What Is Androgen Insensitivity Syndrome (AIS)? What Causes Androgen Insensitivity Syndrome?

Androgen insensitivity syndrome is a genetic disorder in which the XY fetus is unresponsive (insensitive) to androgens. Androgens are male hormones, such as testosterone. A baby with androgen insensitivity syndrome is born externally like a normal girl. However, internally they have a short blind-pouch vagina, and no ovaries, fallopian tubes or womb (uterus). The testes are in the inguinal canal or abdomen.

In other words, androgen insensitivity syndrome is a condition in which the development of the genitals and reproductive organs are affected.

Very early on, all unborn babies have identical genitals, regardless of whether they are female or male. A pair of sex chromosomes in the baby - XX or XY - determines whether they develop male (XY) or female (XX) genitals and reproductive organs.

XX and XY sex chromosomes

Sex chromosomes are a pair of DNA molecules, called X or Y, that decide our sexual development.

• A female has two X chromosomes - XX
• A male has one X and one Y chromosome - XY

The Y chromosome stimulates the development of the testes and halts the development of female ovaries. If no Y chromosome is present, the female reproductive system and genitals develop automatically.

Androgen insensitivity syndrome - a baby with androgen insensitivity syndrome is born with an XY set of hormones - so it should develop male genitals and reproductive organs. The testes (testicles), the male reproductive organs, produce androgens (male hormones), which make the human develop male characteristics and sex organs (such as the penis).

If the human is insensitive or ignores the androgen, the testes will stay inside the body (instead of coming down to the scrotum) and genitals will develop along female lines.

There are two forms of androgen insensitivity syndrome:

• Complete androgen insensitivity syndrome (CAIS) - the human is completely insensitive to androgen. External genitals develop along purely female lines. The majority of babies who are born with CAIS are brought up as daughters.
  
• Partial androgen insensitivity syndrome (PAIS) - there is some sensitivity to androgen, but less than normal. How the genitals develop depends on how sensitive that human is to androgen. The individual may look completely male or female, or neither (in between). Some may have a slightly enlarged clitoris while others have a penis which is almost fully formed. Babies born with PAIS may be brought up as sons or daughters, depending on their degree of androgen sensitivity and subsequent genital development.

Intersex conditions versus gender dysphoria

An intersex condition, such as androgen insensitivity syndrome, is when something went wrong in the development of the baby's reproductive organs and genitals because the body was insensitive (unresponsive) to androgen.

In a case of gender dysphoria the reproductive organs and genitals developed normally, but the individual feels their gender is wrong - a person who is physically completely male feels he is female, or vice versa. Gender dysphoria is also known as trans-sexuality or being transgender.

How common is androgen insensitivity syndrome (AIS)?

Approximately 1 in every 20,400 male births has AIS. Complete AIS (CAIS) is believed to be more common than Partial AIS (PAIS).

Individuals with AIS have normal life spans (life expectancies). Many will need hormone therapy and psychological support.

According to Medilexicon's medical dictionary Androgen resistance syndromes are "a class of disorders associated with 5α-steroid reductase deficiency, testicular feminization, and related disorders."

What are the signs and symptoms of androgen insensitivity syndrome (AIS)?

Males born with androgen insensitivity syndrome (AIS) will be infertile, unless their condition is extremely mild. All females born with AIS will be infertile because their development of internal organs is undermined by the presence of male hormones from testes in the body. Females born with AIS do not have a womb (uterus), fallopian tubes or ovaries.

Signs and symptoms of CAIS (complete androgen insensitivity syndrome):

About 50% of all babies born with CAIS eventually have a hernia due to undescended testes. The hernia is the first indication of possible androgen insensitivity syndrome - there are no external signs in newborn babies.

Signs and symptoms, which mostly appear during puberty include:

• No or extremely little underarm and pubic hair
• Acne, which is linked to puberty, does not occur
• Females do not start having menstrual periods because they have no ovaries
• Females with CAIS have a shorter-than-normal vagina

Signs and symptoms of PAIS (partial androgen insensitivity syndrome):

A child's level of androgen insensitivity dictates how he/she develops. Those whose insensitivity is higher will develop as girls during adolescence, while those whose insensitivity is low will develop as boys (with perhaps some development of breasts).

Sometimes a PAIS baby may initially be brought up as a son, but become more female as puberty arrives. Hormone therapy may help direct puberty towards a specific gender. Parents may choose to postpone puberty until the child is old enough to decide for himself/herself.

Androgen insensitivity syndrome (AIS) grading system:

The AIS grading system goes from 1 to 7, with 7 being the highest androgen insensitivity. 1 to 6 are people with PAIS (partial androgen insensitivity syndrome), while 7 is CAIS (complete androgen insensitivity syndrome):

• Grade 1 (PAIS) - the individual has male genitals and is likely to be infertile.
  
• Grade 2 (PAIS) - there are predominantly male genitals, which are small. The urethra may not end at the end of the penis, but at the underside of the shaft or somewhere else (hypospadia). The child may have undescended (internal) testes (testicles) - known as cryptorchidism.
  
• Grade 3 (PAIS) - there are predominantly male genitals, however they are very small. Possible hypospadias and internal (undescended) testes.
  
• Grade 4 (PAIS) - genitals are ambiguous. There may be a penis, but it is impossible to tell whether it is a clitoris or a penis (phallic structure that is indistinguishable between a penis and a clitoris).
  
• Grade 5 (PAIS) - genitals are essentially female, with separate urethral and vaginal passages. The clitoris may be larger than normal.
  
• Grade 6 (PAIS) - the genitals are female, and there is pubic and underarm hair.
  
• Grade 7 (CAIS) - the genitals are female, but there is no (or very little) pubic and underarm hair.

People with Grade 6 or 7 are visibly indistinguishable before puberty.

What are the causes of androgen insensitivity syndrome?

Each embryo, whether male (with XY chromosomes) or female (XX chromosomes) starts off with the capacity to develop either a female or male reproductive system. During its first 8 weeks of life the embryo has non-specific genitals - in other words, they are all the same. A few weeks later, a healthy XY fetus' non-specific genitals develop into male ones due to the effects of androgens (male hormones) - the androgens are produced by the testes. (An embryo is an unborn, developing child during the first three months of pregnancy, after that it is called a fetus).

The genes that produce androgen receptors are faulty in people with AIS (androgen insensitivity syndrome). Androgen (a hormone) does not work properly until it locks onto androgen receptors (receptor molecules) and cells cannot react to the androgen, or the reaction is too weak. Put simply - a person with AIS does not have enough androgen receptors because of a gene mutation (fault, alteration).

An individual with CAIS (complete androgen insensitivity syndrome) does not react to androgen at all, resulting in male genitals and reproductive organs failing to develop.

In about 30% of cases of AIS, the mutation of the androgen receptor gene first occurs in the family either when the eggs of the mother are being formed, or in one of the embryo cells soon after conception. Experts are not sure why.

In other cases the mutated gene is inherited from the mother (the carrier) as part of the X chromosome.

If a female baby has one faulty X chromosome she will be a carrier, because the 'good' X chromosome will balance out its effect (females have XX chromosome pairs while males have XY pair). However, that female baby will be a carrier - her female offspring may be carriers and her male offspring may have AIS.

If a female has one mutated X chromosome, in each pregnancy there is a:

• 1 in 4 chance that her unaffected baby girl can pass on the mutated gene to her children
• 1 in 4 chance of having a normal son with a normal X and normal Y chromosome
• 1 in 4 chance that her daughter is not affected and is not a carrier; the daughter has two normal X chromosomes
• 1 in 4 chance of having a child with AIS (mutated X and normal Y chromosome)

Diagnosing androgen insensitivity syndrome (AIS)

PAIS (partial androgen insensitivity) is usually diagnosed when the baby is born because the genitals look different.

Most cases of CAIS (complete androgen insensitivity syndrome) are diagnosed in the following circumstances:

• A prenatal amniocentesis discovers male karyotype (male chromosome XY) which are not matched by ultrasound, or obvious female features at birth.
  
• A lump in the inguinal canal is found to be a testis.
  
• Surgery of the abdomen to repair an inguinal hernia or appendicitis discovers the presence of testes, or no uterus and ovaries. Even if there is no inguinal lump perhaps 1% of girls receiving surgery for inguinal hernia are found to have AIS.
  
• The girl or her family seek medical advice because her first menstrual cycle (menarche) has not come.
  
• The child or family seek medical advice because no pubic/underarm hair appears.
  
• A woman seeks medical advice because she has difficulty with sexual intercourse.
  
• A woman seeks medical help for infertility.

A child with CAIS who does not develop a hernia may not be diagnosed until later in life

Blood test - this can confirm a diagnosis of AIS by measuring hormone levels, as well as detecting the altered (mutated) X chromosome.

Ultrasound scan - this device uses ultrasound waves which bounce off tissues; the echoes are converted into a sonogram (an image) which the doctor can see on a monitor. The doctor can get an inside view of soft tissues and body cavities. If AIS is suspected this scan can confirm the absence of a uterus, fallopian tubes and ovaries.

Before the baby is born - after the 11th week of pregnancy AIS can be diagnosed by chorionic villus sampling in which cells from the placenta are taken. From the 15th week of pregnancy amniocentesis can be performed, in which a sample of fluid around the baby is taken out and tested.

AIS is rare and unborn babies are not routinely tested, unless there is a family history of it.

What are the treatment options for androgen insensitivity syndrome?

Children with CAIS (complete insensitivity syndrome) are usually raised as girls because they have female genitals. In other cases the parents will have to decide whether their child should be raised as a son or daughter - this may be difficult decision if the child has PAIS (partial androgen insensitivity syndrome) and their genitals have both male and female features.

Parents should receive advice and counseling from psychologists and medical specialists regarding their child's future development, and the gender that child is most likely to identify with.

The majority of children with PAIS continue keeping the gender they were assigned when they were born. However, some may feel this does not represent their true identity, and change their gender.

Genital reconstructive surgery - this used to be done when the child was very young and a gender had been assigned to him/her. However, these days most doctors postpone genital reconstructive surgery until the child is old enough to decide what to do.

Orchidectomy (removing the testes) - women with CAIS (complete androgen insensitivity syndrome) are advised to have their testes surgically removed, mainly because they can become cancerous. According to the National Health Service (NHS), UK, approximately 9% of women with CAIS develop cancer (extremely rare before puberty).

Orchidectomies used to be performed when the child was very young. These days, however, doctors prefer to wait until the girl has completed puberty. The testes can help convert androgen (the male hormone) to estrogen (the female hormone), allowing the girl to develop a normal female body without hormone treatments being required.

Orchiopexy - surgery to bring down an undescended testis to the scrotum. Boys with hypospadias - in which the urethra does not end where it should, at the tip of the penis - may need surgery to straighten their penis to that they can urinate standing up.

Lengthening the vagina - this is done to make sexual intercourse easier. Doctors used to recommend doing this procedure before puberty. Now they tend to wait until after puberty so that the woman can decide whether to have it done. A method called dilation, in which the vagina is gradually widened and deepened with the use of small plastic rods is usually used. Vaginoplasty, a surgical procedure is also possible.

Clitoris reduction - a woman with PAIS (partial androgen insensitivity syndrome) may decide to have her clitoris surgically reduced, and her vaginal opening enlarged. There is a risk of losing some sensitivity in the clitoris, although losing the ability to reach orgasm is very rare.

Hormone therapy - this may be required for women with CAIS who have had their testes removed and have completed puberty. They will have to take estrogen supplements to prevent menopausal symptoms, including the developing of osteoporosis (weak bones). Estrogen may also stop them from becoming too tall - their Y chromosome carries genes for extra height.

If the testes are removed when the child is young (or a baby) hormone treatment usually begins when they are 10 or 11 years old - the aim is to initiate puberty.

Some children with PAIS may also require hormone supplements. Girls who have undergone an orchidectomy (removal of testes) may require a combination of androgen and estrogen to encourage female development. Boys with PAIS may require androgen supplements to encourage certain male features, such as the growth of facial hair and the deepening of their voice.

Psychological support - this is crucial for both the individual with AIS as well as their parents.

Parents may be shocked when they are told their child has AIS - feelings of shame, anger, guilt, anxiety, and despair can overwhelm and linger. A well-qualified counselor can help parents come to terms with their feelings. The National Health Service (NHS), UK, says that talking to other parents who also have a child with AIS is often helpful.

For a young child with AIS, whose condition is a natural part of his/her life, psychological support may not be necessary. However, for some parents it is difficult to decide what to tell their child, and when. The majority of health care professionals and experienced parents agree that it is probably best to explain the basic facts as soon as possible; gradually adding more information as the child's ability to understand more complex information develops. The NHS adds that a child should ideally understand their condition fully by the time they reach puberty. Puberty is a stressful time for any child, and the pressure to be the same as peers is enormous. Not preparing the child before this period can prove traumatic.

An older child may need and benefit from the support of a well-qualified and experienced therapist. It is recommended that both child and therapist build up a long-term relationship.

If CAIS is not diagnosed until the girl has begun puberty, it can turn out to be a dreadful shock for both the girl and her parents. Psychological counseling should be available for both child and parents.

It is important to stress that with good and appropriate care and support, most people with AIS come to terms with their condition and live normal, productive and happy lives.

Genetic counseling - people who are found to be carrying the mutated X chromosome; who have the potential to have children with AIS, should be offered genetic counseling. The aim of genetic counseling is to provide information about androgen insensitivity syndrome, what effect it may have on the carrier's life, and what options there are for the future.