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An inherited disorder caused by androgen insensitivity
with affected males having a female phenotype with normal female external
genitalia but abnormal or absent internal female organs. Testes are often
intraabdominal, in the inguina, or in the labia. Normal male (46,XY)
karyotype.
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Testicular Feminization; Androgen Receptor Deficiency;
Dihydrotestosterone Receptor Deficiency; Male Pseudohermaphroditism as a
Result of Androgen Insensitivity; Hairless Women Syndrome.
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Estimates vary from 1:7,000-20,000 male live births. No
racial predilection has been reported.
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X-linked recessive with the responsible gene
encoding for the androgen receptor being located on Xq11-q12. More than 200
different mutations have been described.
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The basic etiology of androgen insensitivity
syndrome (AIS) is a mutation in the androgen receptor gene that results in
the gene's loss of function. The functional defects can range from complete
absence of receptors on the cell surface to decreased substrate binding
affinity with loss of signal transmission. Despite normal or elevated levels
of androgen, functional loss of the androgen receptor is clinically
equivalent to a lack of androgen and results in prenatal undervirilization
of external genitalia, and absence of pubic and axillary hair, lack of acne, and
absence of voice changes at puberty. Leydig cell stimulation to estrogen
production occurs probably because of a failure in feedback repression of
the pituitary gland, which shares the unresponsiveness to androgen.
Peripheral conversion of testosterone and androstenedione to estradiol
finally results in elevated estrogen serum levels. This on the one hand
explains the absence of (androgen mediated) axillary and pubic hair, acne,
and voice changes and on the other hand the development of normal breasts in
these patients.
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The clinical findings of inguinal hernia with a labial
mass in infancy and primary amenorrhea despite typical female
secondary sex characteristics, but scant or absent pubic and axillary hair in puberty
should raise suspicion for AIS. Affected males have female external genitalia
associated with normal or high testosterone serum levels. In infancy, plasma
luteinizing hormone (LH) and testosterone levels and the response to
luteinizing hormone-releasing hormone (LHRH) are higher than in age-matched
controls. In puberty, the androgen insensitivity, which also affects the
hypothalamic-pituitary area, results in elevated testicular androgen and
estradiol synthesis.
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These genotypic male patients are phenotypic
females. Anatomically, they have normal female external genitalia but a
blind-ending vaginal pouch and absent uterus and fallopian tubes. The testes
usually are located intraabdominally, in the inguinal canal, or in the
labia. Leydig cells appear hyperplastic and form adenomatous clumps. Primary amenorrhea
and scant pubic and axillary hair contrast with well developed female personality and body shape (including breasts). Patients often appear tall for females, and
the clinical signs result from high estrogen levels. Other features include inguinal
hernia and an increased risk of testicular malignancies (Sertoli cell adenomas,
seminomas, malignant sex-cord stromal tumor) after 25 years of age. Patients often
present for orchiectomy and vaginal lengthening procedures, both now often done at the
end of ...