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Sex hormone signature indicates gender rather than just chromosomes

Help with assigning gender could one day be at hand for intersex individuals whose genital phenotypes and sex chromosomes don't match, thanks to the discovery of a stable sex hormone signature in our cells.

In an article published today in the online open access journal BMC Genomics, researchers have shown for the first time that testosterone leaves an irreversible molecular signature in cells that may provide a far more sophisticated way to look at sex than just ascertaining the presence of the Y chromosome. A team of researchers from the US and Germany were able to pinpoint the role of testosterone by comparing individuals with complete androgen insensitivity syndrome (CAIS) to people without CAIS. The findings provide a platform for future work that may lead to improved counselling for those whose gender is ambiguous.

Lead researcher, Professor Paul-Martin Holterhus, of University-Hospital Schleswig-Holstein, Kiel, Germany, said: "Androgens have long lasting effects during certain sensitive stages of our genital development and this is probably true for other organs". He adds "It is currently increasingly accepted that the brain shows sex-specific development in response to presence or absence of testosterone. This affects sex specific behaviour and probably modulates gender identity."

The role of androgens - especially the male-defining hormone testosterone - in sexual development has long been known. Gender programming begins in the embryo and is thought to continue throughout life, particularly during puberty. However, what's not currently known is the different roles of sex chromosome genes versus the long-term programming effects of sex hormones, namely androgens.

Individuals with CAIS, which affects 1 in 20,000 people, look like normal females. But at a genetic level CAIS women have XY sex chromosomes rather than the usual XX. The condition is due to mutations in the gene coding for the androgen receptor, which means that androgen signalling doesn't work: it essentially knocks out the effect of testosterone. The researchers used skin biopsies of external genitalia to compare the gene expression of normal males and CAIS females. Analysis revealed that between males and females, 440 genes differed in their level of transcription. The activity levels of these genes form a 'signature' that they used to evaluate partial androgen insensitivity syndrome (AIS) samples and could be developed to help understand more about individual AIS cases.

"Since we compared XY females with the XY males, the difference can only be explained by differences in androgen action and not by differences in sex chromosomes," explains Professor Holterhus. "Another intriguing observation is that the one normal female (with a 46,XX genotype) in our study did not differ a lot with respect to the identified genes from the XY females. This is an important reassurance for XY females because it limits the role of the sex chromosomes in gender assignment."

Charlotte Webber | alfa
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