An Overview of Androgen Insensitivity

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Androgen insensitivity is an umbrella term for a number of genetic conditions where the body does not respond appropriately to testosterone and other androgens. There are multiple causes of androgen insensitivity syndromes (AIS). However, these conditions can broadly be divided into partial androgen insensitivity syndromes (PAIS) and complete androgen insensitivity syndromes (CAIS).

With partial androgen insensitivity, the body has limited sensitivity to androgens. With complete androgen insensitivity, the body can't respond to androgens at all. There are also mild androgen insensitivity syndromes (MAIS). 

Androgen insensitivity syndromes fall under the broader category of disorders of sexual development or differences of sexual development—DSDs. These conditions are also known as being intersex. Although that term has fallen out of favor, intersex is easier for some people to understand. People with DSDs have physical characteristics that are between male and female.

Androgen insensitivity syndromes are DSDs because androgen insensitivity affects the sexual development of the body. People are generally taught that sex is determined by chromosomes—either people have male XY chromosomes or female XX chromosomes. However, it isn't that simple. Sex is determined not just by the presence of particular sex chromosomes but their function.

It's also determined by how the body responds to those sex hormones. For example, a person can be born with XY chromosomes but be female. How does that happen? When someone has complete androgen insensitivity syndrome.

Sex hormones are also known as steroid hormones, and they include estrogen and testosterone.

The masculinizing group of steroid hormones are known as androgens (andro- is the Greek prefix for male). This category consists of testosterone, dihydrotestosterone (DHT), androstenedione, and dehydroepiandrosterone (DHEA). When someone has androgen insensitivity, they are less responsive to the signals for maleness. 

Androgen insensitivity is a relatively rare disease. It is thought to affect around 13 out of every 100,000 individuals. Complete androgen insensitivity affects one in every 20,000 to 64,000 newborn males. The prevalence of partial androgen insensitivity is not known. 

Symptoms

Historically, androgen insensitivity syndrome was known as testicular feminization syndrome. This is because it often was not discovered until seemingly normal females did not undergo menarche. When such girls continued to not menstruate, it was discovered that some of them had testes instead of ovaries. It was not until later that it was discovered that androgen insensitivity was caused by mutations in the androgen receptor gene.

The symptoms of androgen insensitivity depend on the type. Individuals with complete androgen insensitivity are XY women. Because their bodies are completely unresponsive to testosterone, they are born with normal-appearing female genitalia.

As such, complete androgen insensitivity may not be diagnosed until puberty. When these girls reach puberty, they do not menstruate. This is because they do not have a uterus. They also do not have pubic or underarm hair, because the growth of this hair is controlled by testosterone. They may be taller than other girls but generally have normal breast development. Because they do not have a uterus, they are infertile. 

The symptoms of partial androgen insensitivity are more variable. At the time of birth, individuals may have genitals that appear almost completely female to almost normally male.

They can also appear anywhere in between. Symptoms of PAIS in individuals who are characterized as males at the time of birth include:

  • Micropenis
  • Hypospadias—a urethral opening midway up the penis rather than at the tip. This is a common birth defect, affecting one out of 150 to 300 male births.
  • Cryptorchidism—where the testicles have few or no germ cells. Individuals with cryptorchidism are more susceptible to testicular cancers.
  • Breast growth during puberty

Individuals with PAIS who are characterized as females at birth may have an enlarged clitoris that grows at the time of puberty. They may also experience fused labia at the time of puberty. To understand this, it helps to know that the labia and scrotum are homologous structures. This means they originate from the same tissue. However, they develop differently depending on hormone exposure. The penis and clitoris are also homologous structures. 

Men with mild androgen insensitivity often develop normally in childhood and adolescence. However, they may experience gynecomastia—male breast growth. They may also have reduced fertility. 

Causes

Androgen insensitivity is caused by mutations in the androgen receptor gene. As such, it is an inherited condition that runs in families as an X-linked trait. That means it occurs on the X chromosome and follows the maternal line. Over one thousand mutations have been identified to date.

Diagnosis

Initial diagnosis of androgen insensitivity is usually because of symptoms. Often, complete androgen insensitivity is not diagnosed until puberty. Lack of menstruation blood in combination with normal breast growth and a lack of pubic and underarm hair should cause doctors to suspect CAIS. Lack of menstruation blood can also be the trigger for doctors to identify that a young woman does not have a uterus on an ultrasound or other exams.

Partial androgen insensitivity may be diagnosed much earlier. If the genitals are clearly ambiguous at the time of birth, a number of tests may be done. These include a karyotype, or a count of the chromosomes. Hormone levels may also be tested. In adult men, a semen analysis may be done. 

At the time of birth, testosterone and luteinizing hormone (LH) levels are usually slightly higher than those for normal males, for individuals with both CAIS and PAIS. During puberty, testosterone and LH levels are usually normal or slightly elevated for individuals with PAIS. However, individuals with CAIS will have very high levels. This is because hormone production is controlled by negative feedback loops. In individuals with CAIS, there is no mechanism for feedback. 

Other tests may include biopsying the gonads. In all individuals with androgen insensitivity, they will have testes rather than ovaries. It is also possible to look for mutations in the androgen receptor genes. However, while this is a reasonably reliable marker for CAIS, it is not for PAIS. Only a fraction of mutations that cause PAIS have been identified to date.

Treatment

Individuals with complete androgen insensitivity usually do not need any treatment prior to puberty. The exception is if their testes cause discomfort or if they can be felt in the abdominal wall. After puberty, the testes are usually removed. This reduces the risk of young women developing testicular cancer in adulthood. Women may also need some psychological support around their identity. In addition, some may need to undergo dilation to increase vaginal depth, similar to with MRKH

Treatment for partial androgen insensitivity is more variable. Historically, individuals with ambiguous genitalia were subject to genital surgeries. These surgeries usually were designed to make the genitals appear more feminine. However, they had permanent effects on individuals' ability to experience sexual satisfaction. Therefore, these surgeries are no longer used as the default.

For individuals who appear female at the time of birth, treatment for PAIS is the same as for CAIS. However, the testicles may be removed before puberty to prevent enlargement of the clitoris and fusion of the labia. Individuals who have a penis are generally assigned and maintain a male gender identity. This is likely, at least in part, because gender development in the brain is also responsive to androgens. However, for these individuals as well, the gonads are usually removed in late adolescence, due to an elevated risk of cancer.

Individuals with AIS may also be given hormone replacement therapy, usually in the form of estrogen. This is because sex hormones play a role in numerous areas of health, including bone health. Individuals with PAIS may have sufficient bone development with their testicular testosterone.

Coping

Individuals with androgen insensitivity generally have good physical outcomes. However, androgen insensitivity can be associated with psychosocial problems. Young people diagnosed with androgen insensitivity may have questions about their gender and sexual identity. They may need support to understand that sex and gender are not as simple as they were taught in school. 

In addition, it can be difficult for any individual to deal with infertility. For some people, learning that they will never be able to have biological children can be devastating. They may question their femininity and/or masculinity. They may also wonder if they can ever have a successful relationship. As such, it may be helpful to seek out support, either from others with similar conditions or others dealing with permanent infertility. There are a number of support groups available around the country, both online and in person.

A Word From Verywell

Perhaps the most important thing to know about androgen insensitivity syndrome is that a diagnosis is not an emergency. If you or your child has been diagnosed with AIS, you don't need to do anything right now. You can take time to do your own research and make your own decisions. People with androgen insensitivity are generally no more or less healthy than anyone else—they're just a little different.

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