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A Polymorphism of the CYP17 Gene Related to Sex Steroid Metabolism is Associated With Female-to-Male But Not Male-to-Female Transsexualism

Bentz, Eva-Katrin; Hefler, Lukas A.; Kaufmann, Ulrike; Huber, Johannes C.; Kolbus, Andrea; Tempfer, Clemens B.

Obstetrical & Gynecological Survey: December 2008 - Volume 63 - Issue 12 - p 775-777
doi: 10.1097/01.ogx.0000338093.21452.0b
Gynecology: Genetics

Transsexualism is a rare condition. Although its etiology is unknown, it has been speculated that sex steroids may play an important role during early brain development. There may be a genetic component based on reports of an association between male to female (MtF) transsexualism and a CA repeat polymorphism in the estrogen receptor beta gene. CYP17 A2 T>C is a functional single nucleotide polymorphism (SNP) of the common cytochome P-450 that is associated with elevated serum and plasma levels of estradiol (E2), progesterone, and testosterone. The authors hypothesized that CYP17 A2 T>C is associated with transsexualism and that mutant alleles would be overrepresented among individuals with this condition.

This case-control study assesses the association between transsexualism and allele and genotype frequencies of CYP17 A2 T>C SNP in a series of Caucasian transsexuals compared with controls. The participants were 102 male-to-female (MtF) and 49 female-to-male (FtM) transsexuals, 756 male controls, and 915 female controls. The mean age at presentation of FtM transsexuals was 33.2 and that of MtF transsexuals was 41.8 years.

CYP17 A2 T>C SNP allele frequencies were statistically significantly different between FtM transsexuals and female controls (CYP17 T: 56% and CYP17 C: 44% versus CYP17 T: [69%] and CYP17 C: [31%], respectively). Genotype distributions were also different between FtM transsexuals and female controls. In contrast, no statistically significantly differences between MtF transsexuals and male controls were found in the CYP17 A2 T>C allele and genotype distributions. The allele distribution of CYP17 A2 T>C was gender-specific among male and female controls in that a higher mutant C allele frequency occurred in the male controls (CYP17 C: males; [40%] versus females [31%]), respectively; P ≤ .001. Allele distribution in the MtF transsexuals was equivalent to male controls. In contrast, FtM transsexuals did not follow the gender-specific allele distribution of female controls but instead had an allele distribution equivalent to MtF transsexuals and male controls.

The overrepresentation of CYP17 A2 T>C SNP among FtM transsexuals but not MtFs supports this polymorphism as a candidate gene of FtM transsexualism. The loss of a female-specific CYP17 A2 T>C allele distribution pattern may predispose women to become transsexuals.

Departments of Gynecologic Endocrinology and Reproductive Medicine; and Obstetrics and Gynecology, Medical University, Vienna, Vienna, Austria

Fertil Steril 2008;90:56–59

© 2008 Lippincott Williams & Wilkins, Inc.