What Is Androgen Insensitivity Syndrome?

Overview

Androgen insensitivity syndrome (AIS) is a condition that affects the development of sexual characteristics in those who are genetically male (having XY chromosomes), leading to intersex traits. In AIS, individuals who possess one X chromosome and one Y chromosome, typically indicating male genetic makeup, have a resistance to the effects of male sex hormones called androgens. 

Due to this resistance, their bodies do not respond in the usual way to these hormones, resulting in the atypical development of external genitalia. Instead of developing typical male genitals, they may exhibit female external genitalia, partially developed male external genitalia, and/or experience infertility. Consequently, individuals with AIS may be assigned a range of genders at birth.

Types of AIS

Complete androgen insensitivity syndrome (CAIS) and partial androgen insensitivity syndrome (PAIS) are the two main forms of AIS. According to medical literature, CAIS affects approximately 5 out of every 100,000 males, while PAIS affects approximately 7 out of every 1 million males. 

In the case of CAIS, individuals experience the development of typical female external genitalia, including the vulva, and are, therefore typically assigned female at birth (AFAB). However, internal female reproductive organs such as the ovaries, fallopian tubes, and uterus do not develop. 

PAIS, on the other hand, often leads to the development of ambiguous external genitalia, which means that it is difficult to determine whether the genitalia appear typically male or female, making gender assignment complicated. Some individuals with PAIS may have predominantly female-looking genitals, while others may have genitals that appear primarily male. 

There is a third type of AIS known as mild androgen insensitivity syndrome (MAIS), which causes individuals to have typical male external genitalia and are, therefore typically assigned male at birth (AMAB). However, the main symptom of MAIS is infertility, meaning affected individuals are unable to conceive children. 

Causes of AIS

During the early stages of pregnancy, all unborn babies possess identical genital structures. However, as they develop in the womb, their genitals differentiate into either male or female characteristics. This process is determined by the combination of sex chromosomes inherited from their parents and their ability to respond to the sex hormones produced in their bodies. 

Sex chromosomes, which contain genes designated as X or Y, play a crucial role in the development of a baby's sex. Typically, AFAB people have two X chromosomes (XX), while AMAB people have one X and one Y chromosome (XY). 

In the case of individuals with AIS, they possess XY chromosomes, but a genetic alteration hinders their body's ability to respond to testosterone, the primary male sex hormone.

Consequently, the normal process of male sex development does not occur as expected in individuals with AIS. 

Signs and symptoms of AIS

CAIS is often not diagnosed until puberty, when symptoms become apparent due to the absence or underdevelopment of reproductive organs. 

Symptoms of CAIS may include: 

• Absence of menstrual periods
• Lack of pubic hair
• Absence of armpit hair
• Taller height than usual

PAIS is typically easier to identify due to differences in the appearance of external genitals at birth. Symptoms of PAIS might include. 

• Abnormally large clitoris
• Fused labia
• Undescended testes
• Underdeveloped penis
• Changes in the location of the urethra
• Enlarged breasts (gynecomastia) during puberty
• Moderate pubic hair
• Lack of facial or body hair

While infertility is the most common symptom of MAIS, other symptoms of the condition may include:

• Enlarged breasts during puberty 
• Smaller penis
• Lack of facial or body hair

Management and treatment for AIS

The general consensus is that treatment for AIS should be initiated after the onset of puberty. Delaying treatment until this stage allows the body to go through the natural changes of puberty and enables individuals to make informed decisions about their own treatment. 

For those intersex individuals who opt for treatment, there are various approaches available to align with their personal preferences. These may include:

• Hormone therapy involving the use of estrogen or testosterone
• Surgical removal of undescended testicles (gonadectomy)
• Surgical removal of excess breast tissue
• Surgical procedures to modify or remove male or female external genitalia

While there are multiple treatment options for individuals with AIS, the decision to undergo any form of treatment is always a personal choice that should be made by the individuals themselves.

Diagnosis

AIS is sometimes diagnosed shortly after birth but often remains unnoticed until the child reaches puberty. Doctors may suspect AIS based on the child's physical appearance and sexual development, but further tests are required to confirm the diagnosis. In the case of PAIS, the unusual appearance of the genitals is typically identified soon after birth. 

However, CAIS is often not diagnosed at birth because the external genitalia appears typically female, meaning that they are often AFAB. In some cases, CAIS may be detected if the child develops a hernia. A hernia occurs when an internal organ protrudes through a weak area in the surrounding tissue. If the testicles fail to descend into the scrotum and remain in the abdomen, a hernia may occur. In such cases, CAIS may be identified during hernia repair surgery. Otherwise, the condition may go undiagnosed until puberty, when the absence of menstruation and the lack of pubic and underarm hair becomes apparent. 

To confirm the diagnosis of AIS, various tests and scans can be conducted. Blood tests can check the sex chromosomes, detect genetic changes on the X chromosome (which is involved in AIS), and measure sex hormone levels. An ultrasound scan can also verify the absence of the uterus and ovaries. In cases where testicles are suspected during hernia repair surgery, a small tissue sample (biopsy) may be taken and analyzed to confirm their identity. 

Risk factors

AIS follows an inheritance pattern known as X-linked recessive. In X-linked conditions, the gene mutation responsible for the disorder is located on the X chromosome, one of the two sex chromosomes found in each cell. In individuals who are genetically male and possess only one X chromosome, a single altered copy of the gene is sufficient to cause the condition. However, in genetically female individuals with two X chromosomes, the disorder occurs only when both copies of the gene are mutated. Males are more frequently affected by X-linked recessive disorders compared to females. 

Approximately two-thirds of all AIS cases are inherited from mothers who carry a mutated copy of the AR gene on one of their X chromosomes. The remaining cases result from new mutations that can arise in the mother's egg cell before conception or during the early development of the fetus. 

Complications

If left untreated or not effectively managed, AIS can lead to significant psychological distress for both the individuals with AIS and their families. This distress tends to be more prevalent in adults with PAIS compared to those with CAIS, regardless of their assigned gender at birth. The challenges associated with navigating puberty and adulthood in the context of AIS can contribute to this psychological distress.²

Additionally, individuals with AIS have an increased chance of cancer if a gonadectomy is not performed. In cases of PAIS, the presence of cryptorchidism (undescended testes) should be addressed through early surgical intervention. This approach is essential for preserving testicular function and reducing the risk of malignancy. The tumors that can develop in undescended testes in PAIS are often germ-cell tumors and gonadoblastomas. These tumors are known to occur in approximately 1.5 to 2 percent of cases of cryptorchidism and can potentially become cancerous.¹ The premalignant precursor for tumors associated with AIS is referred to as carcinoma in situ or intratubular germ cell neoplasia unclassified. Therefore, surgical correction of cryptorchidism is crucial in PAIS to maintain testicular health and minimize the risk of malignant developments. 

FAQs

How can I prevent androgen insensitivity syndrome

If there is a family history of AIS and the specific gene causing it has been identified, it may be possible to undergo a blood test to determine if you carry the same gene and are at risk of passing it on to your children. 

In cases where there is a known family history of AIS, testing can also be conducted on unborn babies. There are two main tests available during pregnancy to determine whether a baby has AIS: 

1. Chorionic villus sampling (CVS): This involves removing a sample of cells from the placenta, typically using a needle. CVS is usually performed between weeks 11 and 14 of pregnancy
2. Amniocentesis: This procedure involves extracting a sample of the amniotic fluid surrounding the baby using a needle. Amniocentesis is typically carried out between weeks 15 and 20 of pregnancy 

Deciding whether or not to undergo these tests, which do carry a risk of miscarriage, can be challenging. It is advisable to consult with a genetic counsellor before making a decision. 

How common is androgen insensitivity syndrome

The prevalence of CAIS is estimated to affect 2 to 5 individuals per 100,000 who are genetically male. PAIS is believed to be at least as prevalent as CAIS. In contrast, MAIS is considerably less common. 

When should I see a doctor?

If you present with: 

• Lack of menstrual period
• Enlarged clitoris 
• Gynaecomastia 
• Undescended testes/ underdeveloped penis 

It is advised you contact a doctor to discuss your situation. These symptoms are not 100% indicative of AIS. However, it is worth figuring out what they could mean. 

Summary

Androgen insensitivity syndrome (AIS) is a condition that affects sexual development in males, resulting in intersex traits. It is characterized by a resistance to male sex hormones, leading to atypical development of external genitalia. AIS has different types, including complete (CAIS), partial (PAIS), and mild (MAIS) forms. CAIS typically manifests as typical female external genitalia, while PAIS may result in ambiguous genitalia. MAIS presents with typical male external genitalia but causes infertility. AIS is diagnosed through physical examination, blood tests, genetic analysis, and imaging techniques. If AIS runs in the family, genetic testing can be done during pregnancy. Untreated AIS can cause psychological distress and increases the risk of malignancy, particularly in cases of PAIS where surgical intervention is required to correct cryptorchidism.