A polymorphism of the CYP17 gene related to sex steroid metabolism is associated with female-to-male but not male-to-female transsexualism.

OBJECTIVE: To assess the association between transsexualism and allele and genotype frequencies of the common cytochrome P450 (CYP) 17 -34 T>C single nucleotide polymorphism (SNP). DESIGN: Case-control study. SETTING: Academic research institution. PATIENT(S): 102 male-to-female (MtF) and 49 female-to-male (FtM) transsexuals, 756 male controls, and 915 female controls. INTERVENTION(S): Buccal swabs and multiplex polymerase chain reaction on a microarray system. MAIN OUTCOME MEASURE(S): Analysis of the CYP17 -34 T>C SNP. RESULT(S): CYP17 -34 T>C SNP allele frequencies were statistically significantly different between FtM transsexuals and female controls (CYP17 T: 55/98 [56%] and CYP17 C: 43/98 [44%] versus CYP17 T: 1253/1826 [69%] and CYP17 C: 573/1826 [31%], respectively). In accordance, genotype distributions were also different between FtM transsexuals and female controls using a recessive genotype model (CYP17 T/T+T/C: 39/49 [80%] and C/C 10/49 [20%] vs. CYP17 T/T+T/C: 821/913 [90%] and C/C 92/913 [10%], respectively). The CYP17 -34 T>C allele and genotype distributions were not statistically significantly different between MtF transsexuals and male controls. Of note, the CYP17 -34 T>C allele distribution was gender-specific among controls (CYP17 C: males; 604 of 1512 [40%] vs. females; 573 of 1826 [31%]). The MtF transsexuals had an allele distribution equivalent to male controls, whereas FtM transsexuals did not follow the gender-specific allele distribution of female controls but rather had an allele distribution equivalent to MtF transsexuals and male controls. CONCLUSION(S): These data support CYP17 as a candidate gene of FtM transsexualism and indicate that loss of a female-specific CYP17 T -34C allele distribution pattern is associated with FtM transsexualism.

A common polymorphism of the SRD5A2 gene and transsexualism.

The relation between genetic variation of the androgen metabolism and transsexualism is unknown. In a case-control study of 100 male-to-female (MtF) transsexuals, 47 female-to-male (FtM) transsexuals, and 1670 controls, the authors assess allele and genotype frequencies of the steroid 5-alpha reductase (SRD5A2) Val89Leu polymorphism using polymerase chain reaction. Allele and genotype frequencies are not significantly different between MtF transsexuals and male controls (SRD5A2 V: 137/200 [69%] and SRD5A2 L: 63/200 [31%] vs 1065/1510 [71%] and 445/1510 [29%], respectively; P = .6; odds ratio [OR], 1.10; 95% confidence interval [CI], 0.76-1.58; SRD5A2 V/V+V/L: 92/100 [92%] and L/L 8/100 [8%] vs SRD5A2 683/755 [91%] and 72/755 [9%], respectively, P = .7; OR, 0.82; 95% CI, 0.24-2.84). Allele and genotype frequencies are also not significantly different between FtM transsexuals and female controls (SRD5A2 V: 70/94 [74%] and SRD5A2 L: 24/94 [26%] vs 1253/1830 [69%] and 573/1830 [31%], respectively; P = .3; OR, 0.75; 95% CI, 0.45-1.26; SRD5A2 V/V+V/L: 44/47 [93%] and L/L 3/47 [7%] vs 823/915 [90%] and 92/915 [10%], respectively, P = .6; OR, 0.61; 95% CI, 0.11-3.32). Of note, there is no gender-specific genotype distribution among controls. The SRD5A2 Val89Leu SNP is not associated with transsexualism, refuting SRD5A2 as a candidate gene of transsexualism.

Evidence for several fold more activity of NAD+-dependent uterine prostaglandin 15-hydroxydehydrogenase in transsexual than in non-transsexual women.

The activity of NAD+-dependent PGDH was measured in the cytosolic fractions (100,000 x g) of uterine tissues obtained from transsexual, pregnant and non-pregnant women. The specific activity (mean +/- SD) of the enzyme at maximum velocity of the enzyme reaction in these three groups of women was 5.5 +/- 2.30, 0.53 +/- 0.27 and 0.54 +/- 0.25 mU/mg protein respectively using PGE2 as substrate, and with PGF2 alpha as substrate the respective values were 5.48 +/- 2.80, 0.49 +/- 0.41 and 0.51 +/- 0.30 mU/mg protein. These data suggest that, with either substrate, the uterine enzyme activity in the transsexuals was about 10-fold greater than in pregnant and non-pregnant women (p less than 0.001). However, the Km values of the enzyme for both PGE2 and PGF2 alpha were similar in all three groups, indicating the presence of same enzyme in the uterus of transsexual, pregnant and non-pregnant women. We speculate that PGDH activity was raised in the uterus of transsexual women because of the prolonged androgen therapy they received for the management of female-to-male transsexualism.