Androgen Insensitivity Syndrome
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Direct answer
Androgen insensitivity syndrome is a 46,XY condition in which the androgen receptor does not respond to testosterone, producing a phenotypic female with a blind-ending vagina, an absent uterus and testes instead of ovaries. In the complete form, Sertoli cells secrete anti-Müllerian hormone, so Müllerian structures regress, while testosterone is aromatised to oestrogen, allowing normal breast development. Gonadectomy is generally advised after puberty because of malignancy risk.
What you must remember
- Genetics: an X-linked mutation of the androgen receptor gene on Xq11-12 produces a 46,XY karyotype with male-range or raised testosterone and raised LH.
- Complete AIS: female external genitalia, a blind vaginal pouch, absent uterus and cervix, primary amenorrhoea, scant or absent pubic and axillary hair and normal breast development.
- Why no uterus: anti-Müllerian hormone from intact Sertoli cells causes regression of the Müllerian ducts, so the absence is structural and not due to a lack of oestrogen.
- Gonads: testes lie in the abdomen or inguinal canal, and an inguinal hernia in a female with this condition may contain a testis, so the groin must be examined.
- Partial AIS: variable virilisation or hypospadias depending on the receptor defect, and mild forms may present as infertility or gynaecomastia in a male.
- Gonadectomy timing: remove the testes after puberty is complete, with oestrogen replacement afterwards, because the risk of germ cell tumour rises with retained gonads; books differ on exact timing.
Worked example: primary amenorrhoea with normal breasts
A 19-year-old woman with primary amenorrhoea has normal breasts, absent pubic hair and a short blind vagina. Her ultrasound shows no uterus, and the diagnosis must separate this condition from Mayer-Rokitansky-Kuster-Hauser syndrome. The steps below show the usual sequence.
- Confirm the karyotype: A 46,XY karyotype in a phenotypic female establishes the diagnosis and rules out a 46,XX cause of primary amenorrhoea.
- Check hormones: Testosterone and LH are in the male range or raised, while oestradiol, from aromatisation of testosterone, is enough to drive breast development.
- Image the pelvis: Ultrasound or MRI shows an absent uterus and cervix and gonads in the abdomen or inguinal canal.
- Confirm the receptor defect: Androgen receptor gene sequencing confirms the mutation and supports family counselling.
- Time the gonadectomy: Removal is planned after puberty, with the individual timing discussed by a multidisciplinary team.
- Replace oestrogen alone: No progestogen is needed after gonadectomy because there is no uterus to protect, and dilators or surgery are offered for the vagina.
Where the exam tries to catch you
The classic trap is confusing this 46,XY condition with a 46,XX disorder that also lacks a uterus.
- Trap: Label a 46,XY patient with no uterus as Mayer-Rokitansky-Kuster-Hauser syndrome. Correct: That condition is 46,XX with normal ovaries, so a 46,XY karyotype with testes points to androgen insensitivity or another disorder of sex development.
- Trap: Remove the gonads in infancy as a precaution. Correct: Delay gonadectomy until puberty is complete so that natural breast development occurs, unless a specific clinical indication applies.
- Trap: Add a progestogen to oestrogen after gonadectomy. Correct: No progestogen is required because there is no endometrium to protect from hyperplasia.
- Trap: Dismiss a groin swelling as a simple hernia. Correct: In complete androgen insensitivity the inguinal contents may be a testis, so the karyotype and gonadal status must be considered.
Frequently asked questions
What is the karyotype in complete androgen insensitivity syndrome?
Complete androgen insensitivity syndrome is associated with a 46,XY karyotype and testes. The phenotype is female because the androgen receptor is non-functional, so the body does not respond to testosterone during fetal development.
Why is breast development normal in complete androgen insensitivity syndrome?
Breast development is normal in complete androgen insensitivity syndrome because testosterone is aromatised to oestradiol in peripheral tissues. Oestrogen acts normally even though the androgen receptor is absent, so the breasts develop at puberty.
When should the testes be removed in complete androgen insensitivity syndrome?
Gonadectomy in complete androgen insensitivity syndrome is generally advised after puberty is complete, once breast development has occurred. Timing is individualised and discussed by specialists, and oestrogen replacement follows the operation.
Why is there no uterus in androgen insensitivity syndrome?
The uterus is absent in androgen insensitivity syndrome because Sertoli cells secrete anti-Müllerian hormone, which causes regression of the Müllerian ducts. The regression is structural and occurs even though the individual lacks functional androgen signalling.
Is androgen insensitivity syndrome inherited?
Androgen insensitivity syndrome is inherited in an X-linked recessive pattern, because the androgen receptor gene lies on the X chromosome. Affected individuals are usually counselled about family risk and offered genetic testing.