Androgen Insensitivity Syndrome is a genetic condition that affects a person’s sexual development before birth and during puberty. It is a condition where the body’s cells are unable to respond to androgens like testosterone.

To understand this, it is helpful to use an analogy. Think of hormones as specific keys and the cells in your body as having specialized locks, or receptors. For a hormone to have an effect, its key must fit perfectly into the cell’s lock to open a door and deliver a message.

• In a person with AIS, the body (specifically the testes) produces the testosterone “keys.”
• However, due to a genetic fault, the “locks” on their cells (the androgen receptors) are either misshapen or completely missing.
• Because the testosterone keys cannot fit into the locks, the cells never receive the message to develop in the male direction.
• Without these androgen signals, the body follows its default developmental pathway, which is female.

Therefore, an individual with AIS has XY chromosomes and internal testes (which are usually undescended, remaining in the abdomen), but their body is unable to “hear” the testosterone these testes are producing. Because they do not have a uterus, ovaries, or fallopian tubes, they are infertile and do not menstruate.

The condition exists on a spectrum, which is classified based on the degree of androgen resistance.

• Complete Androgen Insensitivity Syndrome (CAIS): There is a complete inability to respond to androgens. The individual develops as a typical female externally.
• Partial Androgen Insensitivity Syndrome (PAIS): There is some response to androgens, but it is incomplete. This results in ambiguous genitalia at birth, with characteristics that are not clearly male or female.
• Mild Androgen Insensitivity Syndrome (MAIS): There is only a slight impairment in androgen response. These individuals develop as males but may experience issues like breast development (gynecomastia) at puberty or infertility.

Clinically, I’ve seen that people with AIS often grow up identifying as female and only discover their diagnosis during puberty or fertility evaluations, which can be a deeply emotional and complex experience for patients and families alike.

AIS is caused by mutations in the AR (Androgen Receptor) gene. This gene, which is located on the X chromosome, contains the instructions for building the androgen receptor protein, the “lock” for the testosterone “key.”

A mutation in the AR gene results in the production of a receptor protein that is either non-functional, only partially functional, or is not produced at all. The severity of the syndrome whether it is complete, partial, or mild depends on how much the mutation affects the receptor’s ability to bind to testosterone and transmit its signal.

In my experience, genetic counseling is often crucial when AIS is diagnosed. Families are frequently surprised that such a profound condition can exist silently for so long, especially in CAIS, where children may appear completely healthy and female.

AIS is a genetic condition from birth. It’s not something acquired or caused by external factors. A person is born with it due to a mutation in the AR gene, usually inherited in an X-linked recessive pattern.

• The AR gene is on the X chromosome. A person with XY chromosomes has only one X. If that single X chromosome carries the mutated AR gene, they will have the syndrome.
• A person with XX chromosomes who has one mutated AR gene and one normal AR gene is an unaffected carrier. Her normal gene produces enough functional receptors for her body to develop normally.

Inheritance Patterns

• Inherited from a Carrier Mother: In about two-thirds of cases, the mutated gene is passed down from a mother who is a carrier. For each pregnancy, a carrier mother has:
  • A 25% chance of having an affected XY child (with AIS).
  • A 25% chance of having an unaffected XY child.
  • A 25% chance of having a carrier XX child (like herself).
  • A 25% chance of having a non-carrier XX child.
• Spontaneous (de novo) Mutation: In about one-third of cases, the condition is the result of a new mutation in the AR gene that occurs spontaneously in the child. In these cases, there is no prior family history of the condition.

Clinically, I’ve seen AIS come to light in one sibling and prompt testing in others, especially sisters who may be carriers. It’s one of those conditions where family genetic screening becomes just as important as treating the individual.

Symptoms of AIS vary depending on whether it’s complete or partial, and when the condition is diagnosed at birth, during childhood, or at puberty.

Complete Androgen Insensitivity Syndrome (CAIS)

Individuals with CAIS are genetically male (46,XY) but have the external physical appearance of a female. Diagnosis is often not made until puberty or later.

• Presentation in Adolescence: The most common presentation is a teenage girl seeking medical care for primary amenorrhea, the fact that she has never had a menstrual period.
• Physical Examination: On exam, she will have normal breast development (as the body converts the unused testosterone into estrogen) but sparse or absent pubic and underarm hair. A pelvic exam reveals a short or blind-ending vagina and the absence of a cervix, uterus, and ovaries.
• Presentation in Childhood: Sometimes, CAIS is diagnosed in an infant or young girl who is undergoing surgery for an inguinal hernia, and the surgeon discovers a testis in the hernia sac.

Partial Androgen Insensitivity Syndrome (PAIS)

Individuals with PAIS have ambiguous genitalia that are visible at birth. Appearance can fall anywhere on the spectrum between typical male and typical female.

• The infant may have an enlarged clitoris or a very small penis (micropenis).
• The urethral opening may be on the underside of the penis (hypospadias).
• The scrotum may be split or may resemble labia.
• The testes may be undescended.

Mild Androgen Insensitivity Syndrome (MAIS)

Individuals with MAIS are born with and develop as males. The signs are much more subtle.

• They may experience enlarged breasts (gynecomastia) at puberty.
• The primary symptom is often infertility in adulthood due to impaired sperm production.

Patients often tell me they feel confused and even betrayed when they discover they have a Y chromosome despite identifying and appearing female. In these moments, clear, compassionate medical communication is essential.

The diagnostic journey for AIS depends on presentation age. A diagnosis requires a combination of a physical exam, hormone testing, and genetic analysis.

1. Hormone Blood Tests: A blood sample is taken to measure hormone levels. In individuals with AIS (post-puberty), the testosterone level will typically be high, in the normal or even high-normal male range.
2. Karyotype: This is a critical blood test that analyzes a person’s chromosomes. It will reveal the underlying 46,XY genetic makeup, which is often a surprising finding in an individual who appears female.
3. Pelvic Imaging: An ultrasound or MRI of the pelvis is performed to confirm the absence of a uterus and ovaries and to help locate the internal testes.
4. Genetic Testing: The diagnosis can be definitively confirmed by sequencing the AR gene to identify a disease-causing mutation.

I’ve often seen that diagnosis during puberty hits the hardest, it’s when gender identity, body image, and future fertility all collide, and support from both medical and psychological professionals becomes vital.

There is no treatment that can “cure” androgen insensitivity. Management is a lifelong journey focused on supporting the individual’s health, well-being, and gender identity. This requires a sensitive and experienced multidisciplinary team, which may include an endocrinologist, a surgeon (urologist or gynecologist), a geneticist, and, crucially, a mental health professional.

Gender Identity and Assignment

• For CAIS: Individuals have a female body, are raised as girls, and have a female gender identity. Care is focused entirely on supporting this identity.
• For PAIS: In the past, irreversible surgeries were sometimes performed on infants. The modern standard of care involves extensive counseling with the parents and, when possible, delaying any irreversible surgical decisions to allow the child to participate in affirming their own gender identity as they grow older.

Gonadectomy (Removal of the Testes)

The undescended testes in individuals with AIS have a slightly increased risk of developing cancer later in life.

• This is why a gonadectomy is often recommended.
• The timing of this surgery is debatable. Some recommend waiting until puberty is complete. This is because the testes in a person with CAIS produce testosterone, which is then converted into estrogen by the body. This allows the individual to go through a spontaneous puberty with natural breast development.

Hormone Replacement Therapy (HRT)

After the testes are removed, an individual with a female gender identity will require lifelong estrogen replacement therapy. This is essential for maintaining bone density and preventing osteoporosis, and for overall cardiovascular and sexual health.

Vaginal Health

For women with CAIS who have a short vagina, non-surgical vaginal dilation is a highly effective method to gently stretch the vaginal tissue to a length that allows for comfortable sexual intercourse.

Psychological Support

This is a cornerstone of care for individuals and families affected by AIS. A diagnosis can bring up complex feelings about identity, body image, infertility, and disclosure. Ongoing access to a mental health professional who is knowledgeable about DSDs is vital. Connecting with peer support groups, such as the AIS-DSD Support Group, can provide an invaluable sense of community and understanding.

In my experience, the most successful outcomes come when treatment plans are customized, long-term, and multidisciplinary with endocrinologists, surgeons, therapists, and geneticists all working together.

Androgen Insensitivity Syndrome is a complex genetic condition that reveals the intricate relationship between our chromosomes, hormones, and physical development. It is a condition of hormone resistance, not one of choice or identity. The journey for an individual and their family can be challenging, filled with difficult conversations and complex medical decisions. However, it is a manageable medical condition. Clinically, I’ve found that the emotional aspect of AIS often outweighs the physical, what patients need most is clear information, supportive care, and space to navigate their identity with dignity and confidence.

National Institutes of Health, Genetic and Rare Diseases Information Center (GARD). (2023). Androgen insensitivity syndrome. Retrieved from https://rarediseases.info.nih.gov/diseases/5811/androgen-insensitivity-syndrome

National Organization for Rare Disorders (NORD). (2023). Androgen Insensitivity Syndrome. Retrieved from https://rarediseases.org/rare-diseases/androgen-insensitivity-syndrome/

AIS-DSD Support Group. (n.d.). What is AIS? Retrieved from https://aisdsd.org/