Androgen insensitivity syndrome
Androgen insensitivity syndrome: (AIS, or testicular feminization) is the result of inability of the body's cells to respond to testosterone and related hormones. It is associated with a genetic mutation of the androgen receptor gene on the X chromosome.
The majority of those with AIS are women and girls with complete AIS (CAIS). In CAIS, the body's androgen receptors are completely without function. In a 46XY fetus, total insensitivity to androgens results in female differentiation of the external genitalia. The Wolffian ducts, precursors of the male reproductive duct system, do not develop because of the lack of response to androgens. The Müllerian ducts, precursors of the fallopian tubes, uterus and upper one-third of the vagina, regress because the testes release normal amounts of the hormone that causes their regression, Müllerian inhibiting substance or MIS. At puberty, if the gonads remain intact, there is breast development and estrogen effects on the vagina because some testosterone is converted to estrogen, but even the minor testosterone effects that are normal for females (pubic and axillary hair) do not occur.
A minority of those with AIS have Partial AIS (PAIS) and have some function of the androgen receptor. Before birth there is some effect of testosterone on the structure of the external genitalia and at puberty (if the gonads are intact) there may be some virilizing effects, which, however, may consist only of pubic hair growth.
The standard grades of AIS (See Quigley, et. al.) are:
Grades 1 and 2 = minimal AIS (Near "male" end of spectrum anatomically)
Grades 3 and 4 = partial AIS or "Reifenstein Syndrome" (In between female and male anatomically)
Grades 5 and 6 = severe partial AIS (Near "female" end of spectrum anatomically)
Grade 7 = complete AIS
Testosterone may play a role in normal female sexual differentiation and for this reason women with complete AIS (Grade 7) may actually have a smaller clitoris and labia minora than is typical for women.
Those with Grade 6 AIS have typical female external anatomy, but, strictly speaking, are not considered to have complete AIS because they do have some sensitivity to androgens, usually manifested only by pubic (and sometimes axillary) hair growth.
In AIS Grades 5 and 4, the clitoris is enlarged. In Grade 5, there may be partial fusion of the labia majora (outer vaginal lips), in which the posterior (back) portion of the labia form a web of tissue across the back part of the vaginal outlet. In Grade 4, this fusion extends further forward, covering both the vaginal opening and the true urethral opening.
In Grade 3 and the more masculinized form of Grade 4, the labia are completely fused, so that the urethral opening is at the base of the clitoris/penis. The fused labia may have a rugose, or wrinkled appearance and form a bifid, or double, scrotum. The fusion is then more properly called 'labio-scrotal fusion'. The phallus has the appearance of a large clitoris, or a small, bent, penis, bound down in structures called chordee. The chordee is formed from the same tissues that form the labia minora in the female and the frenulum of the penis and the tissues surrounding the urethra (corpus spongiosum) on the underside of the penis in the male. It is not true that the presence of chordee in ambiguous genitalia makes erections painful.
In Grade 2, the genital appearance is that of a male with hypospadias, that is, with a urethral opening located somewhere on the underside of the penis.
In Grade 1, the genital appearance is that of a typical male, but sensitivity to androgens at puberty is less than typical. There is controversy about how common Grade 1 PAIS is, but it may be the reason for some cases of infertility or gynecomastia.
Male fertility is decreased in grades 1 and 2 PAIS and probably absent in grades 3 and higher.
At puberty in PAIS the effects of testosterone are less than is typical for males. There is also usually breast development due to conversion of testosterone to estrogen. In grades 6, 5 and 4 PAIS, testosterone effects from a spontaneous puberty are usually in the range typical for females.
Diagnosis
AIS is usually the first diagnosis considered in a person with female or ambiguous genitalia and testes but without a uterus.
A high blood testosterone level (in the normal male range or higher) for a prolonged period of time without significant virilization (called a "testosterone challenge") confirms a diagnosis of AIS, but is not advisable
when the diagnosis is uncertain.
A diagnosis of AIS can be confirmed by molecular genetics but this is expensive and often unnecessary. Checking that the karyotype is 46XY is usually also unnecessary and, in any case, does not distinguish AIS from a number of other conditions.
AIS is inherited as an X-linked recessive and the family history may be useful both in making a diagnosis and in predicting the natural course of puberty.
In real life, many girls with complete AIS are not diagnosed until the teenage years when they fail to menstruate.
Some are diagnosed as children or infants due to inguinal hernias. About 20% of girls with inguinal hernias have AIS and sometimes a diagnosis of AIS has been made during an operation for hernia. This should be avoided by screening girls with inguinal hernias for AIS before surgical repair or at least planning for the contingency of a diagnosis of AIS. Otherwise, the surgery may be needlessly prolonged.
Some with complete AIS and most with partial AIS are diagnosed at the time of birth when atypical genitalia or abdominal testes in a girl are noticed. Some are diagnosed at birth because a prenatal karyotype was found to be 46XY but the baby was born a girl.
There are a number of other metabolic conditions such as 5-alpha reductase deficiency involving testosterone metabolism which result in a phenotype at birth very similar to what is seen in CAIS or PAIS. The most significant difference is that in most of these other conditions the natural course of puberty is masculinizing while in AIS it is feminizing. When gonadectomy is done before puberty, sometimes it is never clear whether the actual condition is PAIS or another metabolic condition.
PAIS is also sometimes mistakenly used by physicians as an all-purpose "wastepaperbasket" diagnosis for any condition with similar clinical features to AIS.
A large number, perhaps half or one third, of those diagnosed with PAIS, and a few with CAIS, actually have a different metabolic condition. It is important for a girl with any form of AIS and intact gonads to either have a confirmed diagnosis before puberty or to be followed by a physician at the time of puberty in case puberty turns out to be virilizing.
It is not true, as some textbooks state, that those with PAIS will virilize strongly at puberty and that girls with PAIS should have early gonadectomy for this reason. When this happens, it is usually because the original diagnosis of AIS was incorrect.
There is a definitive test to distinguish AIS from the alternative diagnosis of 5-alpha reductase deficiency (the testosterone/DHT ratio) and a somewhat less definitive test to distinguish AIS from other metabolic conditions. (See Sinnecker et. al..)
Treatment
Children with AIS are generally healthy and do not require specialized medical care, except that there is an increased risk of inguinal hernias. Children with grades 5 through 7 AIS should always have a female sex of rearing and cosmetic genital surgery is not an issue for them.
For those with grades 2 through 4 the advice of specialists with knowledge of AIS is needed to decide on the best sex of rearing. This decision should be made expeditiously but not in haste and only after complete information has been gathered. Cosmetic genital surgery in childhood is an area of controversy.
For girls with CAIS or PAIS with a short vagina, non-surgical pressure dilation is a better treatment by all criteria than surgical vaginoplasty. No treatment for vaginal hypoplasia should be attempted before the teenage years.
In low-grade PAIS when the sex of rearing is male, pubertal development will usually include both feminization (breast development) and weak virilization. High-dose testosterone may be helpful in augmenting virilization.
There is a risk of testicular cancer in AIS and for this reason the standard treatment is to remove the gonads at some time between puberty and age 20. Earlier gonadectomy is not beneficial because there is little risk of tumors before age 20 and because the spontaneous feminizing puberty that will occur is beneficial physically and psychologically for those with both CAIS and high-grade PAIS. As noted before, there is usually no need to remove the gonads before puberty in girls with PAIS because if the diagnosis of PAIS is correct, excessive virilization will not occur. There is recent controversy over whether the risk of tumors justifies gonadectomy in CAIS. (See Cools, et. a.). After gonadectomy estrogen hormone replacement is required. Use of progesterone or cyclic administration of hormones is not necessary.
There is a risk of low bone density in AIS. Diligent use of hormone replacement, calcium supplements with Vitamin D and exercise are recommended to prevent this.
Counseling
Children with AIS should, ideally, be informed of their diagnosis and treatment options in age-graduated steps as their level of understanding allows, the information integrated with ordinary sex education. There are some special situations that can occur in AIS.
A girl or woman diagnosed with AIS at the age of puberty or later needs to be fully informed of the diagnosis, but also reassured that she is not "really" a male and that the condition does not make her ineligible for a woman's sex life.
A child with PAIS in a sex of rearing that may be inappropriate for physical or psychological reasons needs to be given full information about his or her condition, treatment options and possible courses of action. Protocols for treatment of gender identity disorder may not be completely appropriate and should not be followed rigidly
A girl with a short vagina being treated by outpatient manual pressure dilation may have conflicts related to moralism about sex and avoidance of masturbation. It may be helpful if the concept of dilation is desexualized by emphasizing that it is a needed medical procedure.
Discovery
First described definitively in medical literature 1953. A few case reports of what was probably AIS much earlier than this.
Frequency
Generally accepted estimate at 1 in 20,000 XY births from Danish records. (Bangsboll S, et al.)
For more on Androgen Insensitivity Syndrome (AIS) see:
For diagrams illustrating the grades of AIS see:
Click on "ALIAS No.6"
References (print):
Bangsboll S, et al. Testicular feminization syndrome and associated tumours in Denmark. Acta Obstet Gynecol Scand 71:63-66, 1992.
Cools, et al. Germ Cell Tumors in the Intersex Gonad: Old Paths, New Directions, Moving Frontiers. Endocrine Reviews. 27(5):468-484. 2006.
Morris J. The syndrome of testicular feminization in male pseudohermaphrodites. Am. J. Obstet. Gynecol, 65: 1192-1211, 1953.
Morris JM. and Mahesh V. B: Further observations on the syndrome, `testicular feminization'. Am. J. Obstet. Gynec. 87: 731-748, 1963.
Quigley CA et al. Androgen Receptor Defects: Historical, Clinical,
and Molecular Perspectives. Endocrine Reviews. 16(3): 271. 1995.
Sinnecker G, Koehler S. Sex Hormone-Binding Globulin Response to the Anabolic Steroid Stanozolol: Evidence for its Suitability as a Biological Androgen Sensitivity Test. 1989. Journal of Clinical Endocrinology and Metabolism. 68:6 pp 1195-1200.
