Androgen Insensitivity Syndrome

Androgen insensitivity syndrome is an X-linked recessive disorder caused by variants in the androgen receptor gene, giving resistance to androgens in 46,XY individuals. Phenotype ranges from complete (female) to partial (ambiguous) to mild (male with infertility or gynaecomastia).

Complete androgen insensitivity occurs in about 1 in 20,000 to 60,000 46,XY births. About one third of cases are new variants. Most patients present with inguinal hernia in infancy or primary amenorrhoea at puberty.

Pathophysiology.

Testes develop and secrete testosterone and anti-Müllerian hormone, so Müllerian structures regress, but the androgen receptor does not respond, so Wolffian ducts and external genitalia stay female in complete disease.

Raised LH drives testosterone, which is aromatised to oestradiol, causing breast development at puberty. Pubic and axillary hair are sparse.

• Complete: female external genitalia, inguinal or labial masses (testes), primary amenorrhoea, normal breast development, scant pubic and axillary hair, short blind ending vagina and no uterus.
• Partial: ambiguous genitalia, hypospadias, micropenis, cryptorchidism and gynaecomastia at puberty.
• Mild: gynaecomastia, reduced facial hair and infertility.

Red flags.

• Abdominal or inguinal testes (malignancy risk after puberty).
• Neonatal ambiguous genitalia needing urgent specialist assessment.

• Karyotype 46,XY. Testosterone normal or raised for age, LH raised (testosterone is not suppressed), oestradiol raised for male, FSH normal or mildly raised, anti-Müllerian hormone normal or high.
• Pelvic ultrasound or MRI: no uterus, testes in the abdomen or inguinal canal.
• Androgen receptor sequencing. Test mothers and sisters to identify carriers.
• In partial disease: human chorionic gonadotrophin stimulation to exclude testosterone synthesis defects (testosterone to androstenedione and dihydrotestosterone ratios).

Differential diagnosis.

• Mayer-Rokitansky-Küster-Hauser syndrome (46,XX, normal female testosterone).
• 5-alpha reductase deficiency, 17-beta hydroxysteroid dehydrogenase 3 deficiency and Leydig cell hypoplasia.
• Gonadal dysgenesis and 17-alpha hydroxylase deficiency.
• Other causes of primary amenorrhoea.

• Complete androgen insensitivity (raised female): delay gonadectomy until after puberty so the testes' oestradiol supports breast and bone development, since the malignancy risk before adulthood is low. Gonadectomy after puberty, or surveillance with ultrasound if the person chooses to keep the gonads.
• After gonadectomy: oestradiol 1 to 2 mg orally daily or transdermal 50 to 100 micrograms/24 h. No progestogen is needed because there is no uterus. Add calcium and vitamin D and monitor bone density.
• Vaginal dilators (first line) or surgery for a short vagina, at the person's request after puberty.
• Partial disease: gender assignment is an individual decision made by a specialist team with the family. Hypospadias repair and orchidopexy. A therapeutic test of testosterone (for example enanthate 25 to 50 mg intramuscularly monthly for 3 months) assesses phallic response.
• Mild disease: treat gynaecomastia and infertility as needed.
• Psychological support and age appropriate disclosure of diagnosis.

Special groups. Genetic counselling: 50% of the 46,XX children of a carrier mother are carriers, and 50% of her 46,XY children are affected. Fertility is not possible in complete disease; adoption and donor options are discussed.

Monitoring. Hormone replacement review yearly, bone density every 2 years, and psychological review.

Referral and escalation. Specialist disorders of sex development team including endocrinology, urology, gynaecology and psychology.