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Cytogenetic
and andrological status and ICSI-results in couples with severe male factor
infertility
G.
Haidl1, B. Peschka2, G. Schwanitz2, M.
Montag3, K.van der Ven3, H. van der Ven3
Asian J Androl 2000 Dec; 2: 293-296
Keywords:
male
infertility; intracytoplasmic sperm injection; chromosome aberrations
Abstract
Aim: To pursue whether cytogenetic aberrations correlate with specific spermatological or hormonal abnormalities. Methods: 305 infertile couples were investigated. All male partners were referred to a complete andrological work-up with physical examination, determination of hormones, HIV testing and semen analysis. Cytogenetic analysis was carried out in both partners by means of standard techniques using cultured lymphocytes from peripheral blood. Results: Among the 305 couples, 10 men (3.2%) and 10 women (3.2%) showed constitutional chromosomal aberrations, including reciprocal translocations (n=7), Robertsonian translocations (n=3), inversions (n=3), other structural aberrations (n=4) and sex chromosome aberrations (n=3). In addition to the impaired sperm count in most of the patients, a tendency to an increased proportion of spermatozoa with acrosome defect was observed. Conclusion: Chromosomal aberrations may contribute to the low fertilization and pregnancy rates in the infertile couples.1 Introduction
It is known for a long time that among the spectrum of causes of male fertility disturbances, chromosomal aberrations occur in about 2-3% of unselected patients with proven subfertility[1]. In patients with sperm counts below 10 million/mL this rate is estimated to be 5-7%, with the percentage of cytogenetically abnormal causes rising up to 10-15% in azoospermic men[2]. Whereas in the pre-ICSI (intracytoplasmic sperm injection) era there was hardly any chance for such patients to father a child, the modern techniques of assisted reproduction now offer new possibilities for patients with severe male factor infertility. Therefore, amore exact andrological characterization of patients with chromosomal abnormalities in addition to the genetic work-up may be helpful for the clinical andrologist, as sperm count alone is quite an unspecific feature. Apart from the ICSI outcome the aim of the present study was to look whether cytogenetic aberrations correlate with specific spermatological or hormonal abnormalities.2 Patient and methods
Between May 1995 and June 1996, 305 couples were counselled at the outpatient clinic of the Dept. of Gynecological Endocrinology and Reproductive Medicine prior to ICSI-treatment. All male partners were referred to a complete andrological work-up with physical examination, determination of hormones, HIV testing, and semen analysis according to WHO standards[3] with the assessment of sperm morphology following the Dsseldorf criteria[4]. Cytogenetic analysis was carried out in both partners by means of standard techniques using cultured lymphocytes from peripheral blood. Most of the couples have undergone one or more ICSI-cycles; some of them had previous IUIs (intrauterine inseminations) or conventional IvF (in vitro fertilization).3 Results
In
10 out of 305 men (3.2%) constitutional
anomalies were detected. Interestingly, also 10 (3.2%) women exhibited
cytogenetic aberrations and in one couple, both partners had anomalies.
The observed aberrations comprised gonosomal disturbances (n=3),
reciprocal translocations (n=7), Robertsonian translocations (n=3),
inversions (n=3), and other aberrations (n=4) (Table 1 a-c).
Table
1. Constitutional chromosome aberrations in 305 couples undergoing ICSI-treatment.
|
|
Age |
Karyotypes |
| 1a:
Gonosomal |
35 |
47,XXX |
| 41 |
47,XXY
(46 XY, 48 XXXY) |
|
| 34 |
46,XY,
der (Y) |
|
| 1b:
Autosomal aberrations |
||
| Reciprocal |
37 |
46,XY,
t(1;2)(p34.1;p21) |
| translocations |
30 |
46,XY,
t(4;5)(q21;q11.2) |
| 30 |
46,XY,
t(1;21)(1;9;21) |
|
| 40 |
46,XX,
t(5;19)(cen,cen) |
|
| 40 |
46,XY,
t(3;12)(p24;p12) |
|
| 38 |
46,XY,
t(1;5)(p32;q31) |
|
| 37 |
46,XX,
t(3;18)(q24;p11.3) |
|
| Robertsonian |
25 |
45,XX,
-13,-14, +t(13;14) |
| translocations |
38 |
45,XY,
-13,-14, +t(13;14) |
| 31 |
45,XX,
-14,-15, +t(14;15) |
|
| 1c:
Inversions |
40 |
46,XX,
inv (5)(p14.2;q22) |
| 34 |
46,XY,
inv(7)(q11.2;q22) |
|
| 32 |
46,XX,
inv(18)(p13.2;q13.1) |
|
| Other
structural |
32 |
46,XX,
dic (21) |
| aberrations |
34 |
46,XY,
der (9) |
| 30 |
46,XX,
der (9),add(9)(p12) |
|
| 24 |
46,XX,
der (9),add(9)(p12) |
|
Sperm
counts in these ten men ranged between 0 and 78 million/mL (median 0.6
million/mL); 0-10% normal spermatozoa were observed with acrosome defects
predominating in two third of the patients. FSH values were within the
normal range in the majority of patients (Table 2).
Table
2. Karyotypes and corresponding semen parameters and hormonal values of
the male patients.
|
Karyotypes |
Semen
parameters |
FSH
(mU/mL) |
||
| Sperm
count (million/mL) |
Progressive
motility (%) |
Normal
forms (%) |
||
| 47,XXY,(46XY,
48XXXY) |
0.1-1 |
0-2 |
0 |
15.5 |
| 46,XY,
der (Y) |
0.1 |
0 |
0 |
14.0 |
| 46,XY,
t(1;2)(p34.1,p21) |
1-5 |
50 |
5 |
4.8 |
| 46,XY,
t(4;5)(q21,q11.2) |
1.2-6.2 |
10-28 |
7 |
6.6 |
| 46,XY,
t(1;21)(1,9,21) |
0.1 |
20 |
0 |
4.1 |
| 46,XY,
t(3;12)(p24;p12) |
51-78 |
32-58 |
10 |
3.8 |
| 46,XY,
t(1;5)(p32;q31) |
0.6-5.5 |
20-75 |
0-10* |
7.9 |
| 46,XY,
inv(7)(q11.2;q22) |
2 |
20 |
10 |
5.2 |
| 46,XY,
der(9) |
0.1 |
2 |
3 |
4.0 |
*before
and after traetment of a varicocele
In
14 out of 19 couples 28 ICSI cycles were performed, with two cycles per
couple, one cycle after MESA (microsurgical epididymal sperm aspiration)
and the other following TESE (testicular sperm extraction). The
fertilization rate ranged between 0 and 100% per cycle (median 42%). One
ongoing pregnancy was achieved in a couple
with the female partner bearing the cytogenetic anomaly 45 XX, -14,
-15, +t (14; 15, and a second one occurred spontaneously, also the female
partner showing a
Robertsonian translocation 45 XX, -13, -14, +t (13; 14). The overall
fertilization rate during the same time period was 66% per cycle, the
rate of ongoing pregnancies amounted to 24% (Table 3). One couple underwent
only one conventional IvF trial (no fertilization).
Table
3. Treatment.
|
|
ICSI-cycles |
Fertilization-rate |
Pregnancy-rate |
| Patients
with Chromosomal Aberrations |
28(n=14) |
42% |
1
(Rob. T.) |
| All
Patients |
485(n=305) |
66% |
24% |
4 Discussion
The
incidence of men with constitutional chromosomal anomalies in our group
of patients with subfertility was 3.2%, which is comparable with other
reports[5,6]. Among
patients with sperm counts below 10 million/mL, this percentage rised
to 6%, which is also within the range reported in the literature[2].
The number of patients
is rather small to draw firm conclusions from certain chromosomal aberrations
to defined disturbances of spermiogenesis. Apart from one patient, sperm
counts were far below 10 million/mL, and with regard to sperm morphology,
there was an increased
prevalence of acrosome defects in this population. FSH values were not
conclusive either. Five out of nine males in our patient group showed
reciprocal translocations
with chromosomes 1, 2, 3, 4, 5, 12, and 21 affected. Reciprocal translocations
of chromosomes 1, 3, 7, 17, 19, and 22 were assumed to lead preferably
to embryonic death, whereas translocations of chromosomes 5, 9, 14, and
21 were associated
with disabled newborn[7,8]. Recently, Robertsonian translocations
of chromosomes 13 and 14 were reported to cause oligoasthenoteratozoospermia[9].
One of our patients showed such a translocation. In view of the low fertilization
rates one may conclude that chromosomal aberrations of the male represent
a major hurdle with regard to fertilization and pregnancy. Two pregnancies
(one spontaneous) were achieved in couples with maternal Robertsonian
translocation. In a follow-up
study it could be confirmed that couples with constitutional aberrations
in the male showed significantly lower fertilization, implantation and
pregnancy rates, whereas female constitutional chromosome aberrations
led to lower fertilization rates with implantation and pregnancy rates
similar to the control group. Whether the impaired fertilization rates
are related to the abnormally distributed
chromosomes in the spermatozoa or to the poor sperm
morphology with subsequently disturbed activation of the oocytes
has still to be worked out. In
all couples where an abortion occurred, mainly parental autosomal aberrations
were involved[10]. Similar results were obtained by other groups[11,12],
however, Causio et al[13] reported no differences in
the rates of developed embryos in couples
with abnormal (n=11) and normal (n=290) chromosomal analysis.
Moreover, Yoshida et al[14]
also detected no difference in the cleavage rates between couples
with karyotypically normal and abnormal men. With regard to the reproductive
relevance of chromosome aberrations, Meschede et al[6]
pointed out that many
of the abnormalities they diagnosed could be classified as carrying only
a small to moderate reproductive risk. In this context the observation
on one of our patients
with a reciprocal translocation of the chromosomes 1 and 5 and an additional
varicocele is of interest, because treatment of the varicocele lead to
a significant improvement of sperm parameters.
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Correspondence
to: Dr.
G. Haidl, Dept. of Dermatology and Andrology, University of Bonn, Sigmund-Freud-Str.
25, 53105, Bonn, Germany.
Tel: +49-228-287 5396 Fax: +49-228-287 4656
e-mail: gerhand.haidl@meb.uni-bonn.de
Received
2000-08-30 Accepted 2000-10-26
