Sex Chromosome Aberrations and Transsexualism: VOL. 79, NO. 3, MARCH 2003

FERTILITY AND STERILITY威
VOL. 79, NO. 3, MARCH 2003

Copyright ©2003 American Society for Reproductive Medicine
Published by Elsevier Science Inc.
Printed on acid-free paper in U.S.A.
Sex chromosome aberrations and transsexualism

Transsexualism is the most extreme form of gender dysphoria, which means that an individual with an
apparently normal somatic sexual differentiation has the unalterable conviction that he or she is a member of
the opposite sex. Hormonal treatment and sex reassignment surgery effectively enable transgender persons to
make their bodies as congruent as possible with the preferred sex. The diagnosis is based on formal psychiatric
classification criteria. However, the phenomenon remains enigmatic.
Chromosomal investigation of putative sex chromosome aberrations are routinely involved in the diag-
nostic management of transsexualism. Although this is more important for enabling diagnostic separation of
transsexualism from, for example, genetically determined intersex, the discussion of to what extent other sex
chromosome aberrations are involved in transsexualism comes up occasionally. Although different studies
analyzing G-banded karyotypes have shown that most transsexuals have no microscopically detectable
abnormalities, this discussion is reinitiated by a few reports describing male-to-female transsexuals with a
47,XYY karyotype. Recently, a female-to-male transsexual with a 47,XXX karyotype was reported (1).
In this study, we cytogenetically analyzed 30 male-to-female and 31 female-to-male transsexuals. They
ranged in age from 19 to 63 years. In Austria, chromosomal investigation of putative sex chromosome
aberrations is a required part of the routine diagnostic management of transsexualism. In addition, as part of
genetic counseling, each patient was asked to sign a written informed consent concerning the other genetic
analyses performed in the course of this study. This written informed consent was designed according to
Austrian gene technology law. Chromosomes were prepared from peripheral lymphocytes, and G-banding was
produced by means of the trypsin-Giemsa method. We could not detect any chromosomal aberrations with the
exception of one balanced translocation 46,XY,t(6;17)(p21.3;q23). Importantly, no sex chromosomal aber-
rations, which would be detectable on the G-banded chromosome level, have been observed.
For a more detailed analysis of putative sex chromosome aberrations we performed fluorescence in situ
hybridization (FISH) analyses using the locus-specific identifier DNA probes for the androgen receptor gene
locus on chromosome Xq12 and for the SRY (sex-determining region of the Y chromosome) locus on
chromosome Yp11.3 (Vysis, Inc., Downer’s Grove, IL) according to the manufacturer’s instructions. It is well
known that aberrations of these regions can affect human sexual development. The aim of these FISH analyses
was also to investigate putative submicroscopic alterations due to, for example, translocations involving sex
chromosomes. This molecular-cytogenetic analysis did not reveal any submicroscopic aberrations in these
regions: In all patients harboring a 46,XX karyotype we found two signals for the androgen receptor gene
locus (on the two X chromosomes), but we did not find an additional signal on any other chromosome or an
SRY-positive gene region. In all 46,XY transsexuals, we found one signal specific for the androgen receptor
region and one SRY-specific signal on the X and the Y chromosome, respectively (Table 1). These data
provide evidence that molecular-cytogenetic alterations affecting the androgen receptor gene region or the
SRY region do not play a role in transsexualism.
Received April 4, 2002;
revised and accepted July In addition to the testis determining factor (SRY), the Y chromosome harbors genes important for
19, 2002. spermatogenesis. Microdeletions in the AZF region on the long arm of the Y chromosome can pathogeneti-
Markus Hengstschläger cally be involved in cases of male factor infertility associated with azoospermia or severe oligozoospermia.
and Michael van This region is divided into three nonoverlapping parts: AZFa, AZFb, and AZFc (the proximal part of the AZFc
Trotsenburg contributed microdeletion is sometimes designated AZFd). The involvement of several different genes within these
equally to this work.
regions, such as DAZ, RBM, DFFRY, DBY, and CDY, has been described. Although all are candidate genes
Reprint requests: Markus
Hengstschläger, Ph.D., for the regulation of spermatogenesis, their real and full functional spectrum remains elusive. It is suggested
Prenatal Diagnosis and that the expected frequency of AZF microdeletions in infertile men could be around 7%, varying between 1%
Therapy, Obstetrics and and 55.5% (2, 3).
Gynecology, University of
Vienna, Währinger Gürtel We performed AZF-specific polymerase chain reaction (PCR) analysis in the 30 male-to-female and 31
18-20, A-1090 Vienna, female-to-male transsexuals. Genomic DNA was prepared from peripheral lymphocytes by the proteinase K
Austria (FAX: 43-1-40400- digest/protein-salting-out method. PCR analysis of the AZF region was performed using the Y chromosome
7848; E-mail: markus.
hengstschlaeger@
deletion detection system from Promega (Madison, WI). This multiplex PCR system consists of 18 primer
akh-wien.ac.at). pairs that are homologous to previously identified and mapped sequence tagged sites to amplify nonpoly-
morphic short DNA regions within the AZF region. As negative and positive controls, every reaction included
0015-0282/03/$30.00 one sample of female and fertile male genomic DNA, respectively. In addition, control genomic DNA from
doi:10.1016/S0015-0282(02)
04805-7 patients known to harbor Y chromosome microdeletions were kindly provided by Prof. M. Simoni (Institute
639
TABLE 1
Sex chromosome aberrations and transsexualism.
30 Male-to-female 31 Female-to-male
Karyotype All normal 46,XY except one 46,XY,t(6;17) All normal 46,XX
FISH for androgen receptor gene All normal (one signal on the X chromosome) All normal (two signals, each on one of the two X
locus chromosomes)
FISH for sex-determining region Y All normal (one signal on the Y chromosome) All normal (no signal detected)
PCR for Y-chromosome 29 normal; 1 deletion carrier All normal (no positive PCR result for the AZF region)
microdeletions
Note: FISH ⫽ fluorescence in situ hybridization; PCR ⫽ polymerase chain reaction.
Hengstschläger. Genetics and transsexualism. Fertil Steril 2003.
of Reproductive Medicine of the University of Münster, Germany). recent discussion of gamete banking before hormonal and sex
In none of the patients with a 46,XX karyotype could we detect reassignment surgery of transsexuals (4).
AZF gene sequences. These data once again provide evidence that
none of them harbors Y chromosome material (translocated to
another chromosome). Interestingly, one of the 30 male-to-female
transsexuals exhibited an AZF microdeletion (Table 1).
The data described here provide evidence that genetic aberra- Acknowledgments: The authors thank M. Rosner, Prenatal Diagnosis and
tions detectable on the chromosome level are not significantly Therapy, and A. Maar, Obstetrics and Gynecology, for helpful discussion
associated with transsexualism. In addition, molecular-cytogenetic and technical support.
FISH analyses did not reveal deletions of the androgen receptor
Markus Hengstschläger, Ph.D.a
gene locus on chromosome Xq12 or of the SRY locus on chromo-
Michael van Trotsenburg, M.D.b
some Yp11.3. Multiplex PCR analyses demonstrated one AZF
Christa Repa, M.L.T.a
deletion in a male-to-female transsexual.
Erika Marton, M.L.T.a
IVF techniques, such as intracytoplasmic sperm injection, en- Johannes C. Huber, M.D.b
able treatment of impaired fertility associated with microdeletions Gerhard Bernaschek, M.D.a
of the Y chromosome. The couple should be informed about the Prenatal Diagnosis and Therapya and Gynecologic
risk that male children will inherit the defective Y chromosome Endocrinology and Reproductive Medicine,b Department
from the father. The patients should further be informed that so far of Obstetrics and Gynecology, University of Vienna,
there is no known evidence of any other health consequences of Vienna, Austria
these microdeletions. There is no doubt that the one case reported References
here of Y chromosome microdeletion associated with transsexual- 1. Turan MT, Esel E, Dündar M, Candemir Z, Bastürk M, Sofuoglu S, et al.
ism should not be involved in up-to-date genetic counseling. It is Female-to-male transsexual with 47,XXX karyotype. Biol Psych 2000;
further important that the description of a female-to-male transsex- 48:1116 –7.
2. Simoni M, Bakker E, Eurlings MCM, Matthijs G, Moro E, Müller CR,
ual with a 47,XXX karyotype (1) is not considered in the course of et al. Laboratory guidelines for molecular diagnosis of Y-chromosomal
genetic counseling for a prenatal diagnosis of a 47,XXX karyotype. microdeletions. Int J Androl 1999;22:292–9.
3. Hargreave TB. Genetics and male infertility. Curr Opin Obstet Gynecol
However, the detection of one carrier of a Y chromosome 2000;12:207–19.
4. De Sutter P. Gender reassignment and assisted reproduction. Present and
microdeletion out of 30 male-to-female transsexuals could argue future reproductive options for transsexual people. Hum Reprod 2001;
for further investigations. This is of special interest in light of the 16:612–4.
640 Hengstschläger et al. Correspondence Vol. 79, No. 3, March 2003

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FERTILITY AND STERILITY威

VOL. 79, NO. 3, MARCH 2003

Sex chromosome aberrations and transsexualism

Sex chromosome aberrations and transsexualism.

640 Hengstschläger et al. Correspondence Vol. 79, No. 3, March 2003

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