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Androgen Insensitivity Syndrome

Androgen Insensitivity Syndrome

Androgen insensitivity syndrome (AIS) is a disorder caused by mutation of the gene for the androgen receptor. This protein binds testosterone and regulates the expression of other genes that stimulate male sexual development. Testosterone is the principal male androgen. AIS is an X-linked recessive disorder that completely or partially prevents development of male sexual characteristics despite the presence of the Y chromosome. Thus, the phenotype of a person with AIS, typified by female or ambiguous sexual characteristics, is at odds with the genotype , which includes the presence of both the X and Y, or male-determining, chromosomes.

The extent of the syndrome ranges from complete androgen insensitivity and development of normal external (but not internal) female sexual anatomy, to partial insensitivity, with altered or ambiguous male or female genitals, to mild insensitivity, with normal male genitals, enlarged breasts, and possibly impotence. Treatments depend on the extent of the syndrome, and may include hormone therapy, surgery, and psychological counseling. Gene testing and genetic counseling are available for families with affected members.

Sexual Development

AIS can best be understood against the background of normal human sexual development, which begins in the womb. The gonads arise from the same embryonic tissue, which is differentiated into one or the other by the actions of several genes not involved in AIS. In males, the most important gene is SRY, located on the Y chromosome. When present, this causes testis development. The genes responsible for ovary development are not as well characterized.

Once differentiated, the ovaries produce estrogen, and testes produce testosterone. These two hormones provide crucial signals for the differentiation of other sex-related characteristics, including an important set of primitive ducts.

The tubes and cavities that will house the adult's eggs or sperm after they leave the gonads develop from two different sets of ducts. Early in development, every fetus has both sets of ducts. One set, called the Wolffian ducts, has the capacity to develop into the male vas deferens and accessory structures, which store, nourish, and ejaculate sperm. The other set, called the Müllerian ducts, has the capacity to become the female fallopian tubes, uterus, cervix, and upper vagina.

In males, testosterone from the testes stimulates the development of the Wolffian ducts. Testosterone also stimulates nearby tissue to swell and form the penis and scrotum. A second hormone made by the testes, called antiMüllerian hormone (AMH), induces the Müllerian ducts to undergo apoptosis , causing them to degenerate. During puberty, testosterone stimulates the development of other male secondary sex characteristics, including facial hair and a deepening of the voice.

In females, the absence of testosterone and AMH causes the Müllerian ducts to develop and the Wolffian ducts to degenerate. The same tissue that forms the penis and scrotum in males forms the clitoris, labia, and lower vagina in females. At puberty, estrogen stimulates development of female secondary sex characteristics, including enlargement of the breasts and onset of menstruation.

Testosterone and Its Receptor

Testosterone is a hormone, a molecule released in one set of cells that regulates the action of other cells. Testosterone exerts its action on these target cells by first binding with a receptor, called the androgen receptor (AR). The receptor is a protein that resides within the target cell. The testosterone-receptor complex moves to the nucleus of the target cell, where it acts as a transcription factor. Transcription factors bind to DNA to control the rate of gene expression. In the case of testosterone, the genes affected are those that "masculinize" the fetus, triggering the transformation of the Wolffian ducts into the mature male sexual anatomy and causing other, more subtle changes, including in the brain. Thus, the interaction of testosterone with its receptor is the principal means by which the male genotype (presence of a Y chromosome) leads to the development of the male phenotype (presence of a vas deferens, penis, and accessory structures).

The Consequences of Androgen Insensitivity

With an understanding of normal sexual development, consider the consequences of complete androgen insensitivity on the events of development in a person with the XY genotype. Since the Y chromosome is present, there will be testes. The testes will produce testosterone and AMH. AMH will cause degeneration of the Müllerian ducts, and so there will be no fallopian tubes, uterus, cervix, or upper vagina. But the defective receptor means that testosterone cannot exert its effects, so the Wolffian ducts also degenerate, and there will be no vas deferens. There will also be no penis or scrotum. Instead, the testes remain in the abdomen (where they originate), and the exterior tissue develops a short vagina that ends in a blind pocket. In milder forms of the syndrome, with only partial insensitivity to androgens, the genital structures may be ambiguous, with varying degrees of male versus female predominance.

The Androgen Receptor Gene and Protein

The AR gene is located on the long arm of the X chromosome, at a location that is designated as Xq11-q12. The gene is about 90,000 nucleotides long, though fewer than 3,000 of these actually code for amino acids in the protein. The protein formed from the gene has different domains that perform different functions. One region binds testosterone, another regulates the movement of the complex to the nucleus, and a third binds the complex to the DNA. Other regions, some overlapping, control other functions.

Mutations to the coding portion for any one of these domains can prevent the receptor complex from functioning properly. All known mutations in the AR gene cause a loss of function and exhibit the recessive inheritance pattern. A male carries only one X chromosome, and receives only one copy of the AR gene. If this gene is mutated, the male will have androgen insensitivity syndrome.

Women with one mutated AR gene will not exhibit the syndrome but instead will be carriers, whose male children have a 50 percent risk of inheriting the mutant gene. Since affected individuals are sterile, they cannot pass it on to offspring. It is believed that about one-third of all cases are due to new mutations, which are not present in the mother's genes but which arise in the development of the early embryo. Genetic testing is available for women who desire children but who have a family history of androgen insensitivity. For women who are carriers, prenatal testing is available to determine if a fetus has inherited the mutant gene.

The Range of Androgen Insensitivity Syndromes

AIS occurs in a range of forms, from complete to mild. Most mutations to the testosterone-binding region, and some other types of mutations, cause complete androgen insensitivity syndrome (CAIS). In this form of the syndrome, the XY person is born phenotypically female, and from birth is raised as a girl. Gender identification (the internal sense of being male or female) is female. Sexual orientation is typically heterosexual, and so most CAIS individuals are attracted to males. At puberty, estrogen production by the adrenal glands causes breasts to develop. However, no pubic or armpit hair develops, since in males and females this is controlled by testosterone, and no menstruation occurs. It is at this point that the condition is usually diagnosed. Once discovered, the testes are usually surgically removed to prevent the possibility of testicular cancer, which is more common in people with CAIS. The woman is infertile, but may be able to enjoy sexual relations if the vagina is long enough to prevent pain during intercourse; or, if the vagina is not long enough, it can be surgically lengthened. CAIS is thought to occur in 2 to 5 births per 100,000.

Those with partial androgen insensitivity syndrome (PAIS) have androgen receptors that are partially responsive to testosterone, and a range of outcomes may result. A person with PAIS may be born with external genital structures that are not typically male or typically female, a condition called intersexuality. The appearance of the genitals may range from predominantly male to predominantly female. There may be a very small penis or enlarged clitoris, abnormalities in the location of the urethra, and partial fusion of the labia. Breasts may develop in males at puberty. Internal gender identification may be with either sex. PAIS is thought to be as common as CAIS.

Ambiguous genitals are often surgically altered at birth. Problems arise when the surgically assigned sex conflicts with the internal gender identification, which develops early and becomes even more pronounced through late childhood and puberty. Increasing understanding of PAIS and sensitivity to the issues of gender identification have brought new awareness about the potential for these problems, but the practice of surgical sex assignment is still common. In 2001 the British Association of Paediatric Surgeons recommended that surgery "only be undertaken with considerable caution and following full multidisciplinary investigation and counseling of the parents." Other therapies include hormone treatments and psychological counseling, including family counseling, and these are often part of the treatment, with or without surgery.

Kennedy Disease

Kennedy disease is a neurological condition that is also due to a mutation of the androgen receptor gene. Affected individuals are phenotypically normal males who are fertile, although after puberty they may develop enlarged breasts, consistent with very mild androgen insensitivity. The disorder causes progressive weakness over several decades, along with tremor, difficulty swallowing, and some sensory problems. The mutation that causes Kennedy disease is an expanded "triplet repeat" of CAG nucleotides, making this condition one of the family of triplet repeat diseases that includes Huntington's disease.

see also Apoptosis; Hormonal Regulation; Inheritance Patterns; Sex Determination; Sexual Orientation; Transcription Factors; Triplet Repeat Disease; X Chromosome; Y Chromosome.

Richard Robinson


Gilbert, Scott. Developmental Biology, 5th ed. Sunderland, MA: Sinauer Associates, 1997.

Internet Resources

Androgen Insensitivity Syndrome. <>.

Statement of the British Association of Paediatric Surgeons Working Party on the Surgical Management of Children Born with Ambiguous Genitalia. <>.

Warne, Garry. Complete Androgen Insensitivity Syndrome. Victoria, Australia: Department of Endocrinology and Diabetes, Royal Children's Hospital. <>;.

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"Androgen Insensitivity Syndrome." Genetics. . 15 Dec. 2017 <>.

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androgen insensitivity syndrome

androgen insensitivity syndrome (AIS) n. an X-linked (see sex-linked) disorder in which the body does not react to androgens because of structural abnormalities in androgen receptors. complete AIS (formerly known as testicular feminization syndrome) the most extreme form of AIS, in which there is a fully female body appearance with breast development and a short vagina (but no uterus; testes are present internally). Psychosexuality is female orientated. partial AIS a form of AIS that becomes most obvious at puberty, with poor development of male genitalia and breast development.

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