What is Androgen Insensitivity Syndrome?
Androgen insensitivity syndrome (AIS) is a common cause of disorders related to sexual development and can lead to a wide range of physical characteristics. These disorders refer to conditions that affect the body’s response to male sex hormones in people who are genetically male (have an XY chromosome). The effect of AIS on a person’s physical characteristics depends on how much their body can interact with these male hormones.
In other words, individuals could show features ranging from completely female to mostly male (but with issues related to fertility and the completion of male physical development). If the body completely resists male hormones, the condition is referred to as complete androgen insensitivity syndrome (CAIS). In this case, even though genetically male, the person will have completely female physical characteristics.
On the other hand, when there is only partial resistance to male hormones, the condition is known as partial androgen insensitivity syndrome (PAIS). Here, there’s a wide range of physical characteristics that can be seen, from largely female to mainly male. Hence, deciding on the gender identity of a newborn baby with PAIS can be quite challenging for doctors.
So, it’s important for doctors to understand how male hormone receptors work to accurately diagnose whether the condition is CAIS or PAIS and plan the suitable treatment from infancy to adulthood.
What Causes Androgen Insensitivity Syndrome?
Androgen insensitivity syndrome is a condition that arises from specific changes, or loss-of-function mutations, in the genetic code of androgen receptors. “Androgens” are male hormones, and “receptors” are like locks that these hormones unlock to function correctly. This condition is linked to the X chromosome, which is one of the two sex chromosomes.
In this case, the changes in the genetic code cause the androgen receptors to malfunction, leading to a resistance to male hormones. As a result, despite having functional testes and producing enough testosterone (the main male hormone), some individuals may not develop as males (a process called virilization). They may have symptoms like infertility, despite having male (46XY) chromosomes.
The condition can present itself in different ways, referred to as Complete Androgen Insensitivity Syndrome (CAIS) and Partial Androgen Insensitivity Syndrome (PAIS). While the symptoms of these two forms can vary, the root causes and the ways in which they affect the body are similar.
Risk Factors and Frequency for Androgen Insensitivity Syndrome
Androgen insensitivity syndrome is defined as a “rare disease” by the National Institutes of Health’s Office of Rare Diseases. This label implies that it affects fewer than 20,000 individuals in the US. Because of its rarity, it can be difficult to gather concrete data regarding the age and clinical presentation of people diagnosed with this condition.
- According to a study conducted in Denmark, the prevalence of females with a 46XY karyotype – a specific type of chromosome arrangement often associated with this syndrome – is 6.4 per 100,000 live-born females.
- The prevalence of androgen insensitivity syndrome was found to be 4.1 per 100,000 live-born females.
- The frequency of Complete Androgen Insensitivity Syndrome, as confirmed by molecular diagnosis, is estimated to range from 1 in 20,400 to 1 in 99,100 genetic males.
Signs and Symptoms of Androgen Insensitivity Syndrome
Androgen insensitivity syndrome is a condition that could be categorized into three subtypes: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), and mild androgen insensitivity syndrome (MAIS).
- Complete Androgen Insensitivity Syndrome (CAIS): The signs of CAIS can vary between infants and adolescent females. It generally makes its presence known through primary amenorrhea in adolescent females (when they do not begin menstruating) or the accidental discovery of testes during a hernia repair in girls. Despite having a typical female appearance at birth, DNA analysis may reveal the presence of a Y chromosome. Additionally, the presence of internal testes and absence of a uterus are notable characteristics. Females with CAIS may also exhibit normal breast development during puberty due to the conversion of androgens to estrogens and can be taller due to the effect of the Y chromosome.
- Partial Androgen Insensitivity Syndrome (PAIS): People with PAIS possess a mix of masculine and feminine physical traits, which vary based on functionality of their androgen receptor. Common physical traits include hypospadias (a condition where the opening of the urethra is on the underside of the penis), a bifid scrotum (split scrotum), and a smaller than average penis.
- Mild Androgen Insensitivity Syndrome (MAIS): Individuals with MAIS usually appear as normal males but may have a small penis. In adulthood, they might struggle with gynecomastia (developing breast tissue) and infertility.
Testing for Androgen Insensitivity Syndrome
In simple terms, the diagnosis of conditions called CAIS (Complete Androgen Insensitivity Syndrome) and PAIS (Partial Androgen Insensitivity Syndrome) includes assessing physical symptoms, hormone levels, as well as ruling out problems with testosterone production. Genetic testing can also be used to confirm these conditions.
To rule out issues with testosterone production, doctors may recommend measuring levels of testosterone, a hormone known as luteinizing hormone (LH), and follicle-stimulating hormone (FSH) within the first year of life. This evaluation will help identify any abnormalities in hormone production which might indicate these syndromes.
In children, a test called the human chorionic gonadotropin (hCG) stimulation test is used to evaluate testosterone production. This test involves measuring levels of various hormones before and after receiving a dose of hCG. In adults, doctors usually measure hormone levels without stimulation.
Through these tests, doctors assess two key problems with hormone synthesis: 17-beta-hydroxysteroid dehydrogenase deficiency and 5-alpha-reductase deficiency. In people with CAIS and PAIS, testosterone responses after the hCG stimulation test are typically normal. Low testosterone production after this test may suggest a 17-beta-hydroxysteroid dehydrogenase deficiency.
The differentiation between CAIS and PAIS and a condition called 5-alpha-reductase deficiency can be identified by looking at the ratio of testosterone to another hormone called dihydrotestosterone (DHT) in the blood. In people with a 5-alpha-reductase deficiency, DHT production decreases, and the ratio of testosterone to DHT increases.
In addition to these tests, genetic testing is very important in diagnosing AIS. Even if the physical symptoms and hormone tests suggest CAIS or PAIS, genetic studies are necessary for a definitive diagnosis. Genetic testing looks for specific mutations in the androgen receptor gene — which is necessary for the body to respond to testosterone — found on the X chromosome. More than 1000 mutations have been found in this gene in people with AIS. Analysis called Multiplex ligation-dependent probe amplification (MLPA) can detect deletions or duplications of parts or the entire gene.
However, understanding the link between PAIS and specific gene mutation still poses a significant challenge for doctors in predicting the nature and course of this condition.
Treatment Options for Androgen Insensitivity Syndrome
Androgen insensitivity syndrome (AIS) is a health disorder where a person is born with parts of both male and female sexual characteristics. Managing this condition involves careful attention to the mental, physical, and social well-being of the person with AIS. This also includes helping their family understand and navigate the challenges associated with this condition. The aim is to ensure the well-being of the individual from infancy into adulthood.
This condition can’t be reversed because it is rooted in the individual’s development before birth. Therefore, an important part of management is counseling families and deciding on the appropriate gender for the individual. The plan also encompasses improving their functionality as they grow older.
Complete Androgen Insensitivity Syndrome (CAIS):
CAIS can be discovered unexpectedly during a hernia repair operation or when a female does not start her period. If a hernia repair reveals gonads (organs that produce sex cells), it’s recommended to take a small sample of the gonad for testing. The gonad is then put back in the body to allow further discussions with the parents about what this diagnosis means and what to do next.
To avoid the risk of cancer, parents can choose to have the gonads removed early when the child is still an infant and unaware of the issues related to CAIS. In such cases, puberty will be induced later by giving the individual estrogen. Moreover, as individuals with CAIS don’t have a uterus, they don’t have the usual risk of cancer caused by estrogen. Alternatively, the gonads can be removed later in life, which also carries a low risk of cancer. In this case, puberty will start naturally, leading to the typical growth spurt and breast development but without menstruation.
Lastly, to ensure normal sexual functioning and psychological well-being, surgical management in CAIS may involve vaginoplasty (surgery to construct or reconstruct the vagina) or using a dilator to gently stretch the vagina.
Partial Androgen Insensitivity Syndrome (PAIS):
Unlike CAIS, infants with PAIS often have ambiguous genitalia, meaning it’s not clear whether they’re male or female. This situation calls for a correct diagnosis and a discussion with the family and caregivers to decide the sex of the infant. Subsequent management will then focus on this decision.
If a male sex is assigned, the individual will receive androgen (a male sex hormone) at the time of puberty. Surgery can be done to correct any issues with the genitals, like hypospadias (where the opening of the urethra is not at the tip of the penis) and undescended testes. It’s preferable to do these surgeries during the 2nd to 3rd year of life. Some individuals with PAIS may develop breasts during puberty, which can be managed by surgery to prevent cancer. However, breast cancer incidence is low in men with PAIS.
If a female sex is assigned, the individual will receive estrogen at the start of puberty, and surgical procedures can be carried out on the genitals and gonads before puberty begins.
What else can Androgen Insensitivity Syndrome be?
When diagnosing Complete Androgen Insensitivity Syndrome (CAIS), doctors usually consider the following conditions:
- Disorders of androgen synthesis or Leydig cell dysfunction: These are issues that affect the production of the male hormone testosterone.
- Müllerian Agenesis: This condition is also known as Mayer-Rokitansky-Küster-Hauser syndrome. Someone with this condition is born without a uterus and has no period. They have normal hair development because their hormone levels are typical.
- Mixed Gonadal Dysgenesis: This is a condition where a person may have some cells with a typical male chromosome pattern (46, XY) and others with a female pattern (45, X). They usually have one testis and one ‘streak’ gonad (undeveloped gonad).
Partial Androgen Insensitivity Syndrome (PAIS) can be a bit more difficult to diagnose because it can present in many different ways. Doctors often consider conditions similar to those listed above, such as:
- Gonadal Dysgenesis: This condition usually presents in people who have a typical male chromosome pattern (46, XY) but have a uterus.
- Partial Gonadal Dysgenesis: This condition also has a 46, XY chromosome pattern, and usually presents with some Müllerian structures (parts of the female reproductive system), but reduced hormones related to the male reproductive system.
These conditions can appear quite similar, so accurate diagnosis can be a challenge.
Surgical Treatment of Androgen Insensitivity Syndrome
Androgen insensitivity syndrome and individuals with undescended testes, also known as cryptorchidism, are at a heightened risk of developing tumors. Cryptorchidism is a condition wherein one or both of the testes fail to descend. If a person has a partial androgen insensitivity syndrome (PAIS), a condition where the body can’t properly respond to male sex hormones, it’s advised to have the cryptorchidism corrected via surgery as soon as possible. The aim is to maintain the healthy functioning of the testes and decrease the risk of cancer.
The tumors that can develop in these cases may be germ cell tumors or gonadoblastomas. These types of tumors are estimated to occur in about 1.5 to 2 percent of undescended testes and have the potential to become malignant, meaning they can spread to other parts of the body.
There’s a condition known as carcinoma in situ or intra-tubular germ cell neoplasia unclassified, which is a pre-cancerous stage where abnormal cells are found within the tubes of the testes where sperm are formed. These abnormal cells are believed to originate from early sperm cells and are considered to be caused by these cells not developing properly. From this stage, more than half of the cases can lead to the development of a gonadoblastoma, a rare tumor that’s generally benign.
Individuals with PAIS are at a higher risk of developing germ-cell tumors than those with complete androgen insensitivity syndrome (CAIS). Some studies suggest that up to 15% of people with PAIS can develop these tumors, and the risk is even higher if the testes are not in their normal position within the scrotum.
Women who have CAIS are strongly recommended to have a gonadectomy, which is the surgical removal of the testes because the risk of developing a tumor can substantially increase with age. Monitoring for the formation of carcinoma is predominantly based on imaging studies, like ultrasound and MRI. These studies can help spot any abnormal growths in the testes early on when they are easier to treat.
What to expect with Androgen Insensitivity Syndrome
Research has shown that if a type of operation called a gonadectomy isn’t performed, there’s a risk that’s more than 30% higher of developing a tumor later in life. This tends to be particularly true for boys who have a confirmed genetic condition called Partial Androgen Insensitivity Syndrome (PAIS). They often have a harder time than boys with XY DSD, which simply means they have typical male sex chromosomes. This difficult time is especially true if they have normal testosterone production and no detectable changes in the androgen receptor, a protein that responds to testosterone.
Possible Complications When Diagnosed with Androgen Insensitivity Syndrome
Not treating or improperly managing Androgen Insensitivity Syndrome (AIS) could cause serious mental distress for patients as they transition from adolescence to adulthood, as well as their families. Mental distress tends to be more common in adults with partial Androgen Insensitivity Syndrome compared to those with the complete form, regardless of whether they were raised as male or female. A study by Bouvattier C and colleagues found that among men with partial AIS, all types of sexual activity were significantly affected.
Possible Consequences:
- Severe mental distress for patients transitioning from adolescence to adulthood
- Mental distress for their families
- Increased mental distress in adults with partial AIS compared to complete AIS
- All types of sexual activity can be significantly affected, particularly in men with partial AIS
Recovery from Androgen Insensitivity Syndrome
Children who are diagnosed with AIS, or Androgen Insensitivity Syndrome, are recommended to undergo a surgical procedure called gonadectomy before they hit puberty. This procedure helps to prevent female children from developing male traits and also stops the growth of tumors in the gonads, or the reproductive glands. Surgery to create a functional vagina is rarely required.
For girls who have a shorter than average vagina, vaginal dilators are a successful primary treatment option to help increase the length. A group of medical professionals work together to provide complete care for patients with AIS, from the time they are diagnosed and beyond.
Talks about post-operative care are important and should be done in an open and understanding manner, keeping in mind both the patient and their family’s viewpoints and needs. The mental and emotional wellbeing of both the patients and their families are also considered key aspects of AIS management and are given as much importance as physical health.
Preventing Androgen Insensitivity Syndrome
Teaching families with newborns who have Androgen Insensitivity Syndrome (AIS), a condition where the body can’t process male hormones, is extremely important. This education helps create a care plan that will benefit the newborn as they grow up. This is best done through a team approach, involving not just the usual doctor or nurse, but also a specialist in genetic disorders. Support groups are also valuable, because they help address the unique needs of the child with AIS and their family.
Nurses play an incredibly important role in this process. They help to educate the patients and their families about AIS. They also ensure that the family has access to community support groups and educational materials. This all helps the family to understand the condition better and feel more supported as they navigate it.
