Androgen insensitivity syndrome
Androgen insensitivity syndrome
Definition
Androgen insensitivity syndrome is a genetic condition where affected people have male chromosomes and male gonads (testicles). The external genitals, however, have mild to complete feminization.
Description
Normal sexual development
In normal development, the chromosome sex determines the gonadal sex, which in turns determines the phenotypic sex. The chromosome sex is determined at conception; a male has the sex chromosome pair XY and a female has the chromosome pair XX. During the first 40 days of gestation, a male and female embryo appear the same and have undifferentiated gonads, which have the potential of becoming testes or ovaries. The presence of the Y chromosome in the male directs the undifferentiated gonads to become testicles. If no Y chromosome is present, such as in the female chromosome pair, the undifferentiated gonads become ovaries.
In males, the phenotypic sex, including the internal male structures and the external male genitalia, arises as a result of the hormones secreted from the testicles. The two main hormones secreted by the testicles are testosterone and mullerian duct inhibitor. Testosterone acts directly on the wolffian duct, which give rise to the internal male structures including the epididymides, vasa deferentia, and seminal vesicles. Testosterone is converted into dihydrotestosterone, the hormone responsible for the development of the male urethra and prostate, and the external genitalia of the penis and the scrotum. The mullerian duct inhibitor is the hormone that suppresses the mullerian ducts and prevents the development of fallopian tubes, upper vagina, and uterus in males.
If no testicles are present, as with females, no mullerian duct inhibitor is formed and the mullerian ducts become the fallopian tubes, the upper vagina, and the uterus. The wolffian ducts regress. Due to the lack of dihydrotestosterone, the external genitals are not masculinized and become female. Studies have shown that an ovary is not required for the formation of the internal female structures or the feminization of the genitals. If a testicle is not present, the development of the embryo will default to female development.
In most cases, the chromosomal sex, the gonadal sex, and the phenotypic sex are in agreement. Males have 46,XY chromosomes, testicles, and male internal structures and genitals. Females have 46,XX chromosomes, ovaries, and internal female structures and genitals.
Androgen insensitivity syndrome
Androgen insensitivity syndrome (AIS), also known as testicular feminization, is one of the most common conditions where the chromosome sex and gonadal sex do not agree with the phenotypic sex. Affected people have normal male chromosomes, 46,XY and testicles. The testicles secrete both testosterone and mullerian duct inhibitor as normal and no internal female structures form. However, due to defective androgen receptors, the wolffian ducts and genitals cannot respond to the androgens testosterone and dihydrotestosterone. As a result, no male internal structures are formed from the wolffian ducts and the external genitals are feminized.
The amount of feminization depends on the severity of the androgen receptor defect and is often characterized as complete androgen insensitivity (CAIS), partial androgen insensitivity (PAIS), and mild androgen insensitivity (MAIS). In complete androgen insensitivity, the alteration in the androgen receptor results in complete female
| Classification of AIS Phenotypes | ||
| Type | External genitalia (synonyms) | Findings |
| CAIS | Female (“testicular feminization”) | Absent or rudimentary wolffian duct derivatives |
| Inguinal or labial testes; short blind-ending vagina | ||
| Little or no pubic and/or axillary hair | ||
| CAIS or PAIS | Predominantly female (incomplete AIS) | Inguinal or labial testes |
| Labial fusion and enlarged clitoris | ||
| Distinct urethral and vaginal openings or a urogenital sinus | ||
| PAIS | Ambiguous | Microphallus (<1 cm) with clitoris-like underdeveloped glans; labia majora-like bifid scrotum |
| Descended or undescended testes | ||
| Perineoscrotal hypospadias or urogenital sinus | ||
| Excessive development of the male breasts during puberty | ||
| Predominantly male | Simple (glandular or penile) or severe (perineal) “isolated” hypospadias with a normal-sized penis and descended testes or severe hypospadias with micropenis, bifid scrotum, and either descended or undescended testes | |
| Excessive development of the male breasts during puberty | ||
| MAIS | Male (undervirilized male syndrome) | Impaired sperm development and/or impaired masculinization |
| Overdevelopment of the male breasts during puberty | ||
external genitals. In partial androgen insensitivity, also called Reifenstein syndrome, partial androgen insensitivity results in female genitalia with some masculinization, ambiguous genitalia, or male genitalia with partial feminization. With mild androgen insensitivity, mild androgen resistance results in normal male genitals or a male with mild feminization.
In both CAIS and PAIS, affected individuals are sterile (can not have a child). In MAIS, the affected male may have fertility problems because of oligospermia, low sperm production, or azoospermia, no sperm production. In all types of AIS, secondary sex characteristics such as body and pubic hair can be abnormal. Mental impairment is not found in any of the types of androgen insensitivity syndromes, though poor visual-spatial ability has been observed. People with AIS can also be rather tall, though bone age is usually normal.
Genetic profile
Androgen insensitivity syndrome is a genetic condition that results from mutations (alterations) of the gene for the androgen receptor. The androgen receptor is located on the long arm of the X chromosome (Xq11-q12). As women have two X-chromosomes, they also have two androgen receptor genes. Men have only one X chromosome and a Y chromosome; hence they only have one copy of the androgen receptor gene.
When women have one copy of the androgen receptor altered, they are considered carriers of AIS. In most cases, the second, normal copy of the androgen receptor can compensate for the altered copy. However, in approximately 10% of women who are carriers for the altered androgen receptor gene, clinical signs such as sparse pubic hair and armpit hair or a delay to the start of their first menstrual period is observed.
46,XY conceptions that have alterations in the androgen receptor gene do not have a second copy to compensate for the altered copy. Hence, these people will have AIS. If the androgen receptor is severely altered, they will have CAIS. If not severely altered, they will have PAIS or MAIS.
All forms of AIS are inherited in an X-linked recessive pattern. This means women who are carriers have a 25% chance of having an affected child. If a carrier woman has a 46,XY conception, there is a 50% chance the child will have AIS. If a carrier woman has a 46,XX conception, there will be a 50% chance the daughter will also be a carrier.
When a person has AIS and has no other family history of the condition, approximately 2/3 of the time the affected person inherited the gene alteration from his or her mother. The other 1/3 of the time, the alteration of the androgen receptor was a new event (new mutation) in the affected person and was not inherited.
Cases of both gonadal mosaicism and somatic mosaicism have been reported with AIS. Gonadal mosaicism occurs when the alteration in the androgen receptor occurred not at conception, but in one of the gamete cells (sperm or egg). The rest of the cells of the body do not have the altered androgen receptor. With AIS, this can occur when one of a woman's early gamete cell has the new alteration in the androgen receptor but the rest of the cells in her body do not. All the eggs that come from the early gamete cell will also have the alteration. Her risk for having a child with AIS is increased. Somatic mosaicism occurs when the alteration in the androgen receptor occurs after conception but not in a gamete cell. Some of the person's cells will have the altered androgen receptor and other cells will not. The amount of cells with altered receptors and the location of those cells within the body will determine how severely affected a person will be.
Mutations within the androgen receptor gene are also responsible for the neuromuscular condition spinobulbar muscular atrophy or Kennedy disease . See separate entry for more information.
Demographics
Complete androgen insensitivity syndrome occurs in approximately 1/64,000 46,XY births or 2-5/100,000 births overall. Partial AIS is at least as common as complete AIS. The incident of mild AIS is unknown, but is estimated to account for approximately 40% of male infertility due to severe oligospermia or azoospermia.
Signs and symptoms
Complete androgen insensitivity
Individuals with CAIS are born looking like normal female babies. Often, the condition is discovered in one of two ways. The child can have an inguinal hernia that upon repair is found to contain testicles. The most common presentation is during puberty with primary amenorrhea, or lack of the onset of the menstrual period. Affected individuals have a short, blind ending vagina and no uterus, cervix, fallopian tubes, or ovaries. During puberty, some girls will have absent or decreased sexual hair. Breasts develop normally and can be large in size with pale and immature nipples and areola. People with CAIS are usually raised as females and have normal female sexual orientation. All women with CAIS are sterile. In families with CAIS, all affected members will have complete androgen insensitivity and similar physical features.
Partial androgen insensitivity syndrome
Children with PAIS usually present at birth due to ambiguous genitalia. The genitalia can look like female genitals with some masculinization, completely ambiguous genitals where the sex of the baby cannot be immediately determined, or male genitals with some feminization. The degree of severity is a direct result of the degree of severity of the genetic alteration in the androgen receptor and resulting amount of functional androgen receptor. The internal structures of PAIS are the same as CAIS, with absent fallopian tubes, cervix, uterus, and ovaries. Testes are present but do not produce sperm. Hence, people with PAIS are also sterile. People with PAIS also have primary amenorrhea, and breast development occurs in puberty. Unlike CAIS, affected individuals in the same family with presumably the same genetic alteration can have varying degrees of masculinization. As a result, some affected people may be raised as females whereas others may be raised as males. Sex assignment is made based upon the structure of the genitals, the surgical correction needed, and the predicted response to androgens during puberty.
Mild androgen insensitivity
Males with mild androgen insensitivity usually have normal male genitals and internal male structures. During puberty, males with MAIS may have breast enlargement, sparse facial and body hair, and small penis. Some affected males may also have impaired sperm production resulting in oligospermia or azoospermia, decreased or absent sperm. As with CAIS, affected men within the same family usually have similar features.
Diagnosis
Diagnosis is usually made based upon clinical features, chromosome analysis, hormone levels, and analysis of androgen receptor function in skin fibroblasts. Clinical features are listed above for CAIS, PAIS, and MAIS. Chromosome analysis reveals normal male chromosomes. Affected individuals can have elevated luteinizing hormone, normal to slightly elevated testosterone, and high estradiol for men. Follicle stimulating hormone may also be normal to elevated. Reduced androgen receptor function in skin fibroblast cells is also used to aid in a diagnosis.
As of 2001, direct genetic testing for molecular defects in the androgen receptor gene is being done on a research basis only.
Treatment and management
Complete androgen insensitivity
Treatment of CAIS requires the removal of the testicles from the pelvis or inguinal canal to decrease risk of testicular malignancy. Because the overall risk of malignancy is approximately 5% and rarely occurs before age 25, the testicles are usually removed after the development of the secondary sex characteristics, as the testes are needed for estrogen formation. After the removal of the testes, estrogen supplementation is started to aid in the development of secondary sex characteristics and to help prevent osteoporosis. Surgery to lengthen the vagina may be necessary.
Partial androgen insensitivity syndrome
For those affected individuals raised as females, treatment is similar to CAIS except the removal of the testicles is done earlier because it may cause enlargement of the clitoris during puberty. Reconstructive surgery of the genitals and lengthening of the vagina may be necessary.
People with PAIS raised as boys may need surgery to improve the appearance of the genitals. Androgen supplementation may be implemented, though long-term affects of androgen therapy are not known. Breast reduction surgery may be necessary after puberty.
Mild androgen insensitivity
Males with MAIS may require no treatment at all or breast reduction surgery after puberty. Males who are infertile may benefit from assisted reproductive technologies.
Prognosis
For CAIS and MAIS, the prognosis is excellent. Generally, gender assignment is not difficult and sexual orientation is female for CAIS and male for MAIS. Treatment usually involves minimal surgery and hormone supplementation. For individuals with PAIS, the prognosis is very dependent upon the severity of the condition. Assignment of gender can be difficult and genital surgery can be more involved. Recently, some individuals with PAIS and other intersex conditions have encouraged the delay of assigning gender until the child is old enough to express a preference. As of 2001, this idea has not been readily embraced in the medical community of the United States.
Resources
BOOKS
Wilson, J. D., and J. E. Griffin. "Disorders of Sexual Differentiation." In Harrison's Online, edited by Eugene Braunwald, et al. New York: McGraw-Hill, 2001.
PERIODICALS
Warne, G. L., et al. "Androgen insensitivity syndrome in the era of the molecular genetics and the internet: A point of view." Journal of Pediatric Endocrinology & Metabolism 11 (1998): 3-9.
ORGANIZATIONS
AIS Support Group (AISSG). PO Box 269, Banbury, Oxon, OX15 6YT UK <http://www.medhelp.org/www/ais>.
Intersex Society of North America. PO Box 301, Petaluma, CA 94953-0301. <http://www.isna.org>.
WEBSITES
Androgen Receptor Gene Mutations Database. <http://www.mcgill.ca/androgendb>.
Pinsky, L. P. "Androgen Insensitivity Syndrome." Gene Clinics: Clinical Information Resource University of Washington, Seattle. <http://www.geneclinics.org/profiles/andrgoen/details.html>. February 6, 2001 (Updated March 23, 1999).
Carin Lea Beltz, MS, CGC
Androgen Insensitivity Syndrome
Androgen insensitivity syndrome
Definition
Androgen insensitivity syndrome is a genetic condition where affected people have male chromosomes and male gonads (testicles). The external genitals, however, have mild to complete feminization.
Description
Normal sexual development
In normal development, the chromosome sex determines the gonadal sex, which in turns determines the phenotypic sex. The chromosome sex is determined at conception; a male has the sex chromosome pair XY and a female has the chromosome pair XX. During the first 40 days of gestation, a male and female embryo appear the same and have undifferentiated gonads, which have the potential of becoming testes or ovaries. The presence of the Y chromosome in the male directs the undifferentiated gonads to become testicles. If no Y chromosome is present, such as in the female chromosome pair, the undifferentiated gonads become ovaries.
In males, the phenotypic sex, including the internal male structures and the external male genitalia, arises as a result of the hormones secreted from the testicles. The two main hormones secreted by the testicles are testosterone and mullerian duct inhibitor. Testosterone acts directly on the wolffian duct, which give rise to the internal male structures including the epididymides, vasa deferentia, and seminal vesicles. Testosterone is converted into dihydrotestosterone, the hormone responsible for the development of the male urethra and prostate, and the external genitalia of the penis and the scrotum. The mullerian duct inhibitor is the hormone that suppresses the mullerian ducts and prevents the development of fallopian tubes, upper vagina, and uterus in males.
If no testicles are present, as with females, no mullerian duct inhibitor is formed and the mullerian ducts become the fallopian tubes, the upper vagina, and the uterus. The wolffian ducts regress. Due to the lack of dihydrotestosterone, the external genitals are not masculinized and become female. Studies have shown that an ovary is not required for the formation of the internal female structures or the feminization of the genitals. If a testicle is not present, the development of the embryo will default to female development.
In most cases, the chromosomal sex, the gonadal sex, and the phenotypic sex are in agreement. Males have 46,XY chromosomes, testicles, and male internal structures and genitals. Females have 46,XX chromosomes, ovaries, and internal female structures and genitals.
Androgen insensitivity syndrome
Androgen insensitivity syndrome (AIS), also known as testicular feminization, is one of the most common conditions where the chromosome sex and gonadal sex do not agree with the phenotypic sex. Affected people have normal male chromosomes, 46,XY and testicles. The testicles secrete both testosterone and mullerian duct inhibitor as normal and no internal female structures form. However, due to defective androgen receptors, the wolffian ducts and genitals cannot respond to the androgens testosterone and dihydrotestosterone. As a result, no male internal structures are formed from the wolffian ducts and the external genitals are feminized.
The amount of feminization depends on the severity of the androgen receptor defect and is often characterized as complete androgen insensitivity (CAIS), partial androgen insensitivity (PAIS), and mild androgen insensitivity (MAIS). In complete androgen insensitivity, the alteration in the androgen receptor results in complete female external genitals. In partial androgen insensitivity, also called Reifenstein syndrome, partial androgen insensitivity results in female genitalia with some masculinization, ambiguous genitalia , or male genitalia with partial feminization. With mild androgen insensitivity, mild androgen resistance results in normal male genitals or a male with mild feminization.
In both CAIS and PAIS, affected individuals are sterile (can not have a child). In MAIS, the affected male may have fertility problems because of oligospermia, low sperm production, or azoospermia, no sperm production. In all types of AIS, secondary sex characteristics such as body and pubic hair can be abnormal. Mental impairment is not found in any of the types of androgen insensitivity syndromes, though poor visual-spatial ability has been observed. People with AIS can also be rather tall, though bone age is usually normal.
Genetic profile
Androgen insensitivity syndrome is a genetic condition that results from mutations (alterations) of the gene for the androgen receptor. The androgen receptor is located on the long arm of the X chromosome (Xq11-q12). As women have two X-chromosomes, they also have two androgen receptor genes. Men have only one X chromosome and a Y chromosome; hence they only have one copy of the androgen receptor gene.
When women have one copy of the androgen receptor altered, they are considered carriers of AIS. In most cases, the second, normal copy of the androgen receptor can compensate for the altered copy. However, in approximately 10% of women who are carriers for the altered androgen receptor gene, clinical signs such as sparse pubic hair and armpit hair or a delay to the start of their first menstrual period is observed.
46,XY conceptions that have alterations in the androgen receptor gene do not have a second copy to compensate for the altered copy. Hence, these people will have AIS. If the androgen receptor is severely altered, they will have CAIS. If not severely altered, they will have PAIS or MAIS.
All forms of AIS are inherited in an X-linked recessive pattern. This means women who are carriers have a 25% chance of having an affected child. If a carrier woman has a 46,XY conception, there is a 50% chance the child will have AIS. If a carrier woman has a 46,XX conception, there will be a 50% chance the daughter will also be a carrier.
When a person has AIS and has no other family history of the condition, approximately 2/3 of the time the affected person inherited the gene alteration from his or her mother. The other 1/3 of the time, the alteration of the androgen receptor was a new event (new mutation) in the affected person and was not inherited.
Cases of both gonadal mosaicism and somatic mosaicism have been reported with AIS. Gonadal mosaicism occurs when the alteration in the androgen receptor occurred not at conception, but in one of the gamete cells (sperm or egg). The rest of the cells of the body do not have the altered androgen receptor. With AIS, this can occur when one of a woman's early gamete cell has the new alteration in the androgen receptor but the rest of the cells in her body do not. All the eggs that come from the early gamete cell will also have the alteration. Her risk for having a child with AIS is increased. Somatic mosaicism occurs when the alteration in the androgen receptor occurs after conception but not in a gamete cell. Some of the person's cells will have the altered androgen receptor and other cells will not. The amount of cells with altered receptors and the location of those cells within the body will determine how severely affected a person will be.
Mutations within the androgen receptor gene are also responsible for the neuromuscular condition spinobulbar muscular atrophy or Kennedy disease . See separate entry for more information.
Demographics
Complete androgen insensitivity syndrome occurs in approximately one in 64,000 46,XY births or 2-5 in 100,000 births overall. Partial AIS is at least as common as complete AIS. The incident of mild AIS is unknown, but is estimated to account for approximately 40% of male infertility due to severe oligospermia or azoospermia.
Signs and symptoms
Complete androgen insensitivity
Individuals with CAIS are born looking like normal female babies. Often, the condition is discovered in one of two ways. The child can have an inguinal hernia that upon repair is found to contain testicles. The most common presentation is during puberty with primary amenorrhea, or lack of the onset of the menstrual period. Affected individuals have a short, blind ending vagina and no uterus, cervix, fallopian tubes, or ovaries. During puberty, some girls will have absent or decreased sexual hair. Breasts develop normally and can be large in size with pale and immature nipples and areola. People with CAIS are usually raised as females and have normal female sexual orientation. All women with CAIS are sterile. In families with CAIS, all affected members will have complete androgen insensitivity and similar physical features.
Partial androgen insensitivity syndrome
Children with PAIS usually present at birth due to ambiguous genitalia. The genitalia can look like female genitals with some masculinization, completely ambiguous genitals where the sex of the baby cannot be immediately determined, or male genitals with some feminization. The degree of severity is a direct result of the degree of severity of the genetic alteration in the androgen receptor and resulting amount of functional androgen receptor. The internal structures of PAIS are the same as CAIS, with absent fallopian tubes, cervix, uterus, and ovaries. Testes are present but do not produce sperm. Hence, people with PAIS are also sterile. People with PAIS also have primary amenorrhea, and breast development occurs in puberty. Unlike CAIS, affected individuals in the same family with presumably the same genetic alteration can have varying degrees of masculinization. As a result, some affected people may be raised as females whereas others may be raised as males. Sex assignment is made based upon the structure of the genitals, the surgical correction needed, and the predicted response to androgens during puberty.
Mild androgen insensitivity
Males with mild androgen insensitivity usually have normal male genitals and internal male structures. During puberty, males with MAIS may have breast enlargement, sparse facial and body hair, and small penis. Some affected males may also have impaired sperm production resulting in oligospermia or azoospermia, decreased or absent sperm. As with CAIS, affected men within the same family usually have similar features.
Diagnosis
Diagnosis is usually made based upon clinical features, chromosome analysis, hormone levels, and analysis of androgen receptor function in skin fibroblasts. Clinical features are listed above for CAIS, PAIS, and MAIS. Chromosome analysis reveals normal male chromosomes. Affected individuals can have elevated luteinizing hormone, normal to slightly elevated testosterone, and high estradiol for men. Follicle stimulating hormone may also be normal to elevated. Reduced androgen receptor function in skin fibroblast cells is also used to aid in a diagnosis.
Direct genetic testing for molecular defects in the androgen receptor gene is being done on a research basis only.
Classification of AIS Phenotypes
| Type | External genitalia (synonyms) | Findings |
| CAIS | Female ("testicular feminization") | Absent or rudimentary wolffian duct derivatives |
| Inguinal or labial testes; short blind-ending vagina | ||
| Little or no pubic and/or axillary hair | ||
| CAIS or PAIS | Predominantly female (incomplete AIS) | Inguinal or labial testes |
| Labial fusion and enlarged clitoris | ||
| Distinct urethral and vaginal openings or a urogenital sinus | ||
| PAIS | Ambiguous | Microphallus (<1 cm) with clitoris-like underdeveloped glans; labia majora-like bifid scrotum |
| Descended or undescended testes | ||
| Perineoscrotal hypospadias or urogenital sinus | ||
| Excessive development of the male breasts during puberty | ||
| Predominantly male | Simple (glandular or penile) or severe (perineal) "isolated" hypospadias with a normal-sized penis and descended testes or severe hypospadias with micropenis, bifid scrotum, and either descended or undescended testes | |
| Excessive development of the male breasts during puberty | ||
| MAIS | Male (undervirilized male syndrome) | Impaired sperm development and/or impaired masculinization |
| Overdevelopment of the male breasts during puberty |
Treatment and management
Complete androgen insensitivity
Treatment of CAIS requires the removal of the testicles from the pelvis or inguinal canal to decrease risk of testicular malignancy. Because the overall risk of malignancy is approximately 5% and rarely occurs before age 25, the testicles are usually removed after the development of the secondary sex characteristics, as the testes are needed for estrogen formation. After the removal of the testes, estrogen supplementation is started to aid in the development of secondary sex characteristics and to help prevent osteoporosis . Surgery to lengthen the vagina may be necessary.
Partial androgen insensitivity syndrome
For those affected individuals raised as females, treatment is similar to CAIS except the removal of the testicles is done earlier because it may cause enlargement of the clitoris during puberty. Reconstructive surgery of the genitals and lengthening of the vagina may be necessary.
People with PAIS raised as boys may need surgery to improve the appearance of the genitals. Androgen supplementation may be implemented, though long-term affects of androgen therapy are not known. Breast reduction surgery may be necessary after puberty.
Mild androgen insensitivity
Males with MAIS may require no treatment at all or breast reduction surgery after puberty. Males who are infertile may benefit from assisted reproductive technologies.
Prognosis
For CAIS and MAIS, the prognosis is excellent. Generally, gender assignment is not difficult and sexual orientation is female for CAIS and male for MAIS. Treatment usually involves minimal surgery and hormone supplementation. For individuals with PAIS, the prognosis is very dependent upon the severity of the condition. Assignment of gender can be difficult and genital surgery can be more involved. Recently, some individuals with PAIS and other intersex conditions have encouraged the delay of assigning gender until the child is old enough to express a preference. This idea has not been readily embraced in the medical community of the United States.
Resources
BOOKS
Wilson, J. D., and J. E. Griffin. "Disorders of Sexual Differentiation." In Harrison's Online, edited by Eugene Braunwald, et al. New York: McGraw-Hill, 2001.
PERIODICALS
Warne, G. L., et al. "Androgen insensitivity syndrome in the era of the molecular genetics and the internet: A point of view." Journal of Pediatric Endocrinology & Metabolism 11 (1998): 3-9.
ORGANIZATIONS
AIS Support Group (AISSG). PO Box 269, Banbury, Oxon, OX15 6YT UK <http://www.medhelp.org/www/ais>.
Intersex Society of North America. PO Box 301, Petaluma, CA 94953-0301. <http://www.isna.org>.
WEBSITES
Androgen Receptor Gene Mutations Database. <http://www.mcgill.ca/androgendb>.
Pinsky, L. P. "Androgen Insensitivity Syndrome." GeneClinics: Clinical Information Resource University of Washington, Seattle. <http://www.geneclinics.org/profiles/andrgoen/details.html>. February 6, 2001 (Updated March 23, 1999).
Carin Lea Beltz, MS, CGC
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
Bibliography
Gilbert, Scott. Developmental Biology, 5th ed. Sunderland, MA: Sinauer Associates, 1997.
Internet Resources
Androgen Insensitivity Syndrome. <http://www.emedicine.com/PED/topic2222.htm>.
Statement of the British Association of Paediatric Surgeons Working Party on the Surgical Management of Children Born with Ambiguous Genitalia. <http://www.baps.org.uk/documents/Intersex%20statement.htm>.
Warne, Garry. Complete Androgen Insensitivity Syndrome. Victoria, Australia: Department of Endocrinology and Diabetes, Royal Children's Hospital. <http://www.rch.unimelb.edu.au/publications/CAIS.pdf>;.