Sex steroid-related genes and male-to-female transsexualism
Introduction
The term transsexualism denotes people whose gender identity is at conflict with their genetic sex and physical appearance. Transsexuals are often said to be ‘trapped in the body of the wrong sex’, and they urge to change their physical appearance to resemble the opposite sex as closely as possible (World Health Organization, Cohen-Kettenis and Gooren, 1999). Although transsexualism is a rare phenomenon—the prevalence of male-to-female transsexualism has been estimated to 1:12.000–1:40.000 (Landén et al., 1996b)—the condition raises important questions as to how the gender identity is moulded in humans.
Many authors have suggested that transsexualism may be due to an aberration in the early organizational influence of sex steroids on brain development (Dörner et al., 1991, Bosinski et al., 1997, van Goozen et al., 2002), a notion that has gained considerable support from the study of intersexed individuals (Diamond and Sigmundson, 1997, Berenbaum and Bailey, 2003, Servin et al., 2003) and is compatible with findings in neurobiological studies (Zhou et al., 1995, Kruijver et al., 2000). The involvement of genetic factors in male-to-female transsexualism gains support from case reports on twin and non-twin siblings being concordant for this very rare condition, and from reports on families with more than one member being a male-to-female transsexual (Green, 2000). There is, however, no information available on specific gene variants enhancing or reducing the likelihood of developing transsexualism.
Animal experiments have clearly demonstrated the importance of pre- and neonatal androgen production for the sexual differentiation of the brain. The masculinizing effect of androgens on the developing male brain appears to be exerted mainly through the conversion of testosterone into estrogen by aromatase (estrogen synthetase; Cyp 19), and the consequent activation of estrogen receptors (ERs) of the α and β subtypes (Cooke et al., 1998). Androgen receptors (ARs), however, are of importance for the activity and expression of aromatase in the hypothalamus during embryonic development (Hutchison, 1997), and may also exert a direct effect on sexual differentiation parallel with that of ERs (Sato et al., 2004). A behavioural feminization of male rodents may hence be obtained by a pre- or neonatal administration of compounds inhibiting the ARs, the aromatase, or the ERs.
Hence, the genes coding for the AR, aromatase, and ERβ are reasonable candidates in the quest for genes that may influence the likelihood of developing transsexualism. These three genes all comprise intron or exon repeat polymorphisms, three of which were examined in this investigation.
In the AR gene, a CAG trinucleotide repeat sequence in exon 1 of the gene (Choong and Wilson, 1998) was studied. The length of this microsatellite has been shown to correlate inversely with the activity of the AR as a transcription factor (Irvine et al., 2000). A relatively long CAG repeat length, within the normal range, is hence assumed to lead to low androgen receptor activity, and has been associated with a low risk of prostate cancer and benign prostate hyperplasia, and to a high risk of infertility (Yong et al., 2000). The androgen receptor is located on the X chromosome; in males there is hence only one allele in each individual to consider.
The polymorphism studied in the aromatase gene is a tetranucleotide repeat region in the fourth intron. There are reasons to believe that the length of repeat nucleotide sequences (micro/minisatellites) influence the transcription and the translation of a gene also when the repeat is situated in an intron (Comings, 1998). In fact, recent studies have found the aromatase intron repeat polymorphism to be associated with breast cancer (Dunning et al., 1999), endometrial cancer (Berstein et al., 2001), and serum levels of sex steroids (Haiman et al., 2000).
Two ERs have been identified, the α and the β subtype (Enmark and Gustafsson, 1999). The relative importance of these two variants for the sexual differentiation of the brain remains to be clarified. It is notably though, that the expression of the β subtype is higher than the α subtype in several brain areas (Österlund and Hurd, 2001) and that mice devoid of ERβ receptors display abnormal development of the central nervous system (Wang et al., 2001). We choose therefore to examine a polymorphism of the ERβ gene. This dinucleotide CA repeat sequence located in intron 5 of the gene (Tsukamoto et al., 1998) has previously been associated with bone mineral density (Ogawa et al., 2000b), blood pressure (Ogawa et al., 2000a), and androgen levels in women (Westberg et al., 2001).
The aim of the present study was to investigate the potential importance of these three polymorphisms and their interactions for the susceptibility for transsexualism. Notably, the polymorphisms studied are all much more common than is transsexualism; hence, the goal of this study was not to reveal the primary cause of transsexualism, but to elucidate whether the studied genes may facilitate or prevent the development of this very rare condition.
Section snippets
Subjects
Three University clinics in Sweden (Göteborg, Umeå, and Uppsala), specialized in assessment and treatment of patients with gender identity disorders, recruited 29 Caucasian male-to-female transsexuals. All subjects fulfilled the diagnostic criteria for gender identity disorder in DSM-IV (American Psychiatric Association, 1994). Controls were recruited from a cohort of men identified by means of the National Population Registry that were born during the first 6 months of 1944 and living in
Results
Seventeen different alleles were identified for the AR gene polymorphism, six for the aromatase repeat, and 12 for the ERβ repeat polymorphism. The frequencies of the alleles in controls and transsexuals are shown in Table 1. The percentages of each allele are shown in Fig. 1a (AR), b (aromatase), and c (ERβ). With respect to the individual polymorphisms, only the ERβ repeat differed significantly between transsexuals and controls, the mean length being greater in transsexuals (P=0.03). The
Discussion
Whereas transsexualism is a very rare condition, the gene variants investigated in this study are relatively common; none of the studied variants could hence be assumed to be a primary cause of this condition. On the other hand, it is not unlikely that polymorphisms in genes of importance for the sexual differentiation of the brain may enhance or reduce the likelihood for developing transsexualism. Accordingly, the current results do suggest that a long ERβ repeat is more common among
Acknowledgements
The authors are indebted to the patients and controls participating in this study. We thank study nurse Benita Gezelius and technicians Inger Oscarsson and Gunilla Bourghardt for skilful assistance. This study was supported by grants from the Swedish Medical Research Council (Grant Nos 8668, 12260, 12345 and 529-2002-6696), Lundberg's Foundation, Wallenberg's Foundation, Thuring's Foundation, Lundbeck's Foundation, and Torsten Amundson's Foundation.
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