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Androgen Insensitivity Syndrome


For two months after conception the human embryo is sexually indeterminate. There is tissue (the genital ridge) which will become the fetus's genitalia, but the sex is so far  indeterminate, and everything hangs on the production of testosterone. If the embryo is genetically male (equipped with XY chromosomes), its genes stimulate these genital tissues to produce testosterone, which causes tissues to differentiate into testes, epididymis, vas deferens, and seminal vesicles. The penile shaft and the glans emerge from the genital ridge when testosterone in the embryo is converted into dihydrotestosterone. At the same time, another type of cell inside the testes known as the Sertoli cells emit a hormone called Muellerian inhibiting factor (MIF), which prevents any of the embryo's tissues developing as female.

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A similar process occurs when the embryo is female, and has XX chromosomes. When the stimulus for testosterone goes out in the eighth week, nothing happens (there is no Y chromosome). And since there are no testicles to manufacture testosterone, the gonads automatically develop into the default female pattern, five weeks later forming the ovaries, clitoris and labia, uterus, Fallopian tubes, and vagina. In other words, the human embryo's "default" path of development is female.

What this means is that  it is the hormones which really determine the sex of the fetus: indeed, though you might say that the chromosomes are essential, it is the interaction of hormones on cells which control sexual development.

Testicular feminization, or Androgen insensitivity syndrome (AIS), is an X-chromosome linked recessive genetic condition which results in a lack of normal masculinization of the external genitalia in XY babies. The cause of the problem is a malfunction of the androgen receptors on the cell walls of the baby's tissues. This failure of masculinization can be complete or partial, (hence complete androgen insensitivity syndrome (CAIS) and similarly partial androgen insensitivity syndrome (PAIS)), and this depends on the amount of testosterone receptor function.

Both PAIS and CAIS babies have 46,XY chromosomal karyotypes. Those with CAIS have female external genitalia with normal labia, clitoris, and an opening to the vagina. Those with PAIS may range from babies with mildly masculinized female external genitalia, such as a large clitoris, to mildly undermasculinized male external genitalia, such as a penis with hypospadias or reduced penis size. The important thing is that all these individuals have normal testes and produce testosterone and have a normal conversion in their tissues to dihydrotestosterone (DHT); there is another condition called 5-alpha reductase deficiency which prevents conversion of testosterone to the more active form of DHT, which can also result in under-masculinization. It is the normal conversion to DHT in the tissues of PAIS and CAIS individuals which is the distinguishing factor. In testicular feminization, the testes produce normal quantities of müllerian-inhibiting factor (MIF), so affected individuals do not grow fallopian tubes, a uterus, or the upper part of the vagina.

The basic etiology of AIS, whether CAIS or PAIS, is a mutation in the androgen receptor gene which means it cannot function correctly. This androgen receptor gene is located in the long arm of the X chromosome; there are in fact over 200 or so mutations in this gene, which range from complete and partial gene deletions through smaller point mutations to insertions/deletions. As you would expect, these mutations invoke a variety of functional defects, which range from a complete loss of androgen receptors on the tissue cell surface (caused by incomplete protein synthesis) to alterations in testosterone binding affinity. Any changes in binding affinity causes a transmission loss of signals from testosterone across the cell membrane, even though there are normal numbers of cell surface receptors. While the genotypes which result in CAIS are uniform in external appearance, the relationship between genes and appearance are less clear in PAIS.

The effect on the individual concerned is essentially a lack of masculinization: even though there are normal levels of androgen synthesis, the post receptor events that mediate the impact of the male hormone testosterone on body tissues do not occur. This means that there is undervirilization of the external genitalia, an absence of pubic and axillary hair at puberty, little or no acne, and absence of other changes at puberty such as deepening of the voice.

AIS occurs in about 1 in 20,400 male births. CAIS may be more common than PAIS, but exact figures are simply not available. Complete or partial AIS is a medical handicap and not a condition with a fatal risk - but it is a significant issue for those who have it. There is a risk of malignant degeneration of genital tissues and the development of gonadoblastoma of testicular tissue, but the frequency of such events is unknown. The main effects are psychological.

Girls who do not menstruate at puberty are sometimes discovered to be genetic males - needless to say, this may produce significant psychosocial problems which need sensitive psychological support. They experience problems ranging from issues with identity to problems based on the broad gender perceptions of society as a whole. They have often not been treated sensitively by the medical system, though hopefully this has changed recently. Of course, most of the girls with this condition experience psychological trauma when they are diagnosed, and if treated disrespectfully by the medical staff - such as being told they are not women but are in fact men because of the presence of a Y chromosome and testes - they will suffer shame, anger, and low self-esteem. 

All individuals who have AIS are both chromosomally and gonadally male. But bear in mind that the concepts of sex and gender are crucial here, since we ascribe someone's sex on the basis of their physical attributes, while the idea of gender tends to be based on a person's self-concept. Most people with CAIS accept a female gender: they feel like women, a fact that is due to a combination of sex role assignment before the diagnosis and the lack of masculinization of their brain. As you would expect, PAIS presents more challenges in assessing gender identity. The external and internal genitals may be very  varied in the extent of their virilization, and the associated gender identity may be either male or female.

Most cases of testicular feminization or androgen insensitivity syndrome (AIS) are picked up just after birth because of the presence of inguinal masses, which will be identified as testes when surgery takes place, though, as stated above, some people will not be identified until their teenage years when they fail to menstruate. In newborn babies with CAIS, unilateral or bilateral masses are often found in the inguinal canals and these may turn out to be testes: hernias may be present as well. In adolescents inguinal masses are often found, and may or may not be linked to the presence of hernias. They will have no pubic or axillary hair, scant body hair, and normal breast development because of the conversion of their testosterone to estradiol.