General Medical Information

Complete Androgen Insensitivity

Joe Leigh Simpson

In complete androgen insensitivity (CAI; or complete testicular feminization), 46,XY individuals show bilateral testes, female external genitalia, a blindly ending vagina, and no müllerian derivatives. These findings are entirely predictable, given the underlying pathogenesis involving inability to respond to testosterone. AMH is synthesized, as in the normal testis. The body responds normally to AMH, for which reason no uterus is present. As predicted on the basis of testes synthesizing estrogens in unimpeded fashion, affected individuals manifest breast development and pubertal feminization.

Despite pubertal feminization, some individuals with androgen insensitivity show clitoral enlargement and labioscrotal fusion. The term incomplete or partial androgen insensitivity (PAI) (incomplete testicular feminization) is applied to these patients. The mildest end of the spectrum consists of males only manifesting gynecomastia and oligospermia/azoospermia. Complete, incomplete (partial), and mild androgen insensitivity are all inherited in X-linked recessive fashion. All result from mutations of the androgen receptor gene present on the X long arm (Xq11).

As adults, individuals with CAI may be quite attractive and show excellent breast development. Despite this traditional textbook description, most cases are actually similar in appearance to unaffected females in the general population. Breasts contain normal ductal and glandular tissue, but areolae often are pale and underdeveloped. Pubic hair and axillary hair (terminal) usually are sparse (only vellus hair present), but scalp hair is normal. The vagina terminates blindly, and sometimes vaginal length is shorter than usual. Occasionally, the vagina is only 1 to 2 cm long or is represented merely by a dimple. Surgery to create a neovagina or use of dilations may be necessary, but usually vaginal length is adequate without intervention. Neither a uterus nor fallopian tubes are ordinarily present, but there may be fibromuscular remnants, rudimentary fallopian tubes, or, rarely, even a uterus.

Testes usually are normal in size. They may be located in the abdomen, inguinal canal, labia, or anywhere along the path of embryonic testicular descent. If located in the inguinal canal, the testes may produce inguinal hernias. One half of all individuals with testicular feminization develop inguinal hernias. Therefore, it is worthwhile to determine the cytogenetic status of prepubertal girls with inguinal hernias, although most will be 46,XX. Height is slightly increased compared with normal women but unremarkable compared to 46,XY males.

Frequency of gonadal neoplasia is increased, but not so much as once assumed. The actual risk is probably no greater than 5%. The risk of malignancy is low before 25 to 30 years of age. Benign tubular adenomas (Pick adenomas) are common in postpubertal patients, probably as a result of increased LH secretion. Orchiectomy eventually is necessary, but it is acceptable to leave the testes in situ until after spontaneous pubertal feminization. However, if a herniorrhaphy proves necessary before puberty, most surgeons perform the orchiectomy at the same time. There also may be some psychological benefit in prepubertal orchiectomies.

The androgen receptor gene is localized to Xq11-12. This gene consists of eight exons; exons 2 and 3 are the DNA-binding domains, whereas exons 4 through 8 are androgen-binding domains. Many different mutations have been reported and tabulated yearly. No single perturbation has proved paramount. Deletions and insertions are rare; point mutations are far more common. These include deletion of three nucleotides with preservation of an open reading frame, or single nucleotide changes resulting in either substitution of an unscheduled amino acid or changes generating a stop codon that would result in premature message termination and production of a nonfunctional protein.

Mutations are found throughout the gene, but particularly in exons 4 through 8 (the androgen-binding domain). In exons 5 through 8, the preponderance of mutations are missense, and again both PAI and CAI arise. Mutations in exon 1 usually cause CAI, and mutations in exons 2 and 3 (the DNA-binding domain) produce either CAI and PAI. In general, large deletions and mutations resulting in premature termination (stop codon) predictably produce no functional receptor and cause CAI. Point mutations resulting from single nucleotide substitutions have a similar phenotype but also may be compatible with production of some androgen receptor. Irrespective, the receptor may be unstable or display poor binding.