What is androgen insensitivity syndrome?

Quick Answer
The sex of a baby is usually determined at conception by the sex chromosomes, but other genetic events can alter the outcome. One such condition is androgen insensitivity syndrome, which can cause a child with male chromosomes to be born with feminized or ambiguous genitals.
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Risk Factors

Individuals whose mothers carry a mutated copy of the AR gene on one of their two X chromosomes are at risk for androgen insensitivity syndrome. About 70 percent of all cases of this disorder are inherited from mothers with this altered gene. The remaining cases result from a new mutation that can occur in the mother’s egg cell before the child’s conception or during early fetal development.

Etiology and Genetics

Introductory biology courses teach that a fertilized egg that receives two X chromosomes at conception will be a girl, whereas a fertilized egg that receives an X and a Y chromosome will become a boy. However, other factors can also affect the development of a person’s sex. Sex development in mammals begins at conception with the establishment of chromosomal sex (the presence of XX or XY chromosomes). Even twelve weeks into development, male and female embryos have the same external appearance. Internal structures for both sexes are also similar. However, the machinery has been set in motion to cause the external genitals to become male or female, with corresponding internal structures of the appropriate sex. The baby is usually born with the proper phenotype to match its chromosomal sex. However, development of the sex organs is controlled by several genes. This leaves a great deal of room for developmental errors to occur.

The AR gene, the primary gene involved in sex determination, is carried on the Y chromosome. This gene is responsible for converting the early unisex gonads into testes. Once formed, the testes then produce the balance of androgen and estrogen that pushes development in the direction of the male phenotype. In the absence of this gene, the undetermined gonads become ovaries, and the female phenotype emerges. Therefore, the main cause of sex determination is not XX or XY chromosomes, but rather the presence or absence of the gene that promotes testis differentiation.

In order for the male hormones to have an influence on the development of the internal and external reproductive structures, the cells of those structures must receive a signal that they are part of a male animal. The androgens produced by the testes are capable of entering a cell through the cell membrane. Inside the cell, the androgens attach to specific protein receptor molecules (androgen receptors). Attachment causes the receptors to move from the cytoplasm into the nucleus of the cell. Once in the nucleus, the receptor-steroid complexes bind to DNA near genes that are designed to respond to the presence of these hormones. The binding event is part of the process that turns on specific genes—in this case, the genes that direct the process of building male genitals from the unisex embryonic structures, as well as those that suppress the embryonic female uterus and tubes present in the embryo’s abdomen.

In cases of complete androgen insensitivity syndrome (CAIS), androgen receptors are missing from male cells. This is the result of a recessive allele located on the X chromosome. Because normal males have only one X, the presence of a recessive allele on that X will result in no production of the androgen receptor in that individual. The developing embryo is producing androgen in the testes; without the receptor molecules, however, the cells of the genitals are unable to sense the androgen and respond to it. In partial androgen insensitivity syndrome (PAIS), some androgen is received and responded to, leading to the development of mostly male or ambiguous genitals. CAIS and PAIS are believed to be equally common.


In individuals with CAIS, the cells of the genitals are still capable of responding to estrogen from the testes. As a result, the genitals become feminized: labia and clitoris instead of a scrotum and penis, and a short, blind vagina. To the obstetrician and parents, the baby appears to be a healthy girl. An internal examination would show the presence of testes rather than ovaries and the lack of a uterus and fallopian tubes, but there would normally be no reason for such an examination.

In cases of PAIS, the affected individual may have mostly female, mostly male, or ambiguous genitals, depending upon the degree to which the cells of genitals are capable of responding to androgen from the testes. Those who appear mostly female may have an enlarged clitoris, fused labia, or testes in the labia or elsewhere in the groin. Those with a mostly male appearance may have a penis of either average or below average size with a urethral opening not at the tip (hypospadias), a cleft scrotum, descended or undescended testes, and breast development in puberty (gynecomastia). Those with ambiguous genitalia may have a micropenis, a cleft scrotum, descended or undescended testes, scrotal hypospadias or a single vaginal-urinary tract, and gynecomastia.

Screening and Diagnosis

Cases of PAIS are usually evident at birth, whereas CAIS may not be detected for many years. Several events may lead to the diagnosis of this condition. The attempted descent of the testes into a nonexistent scrotum will cause pain that may be mistaken for the pain of a hernia; the presence of testes in the child with CAIS will be discovered when the child undergoes repair surgery. In other cases, the child may seek medical help in the midteen years because she does not menstruate. Exploratory surgery would then reveal the presence of testes and the absence of a uterus. Androgen insensitivity syndrome can be detected by blood tests, which check levels of testosterone and other hormones, pelvic ultrasound, and genetic testing.

Treatment and Therapy

As a general rule, the testes are left in the abdomen until after puberty because they are needed as a source of estrogen to promote the secondary sex characteristics, such as breast development. Without this estrogen, the girl would remain childlike in body form. After puberty, the testes are usually removed because they have a tendency to become cancerous. Bone density scans may also be recommended in order to prevent osteoporosis.

As a result of its phenotypic sex, an infant with CAIS is normally raised as a girl whose only problem is an inability to bear children. If the girl has athletic ability, however, other problems may arise. Suspicions of so-called gender fraud by two female Olympians first arose at the Berlin Olympics in 1936; later examinations indicated that they both had intersex conditions. Beginning in 1966, female Olympic athletes were required to submit to a test for the presence of the correct chromosomal sex. In the past, this has meant microscopic examination of cheek cells to count X chromosomes. In 1992, this technique was replaced by a test for the Y chromosome. Individuals who fail the “sex test,” including those with androgen insensitivity syndrome, could not compete against other women. Proponents of such testing have argued that androgens aid muscle development, and the extra testosterone produced by the testes of a normal male would provide an unfair physical advantage. However, because people with androgen insensitivity syndrome are lacking androgen receptors, their muscle development would be unaffected by the extra androgen produced by the testes, and thus they would not be any stronger than well-conditioned women. The International Olympic Committee ended so-called gender verification testing in 2000, but debate over the participation of women with higher testosterone levels in elite women's sports remains.

Those with PAIS may be raised as boys or girls, based on the maleness or femaleness of their external genitals. The families of children with ambiguous genitals typically assign a sex (and corresponding gender) to the child in consultation with medical professionals. Hormonal and prepubertal surgical treatments, such as hypospadias repair and urethroplasty, may be considered.

Prevention and Outcomes

There currently is no cure for or way in which to prevent this condition. However, the prognosis for CAIS is good if the testes are removed before they become cancerous.


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