Androgen Insensitivity Syndrome (AIS)

Androgens are hormones responsible for normal male development, like testosterone or the more potent dihydrotestosterone (DHT) which is the hormone responsible for male pattern baldness in men.

All foetuses start out as female. Under the influence of androgens typically male sexual characteristics develop during foetal development before birth and secondary sexual characteristics later in life. When testosterone enters a target cell, it is aromatised (converted) into estradiol (estrogen) or DHT, or remains as testosterone. Either testosterone or DHT binds with an androgen receptor, a protein consisting of 910 amino acids. DHT has the more intense and prolonged effect, causing the entire binding to move into the nucleus and affect androgen-sensitive genes.

In women who have Androgen Insensitivity Syndrome, a foetus with a 46,XY karyotype will remain either wholly female or become only partially masculinsied. Because an AIS woman has an XY karyotype, the mitosis responsible for the creation of eggs (ova) in women with a 46,XX karyotype isn't possible and she will almost certainly be infertile. Fertility might be possible in more complicated cases such as those who also have a 47,XXY karyotype, which would normally lead to a man with Kleinfelter's Syndrome, but ferttility among people with chromosomal abnormalities is generally very low.

Because the mutation for AIS occurs on the X chromosome and it is a recessive trait, women can be carriers even if they are fully genetically female (ie have a 46,XX karyotype). There is a 50% chance that carriers of the mutated gene will pass it on to their children because each ovum will inherit one of her two X chromosomes at random: the one without the mutation or the one with it.

It's commonly said that men are unlikley to pass on mutation, that's because a 47,XY foetus with the mutation is likely to develop as a woman with AIS and is unlikely to develop as a fertile man. It is therefore also very unlikely that a woman will have two copies of the mutation because she would have inherited one copy from her mother (who had one recessive copy) and one from her father and, as we have seen, few fertile men can carry the mutation. It is possible however in a number of circumstances, such as:

• her father has the genetic mutation but for some reason it wasn't activated;


• her father has a complex karyotype (eg 47,XXY);


• her father is chromosomally mosaic (eg has a 46,XY karyotype but some copies of the X chromosome carry the mutation but others don't; or


• the mutation arises afresh

Complete AIS is the most extreme form of androgen insensitivity syndrome, in which a person develops as a woman would except she has no uterus. This form of AIS is typically diagnosed when she hits puberty and fails to menstruate, or when a mass discovered in the abdomen or groin turns out to be a testicle. People with complete AIS are typically raised as female.

It is estimated that 1 in 20,000 people have the complete form of AIS.