Androgen insensitivity syndrome is a rare genetic disorder in which a male fetus does not respond to male hormones.

The condition affects the development of the genitals and the reproductive system.

It is also known as Reifenstein syndrome, Rosewater syndrome, incomplete testicular feminization, or Type 1 familial incomplete male pseudohermaphroditism.

A newborn with androgen insensitivity syndrome (AIS) appears to be female, but the reproductive features will be unusual. There may be irregularities in the size of the vagina and no ovaries, fallopian tubes, or womb. The testes may remain in the inguinal canal or abdomen.

In the United States (U.S.), AIS affects between 2 and 5 in every 100,000 people.

Individuals with AIS have a normal life expectancy but may require hormone therapy and psychological support.

Fast facts on androgen insensitivity syndrome

  • Androgen insensitivity syndrome (AIS) causes the development of abnormal sexual organs.
  • The condition is genetic and affects the Y chromosome that shapes male sexual development.
  • AIS can be graded on a scale from one to 7. One is very mild, and 7 refers to complete AIS.
  • Gender identity is an extremely important concern for people with AIS, as their genitals may be male at an internal level but female in appearance. Counselling can assist with this.
  • Undescended testicles can be released or removed by surgical means, and hormone therapy may be used to nurture a person with AIS towards their preferred gender.

What are sex chromosomes?

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Androgen insensitivity syndrome is caused by a mutation to the Y chromosome that programs male sexual development.

Sex chromosomes are a pair of DNA molecules, called X or Y, that determine a person's sexual development.

  • A female has two X chromosomes known as XX
  • A male has one X and one Y chromosome, or XY

The Y chromosome stimulates the development of the testes and stops the female ovaries from developing. If there is no Y chromosome, the female reproductive system and genitals develop automatically.

An infant who is born with XY chromosomes should develop male genitals and reproductive organs. The testes, or testicles, are the male reproductive organs that produce androgens, or male hormones. These hormones trigger the development of male characteristics and sex organs, such as the penis.

Causes

For the first 8 weeks of gestation, both male and female embryos have the same genitals. Either a female or male reproductive system can develop.

A healthy XY embryo will develop male genitals, as the testes will release androgens.

The body of a person with AIS will not react to the androgen because a genetic alteration leads to a low number of androgen receptors. A total lack of reaction will lead to complete androgen insensitivity syndrome (CAIS).

The testes will remain in the body instead of descending to the scrotum. Viewed from outside the body, the genitals will resemble those of a female.

In 70 percent of cases, a person with AIS inherits the mutated gene from their mother.

A female with one faulty X chromosome may be a carrier. When considering AIS, a carrier is a woman who has the affected gene and can pass it on without experiencing its effects. Her female offspring may also be carriers, and her male offspring may have the condition.

Other cases are thought to result from a fault that occurs either when the mother's eggs are formed or in an embryo cell soon after conception. The exact reason, however, is unknown.

AIS is an intersex condition and differs from gender dysphoria. A person with gender dysphoria develops normal reproductive organs and genitals but feels that their assigned gender is not accurate. People who are transgender experience gender dysphoria.

Types

There are 3 forms of androgen insensitivity syndrome:

  • Complete: A person with CAIS will have female external genital features, and is likely to develop as a female.
  • Partial: In partial androgen insensitivity syndrome (PAIS), there is some sensitivity to androgen. Depending on the level of sensitivity, the person may appear completely male or female, or they may have some features of both sexes. Children born with this condition may grow into either females or males, depending on their degree of androgen sensitivity and subsequent genital development.
  • Mild: Mild androgen insensitivity syndrome (MAIS) affects males during puberty. They may form female breast tissue. A boy with MAIS may also not be able to produce effective sperm.

Signs and symptoms

Infertility is a common sign of AIS, although it may not present in mild cases.

The internal reproductive organs of females born with AIS will not develop, causing infertility. Non-development of reproductive organs is due to the testes in the body producing male hormones.

Complete androgen insensitivity syndrome

If a girl has an inguinal hernia, it may be due to undescended testes. Between 0.8 and 2.4 percent of cases of inguinal hernia in girls are due to CAIS.

There are normally no external signs or symptoms at birth, and the condition may not appear until the individual reaches puberty. CAIS may become apparent when the individual does not develop pubic or underarm hair, and menstruation does not begin.

Females experiencing CAIS will have a short "pouch" vagina.

Partial androgen insensitivity syndrome

Partial androgen insensitivity affects child development. An individual with high insensitivity will develop as a girl during adolescence. Those with low insensitivity will develop as boys, but breasts may start to develop. They may have a slightly enlarged clitoris or a penis that is almost fully formed.

A child may grow as a boy but develop more female traits with the onset of puberty.

Diagnosis

Androgen insensitivity may be diagnosed at birth if the genitals appear unusual. This can be identified, for example, if the appearance of the genitals does not match those predicted by a prenatal amniocentesis.

During pregnancy, chorionic villus sampling (CVS) may reveal AIS. In CVS, cells are taken from the placenta for testing.

If a woman has an inguinal hernia, is experiencing difficulty conceiving, or has physical problems with sexual intercourse, a physician may diagnose AIS.

A blood test can confirm the diagnosis by measuring hormone levels and detecting the altered chromosome.

An ultrasound scan highlights the soft tissues and cavities inside the body. This may confirm the absence of female reproductive organs.

Unborn babies are not routinely tested for AIS unless there is a family history.

After testing, the condition can be graded from 1 to 7. Grade 7 refers to CAIS, while grades 1 to 6 mean that an individual has PAIS.

With grade 7, the genitals appear as female. A person with grade 1 AIS will have male genitals but is likely to be infertile.

Treatment

Children with CAIS are usually raised as girls due to their outwardly female genitals, but sometimes the parents will have to decide whether to raise their child as a male or a female. This can be difficult if the genitals have both male and female features.

During puberty, hormone therapy may help direct development towards a specific gender. It can also postpone puberty until the child is old enough to decide which gender is appropriate.

Counseling can also help a child with AIS to establish a gender.

Most children with PAIS keep the gender they were assigned at birth, but some feel this does not represent their true identity and choose to change.

Surgery

Reconstructive genital surgery used to be carried out when the child was young and a gender had been assigned. Nowadays, it is normally postponed until the child can decide.

If a woman has testes, a doctor may remove them as they can become cancerous. This is known as an orchidectomy.

The operation is normally performed after puberty, as the testes can convert androgen to estrogen. Estrogen is the hormone that stimulates female reproductive development.

Waiting until after puberty to undergo an orchidectomy allows a girl with AIS to develop a female body without needing hormone treatments.

A person with testes lodged in the abdomen may require an orchiopexy. Orchiopexy is a surgical procedure designed to release an undescended testis into the scrotum.

Another option is surgery to lengthen the vagina. This can ease sexual intercourse for a person with AIS. This procedure is normally performed after puberty, allowing the individual to reach an informed decision.

Some women choose to have the clitoris surgically reduced and the vaginal opening enlarged. This may lead to a partial loss of sensitivity in the clitoris.

Women with complete androgen insensitivity who have their testes removed may undergo hormone therapy after completing puberty.

Estrogen supplements can prevent menopausal symptoms, including the development of osteoporosis. They can also stop a woman from becoming too tall, as their Y chromosome carries genes for taller growth.

If the testes are removed at a young age, hormone treatment may begin at around 10 or 11 years to initiate puberty.

Boys with partial insensitivity may need androgen supplements to encourage certain male features, such as the growth of facial hair and a deeper voice.

Psychological support is also crucial for both the individual with the condition and their parents.