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.
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.
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.
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.
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.
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
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
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.
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.
