Androgen insensitivity syndrome

Definitions & Key takeaways

Androgen insensitivity syndrome (AIS) is a rare genetic disorder that affects how the body responds to testosterone. Testosterone is a hormone that is responsible for the development and maintenance of male sex characteristics. People with AIS either do not have any testosterone receptors, or their receptors are not sensitive to testosterone. As a result, an individual presents with females' physical characteristics, despite having XY chromosomes (genetic makeup for males).

There are three types of AIS: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), and mild androgen insensitivity syndrome (MAIS). CAIS is the most severe type, while MAIS is the mildest. Individuals with AIS will usually have a normal female phenotype of appearance, but they may have infrequent or absent periods and be infertile.

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Introduction0:00–0:30

Androgen insensitivity syndrome is a genetic disorder, in which a person with an XY genotype - genetically a male – is “insensitive” or doesn’t respond to androgens, which are male sex hormones.
Androgens are responsible for primary sex characteristics like development of the penis and testes as well as secondary sex characteristics like height and body shape, so in androgen insensitivity syndrome all of these can be affected.

Embryology0:30–3:44

Okay, normally, very early on in fetal life, male and female genital tissues are undifferentiated and look identical. During the 7th or 8th week, the fetal gonads develop either into testes or ovaries.
In males, a gene on the Y chromosome, called the sex-determining region Y gene, or SRY gene for short, helps the fetal gonads turn into the testes.
By the end of week 8, the testes start producing androgens, the main one being testosterone. A small fraction of testosterone, gets converted by the enzyme 5α- reductase into its more potent form, called dihydrotestosterone, which is mostly responsible for development of male external genitalia.
Looking closely at these structures, at the top there’s the genital tubercle, which is a small projection. Just below that, there's the urethral groove, which is the external opening of the urogenital sinus or the future urethra and bladder and is surrounded by the urethral folds and the labioscrotal swellings.
Now, once dihydrotestosterone reaches the undifferentiated external genital structures, it makes the genital tubercle elongate into the phallus that eventually becomes part of the penis.
The elongating genital tubercle pulls up the urethral folds which fuse in the midline, forming the spongy or penile urethra.
Only the tips of these folds remain unfused to form the external urethral opening at the distal part of the penis. The labioscrotal swellings also grow toward each other fuse medially to form the scrotum, which is the sac skin that contain the testes.
Internally, the urogenital sinus is connected to a set of ducts, called Wolffian and Mullerian ducts. Testosterone also causes the Wolffian ducts to differentiate into the epididymis, vas deferens, and seminal vesicles.
At the same time, the testes also produce a hormone called anti-Müllerian hormone which prevents the Müllerian ducts from developing into the female reproductive tract and instead makes them degenerate.
About two months before birth, testosterone helps the testes descend from the abdomen into the future scrotum and later on, in puberty, testosterone helps sperm cells mature - a process called spermatogenesis.
In females, there’s no Y chromosome so the SRY gene is absent. As a result, ovaries develop from the internal gonads, and androgen levels remain relatively low, so the genital tubercle remains small, forming the clitoris and the urethral folds and labioscrotal swellings remain unfused or separate, forming inner and outer skin folds that surround the opening of the vagina and are called labia minora and labia majora.
Without the testes, anti- Müllerian hormone is also absent, so Müllerian ducts develop into the fallopian tubes, uterus, and upper part of the vagina.

Pathophysiology and symptoms3:44–4:15

In androgen insensitivity syndrome, XY-individuals have testes that produce androgens, but these hormones can’t exert their action, because there’s a defect in the androgen receptor on various target tissues like the external genitalia, genital ducts, and the testes itself.
Androgen insensitivity can be complete, partial, or mild, depending on how well the androgen receptor is able to bind androgens.

Complete Androgen Insensitivity4:15–5:45

In complete androgen insensitivity, the receptor is totally nonfunctional, so the cells don’t respond to androgens at all.
As a result, the testes tries to respond by increasing androgen synthesis. Without the effects of androgens, the testes sometimes don’t descend into the scrotum and instead remain in the abdomen or pelvis, which is called cryptorchidism.
Cryptorchidism is related to a higher chance of developing testicular cancer later in life. In the absence of androgen influence, the epididymis, vas deferens, and seminal vesicles don’t develop normally and spermatogenesis is also affected, so sperm don’t mature.
Additionally, the absence of androgen influence means that the external genitalia don’t masculinize and thus, take a female form, with a normal- looking clitoris, labia, and vaginal opening.
In puberty, the excess testosterone is converted into estrogen, which is the primary female sex hormone, causing the development of normal female secondary sex characteristics, such as breast growth, widening of the hips, and female fat distribution.
Even though androgen influence is missing, the testes still produce anti- Müllerian hormone and that means that these individuals don’t have a uterus, fallopian tubes, and that their vagina ends in blind pouch.
So these individuals look like females, but they don’t have menstrual cycles. In partial androgen insensitivity, there’s some remaining function of the androgen receptor, so the cells and tissues are partially sensitive to the androgen effects.

Partial Androgen Insensitivity5:45–6:06

As a result, the appearance of the external genitalia and secondary sex characteristics varies widely, usually with a mix of masculine and feminine features.

Mild Androgen Insensitivity6:06–6:29

Finally, in mild androgen insensitivity, there’s masculinization of external genitalia, but there may be some female secondary sex characteristics.
In all three types of androgen insensitivity syndrome, individuals are usually infertile, since their testes cannot produce mature sperm, and they have no ovaries or uterus.

Causes6:29–6:52

The androgen receptor gene is on the X-chromosome, and androgen insensitivity syndrome is inherited in an X-linked recessive pattern.
So in males, a single mutant gene causes the condition, and they can pass on the mutant gene to their daughters. Females with a single mutant gene are carriers, and they can pass the mutation to both their sons and their daughters.

Diagnosis6:52–7:28

Androgen insensitivity syndrome can be diagnosed in infants with cryptorchidism. Alternatively it can also remain undiagnosed until puberty, when an individual that has female genitalia doesn’t start menstruation.
A karyotype can be done to visualize the sex chromosomes to ensure that the individual is genetically male. In addition, serum testosterone and dihydrotestosterone levels are typically high.
An ultrasound scan can be done to confirm the absence of the uterus and ovaries, or to locate the testes, in the case of cryptorchidism.

Treatment7:28–8:05

Treatment typically involves surgical removal of the testes, especially in the case of cryptorchidism, to reduce the risk for cancer.
Some individuals with androgen insensitivity syndrome adopt a female gender identity, whereas others adopt a male gender identity.
Those that adopt a female gender identity can use estrogen supplements to help them develop a more feminized body. Those that adopt a male gender identity can use testosterone or dihydrotestosterone supplements as well as surgery for external genitalia to help them develop a more masculinized body.

Review8:05–8:23

All right, as a quick recap, androgen insensitivity syndrome occurs in XY-individuals and is caused by a loss of function of the androgen receptor, which could be complete, partial or mild and affect the development of primary and secondary sex characteristics.