profiles and karyotypes of interest.
Patient
Karyotipe
Sperm conc. (x106/ml) Total motility (%) Forward motility (%) Abnormal morphology (%)
X-chromosome abnormalities
15 patients 47,XYY
0
-
-
-
Y-chromosome abnormalities
C.L.
D.V.
S.G.
A.R.
47,XYY
0.5
1.5
15
3
0
20
50
0
0
10
20
0
100
70
47,XYY
47,XYY
73
46,X,del(Y)(q12)
88
Robertsonian translocation
D.P.*
D.F.
45,der(13;14)(q10;q10)
0.4
1
0
0
0
100
100
85
45,der(13;14)(q10;q10)
45,der(13;15)(q10;q10)
45,der(13;14)(q10;q10)
45,der(13;14)(q10;q10)
45,der(13;14)(q10;q10)
45,der(13;14)(q10;q10)
45,der(14;21)(q10;q10)
45,der(13;14)(q10;q10)
45,der(13;14)(q10;q10)
5
T.A.
1.5
6
10
25
30
0
5
V.G.
10
20
0
70
R.M.
R.R.
12
13
15
18
25
25
78
95
M.S.**
G.L.
20
35
50
35
10
20
40
20
95
73
M.A.**
D.A.
60
78
Reciprocal translocations
P.R.
46,t(12;22)(q13;p11)
0
-
0
-
0
-
P.G.
M.P.
N.M.**
T.Y.
46,t(1;7)(q44;q12.2)
46,t(14;20)(p10;q10)
46,t(2;3)(p12;q26)
46,t(9;17)(p12;q24)
46,t(1;2)(p22;q23)
0.1
0.1
0.7
8
100
100
100
82
0
0
0
0
30
55
10
55
A.A
55
40
Supernumerary bisatellited marker chr.
L.F.
47,+mar
47,+mar
47,+mar
47,+mar
0.5
9
0
0
100
68
P.L.*
T.C.
S.M.
25
30
45
15
30
40
9
75
22
56
Pericentric inversion
G.A.°
46,inv(1)(p34q12)
0.5
0
0
100
Heterochromatin inversions
D.Ma*
D.Mi*
C.T.
46,1ph
46,1ph
46.9ph
46.9ph
46.9ph
46.9ph
46.9ph
46.9ph
46.9ph
46.9ph
46.9ph
12
15
0
35
25
-
25
15
-
60
78
-
U.F.
0
-
-
-
M.D.
R.G.
0.1
1
0
0
100
7
30
20
25
10
55
50
20
10
15
5
C.Mau.*
F.S.
2
87
90
79
48
55
4
M.M.
C.Mas.*
P.S.
12
27
80
55
50
*Maternally inherited; **paternally inherited; °de novo.
680

Chromosomes in male infertility
such as Yqh+, 9ph, double satellites on the short
arm of an acrocentric chromosome. The frequency
of each type of variant chromosome in our infertile
group was not significantly different from that ob-
served in unselected groups (26), with the excep-
tion of 9ph which is three times more frequent (19,
27). The frequency of azoospermia in our sample
was 19.2% (15.7%, 38% and 29.4% respectively
among men with normal, abnormal and variant
karyotype). As expected, most (94%) of the azoo-
spermic patients with abnormal karyotype are
Klinefelter patients.
Table 1 shows the seminal parameters of the non-
azoospermic patients grouped according to their kary-
otype: normal, abnormal and variant. The statistical
analysis of the data by the Student t test showed that
a significant difference in sperm concentration exists
between patients with normal and abnormal kary-
otype. For a more detailed analysis, we evaluated the
distribution of patients belonging to the 3 groups in
different sub-classes of seminal parameters (see Se-
men analysis). The results showed that chromosomal
variants have only a minimal influence on seminal pa-
rameters (and this only on the worst class of sperm
concentration), whilst chromosomal abnormalities play
a negative role in sperm concentration and morphol-
ogy, but have no impact on sperm motility: 1) 42% of
males with abnormal karyotype (vs 26% of those with
normal karyotype) fall into the worst class sperm con-
centration (>0 and <5x106/ml); 2) 38% of males with
abnormal karyotype (vs 19% of males with normal
karyotype) fall into the worst class for atypical forms
(100-91%); 3) only 17% of males with abnormal kary-
otype (vs 33% of men with normal karyotype) show
both normal sperm concentration (>20x 106/ml) and
normal rate of atypical forms (<70%); 4) 71% of infer-
tile men with normal karyotype and 80% of infertile
men with abnormal karyotype (not significantly dif-
ferent rates) show sperm motility lower than 25% .
Hormonal studies, as expected, showed an inverse
correlation between gonadotropin concentration and
sperm concentration (Table 2); the highest values
were found in the azoospermic patients, especially in
those affected by Klinefelter syndrome. These data
show a correlation between spermatogenesis im-
pairment and gonadotropins concentration, in par-
ticular in patients with chromosomal alterations, in
agreement with Foresta et al. (28). Prolactin and
testosterone values remained in the normal range.
To better correlate seminal parameters to the dif-
ferent chromosome constitutions, we grouped the
infertile males showing similar chromosome ab-
normalities (Table 3). We also included heterochro-
matin inversions of chromosome 9, because of their
still debated role in male infertility. The main con-
siderations we can draw are:
1) Robertsonian translocations are the most frequent
autosomal rearrangement in our group (3%),
whereas it is rare in the general population (0.07-
0.22%) (29). Independently of the chromosomes
involved, the majority of the patients showed ab-
normal seminal parameters with individual differ-
ences that may depend on different breakpoints
and/or different genetic background (30);
2) the 6 patients carrying reciprocal translocations
had different seminal characteristics, ranging
from normality to azoospermia. This correlates
well with the expected meiotic behavior of the
chromosomes involved in each translocation
based on the breakpoint localizations. Three
examples are shown in Figure 1. Indeed the t
(1;2) carrier is normozoospermic whereas the
(1;7) carrier showed the worst seminal profile
of the translocation carriers according to the
shortness of one arm in the quadrivalent con-
figuration expected in patient meiosis;
Fig. 1 - Examples of chromosomal rear-
rangements associated with different de-
grees of seminal impairment. a, b, c: the
reciprocal translocations observed re-
→
→
spectively in the patients A.A., N.M. and
→
→
→
P.G. The arrows indicate the breakpoints;
d: the pericentric inversion of chromo-
some 1 observed in the patient G.A. The
a
b
c
arrows indicate the breakpoints; e, f: the
supernumerary marker chromosomes ob-
served respectively in the patients S.M.
and P.L. Both markers are bisatellited (see
the specific staining of NORs, on the left
of each figure), but show different amount
of pericentromeric heterochromatin (see
C-positive regions, on the right of each
figure). The arrows indicate the marker
→
→
e
f
d
chromosomes.
681

A. Antonelli, L. Gandini, P. Petrinelli, et al.
4. Van Assche E., Bonduelle M., Tournaye H., Joris H.,
Verheyen G., Devroey P., Van Stirteghem A.,
Liebaers I.
3) of the 4 supernumerary bisatellited marker chro-
mosomes studied, one (patient S.M.) showed a sin-
gle centromeric C-band and the other three had a
bipartite centromeric C-band. According to the
classification proposed by Steinbach et al. (31), they
are presumed to be without phenotipic effects, but
all were carried by infertile men. In particular, the
presence of the marker characterized by a single
centromeric C-band is associated with the less se-
vere spermatogenic impairment (Fig. 1);
4) 7 of the 9 patiens carrying the inversions that in-
volve the pericentromeric heterochromatin of
chromosome 9 show azoospermia or severe
oligoasthenoteratozoospermia, although 9ph is
referred to as variant in the literature.
In conclusion, the incidence of chromosomal ano-
malies among the infertile men in this series (7.8%)
strongly suggests that cytogenetic screening should
be a part of preparatory evaluation prior to every
kind of assisted reproduction. Therefore, constitu-
tional chromosome analysis is to be recommend-
ed, above all prior to ICSI, in which selective hur-
dles eliminating abnormal germ cells are bypassed.
This kind of investigation is a pre-requisite for eval-
uating sperm aneuploidy frequency in order to
avoid unexplained failures and to minimize the risk
of transmitting chromosomal abnormalities poten-
tially responsible for increased male infertility and
even for multiple congenital anomalies of the con-
ceptus. Therefore, close cooperation between an-
drologists and cytogenetists could ensure good se-
lection of the infertile male at risk undoubtedly re-
sulting in a positive cost/benefit ratio (32, 33).
Cytogenetics of infertile men.
Hum. Reprod. 1996, 11 (Suppl. 4): 1-26.
5. Egozcue S., Blanco J., Vendrell J.M., Garcia F., Veiga
A., Aran B., Barri P.N., Vidal F., Egozcue J.
Human male infertility: chromosome anomalies, mei-
otic disorders, abnormal spermatozoa and recurrent
abortion.
Hum. Reprod. Update 2000, 6: 93-105.
6. Lifschytz E., Lindsley D.L.
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7. Odorisio T., Rodriguez T.A., Evans E.P., Clarke A.R.,
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The meiotic checkpoint monitoring synapsis elim-
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ACKNOWLEDGMENTS
This work was partially supported by a grant of “La Sapienza”
University, Rome. We are grateful to M. Proietti and L. Verni for
their skilful technical participation in this work.
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682

Chromosomes in male infertility
X-Y quadrivalent association and sterility in a man
carrier of a reciprocal autosomal translocation in-
volving the whole arm of an acrocentric chromosome
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