Androgen insensitivity (AIS)

The clinical phenotype spans a continuum from complete to minimal androgen insensitivity.

In complete androgen insensitivity (CAIS), the external genitalia are typically female while internal Müllerian structures (uterus, cervix, and proximal vagina) are absent; affected individuals present either before puberty with inguinal masses later identified as testes or at puberty with primary amenorrhoea and sparse to absent pubic and axillary hair.

Partial androgen insensitivity (PAIS) produces ambiguous or predominantly female or male genitalia, with gynaecomastia and impaired spermatogenesis developing at puberty.

In minimal androgen insensitivity (MAIS), the external genitalia are unambiguously male; presentation is usually at puberty with gynaecomastia and undervirilisation, such as sparse facial and body hair, and the minimalest forms may declare only in adulthood as isolated male infertility with variable spermatogenic impairment. Intra-abdominal or inguinal testes carry an increased risk of gonadal germ-cell tumours (0.8–2% before puberty), most notably in the complete form, which informs individualised decisions on gonadal surveillance or gonadectomy timing.

The estimated prevalence of complete androgen insensitivity is 1/20,000 to 1/50,000, applying to the complete form only. A survey in the Netherlands reported a minimal incidence of 1/99,000; the prevalence of partial and minimal forms has not been reliably determined.

AIS results from hemizygous germline pathogenic variants in AR (Xq12), which encodes the androgen receptor. The receptor comprises an N-terminal transactivation domain, a central DNA-binding domain, and a C-terminal androgen-binding domain. Most are missense variants that impair DNA or androgen binding and reduce transactivation. The resulting tissue-level resistance to circulating androgens produces the CAIS, PAIS, or MAIS phenotype despite normal or increased testicular testosterone synthesis.

AIS is inherited in an X-linked recessive manner. The mother of an affected 46,XY individual is often a heterozygous carrier; female heterozygotes have a 50% risk of transmitting the germline AR pathogenic variant to each pregnancy. Maternal germline mosaicism is documented, so even when the pathogenic variant is undetectable in maternal leukocyte DNA the recurrence risk to sibs remains low but above that of the general population. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis of AIS is established by molecular genetic testing of AR following the karyotyping results, which showed a 46,XY constitution. Supportive biochemical findings include normal or increased testosterone with normal conversion to dihydrotestosterone and normal or raised luteinising hormone, together with higher-than-normal anti-müllerian hormone in the predominantly male phenotype. Pelvic ultrasonography typically shows absent or rudimentary müllerian structures alongside testes.

Main differential diagnoses include:

• 5-alpha-reductase type 2 deficiency: Wolffian-duct male reproductive structures present; impaired testosterone-to-dihydrotestosterone (DHT) conversion; SRD5A2
• 17-beta-hydroxysteroid dehydrogenase III deficiency: androgen-synthesis defect mimicking partial AIS (elevated androstenedione/testosterone ratio); HSD17B3
• Mayer-Rokitansky-Küster-Hauser syndrome: Müllerian aplasia with amenorrhoea but a 46,XX karyotype; aetiology largely idiopathic with rare WNT4 or HNF1B variants
• Partial testosterone biosynthetic defect: raised testosterone precursors with compensatory luteinising hormone
• Testicular organogenesis defect or gonadal dysgenesis: Müllerian derivatives from impaired anti-müllerian hormone; SRY, NR5A1

• Genetic testing establishes the molecular diagnosis and confirms the clinical suspicion.
• Identification of the pathogenic germline variant supports condition-specific monitoring and management, including follow-up of genitalia that were ambiguous at birth, made by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant is known, testing of at-risk relatives can clarify their carrier or affected status.

• Gottlieb B, Trifiro MA. Androgen Insensitivity Syndrome. 2017 May 11. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2024. Available at (accessed July 2026).
• Boehmer AL, Brinkmann O, Brüggenwirth H, van Assendelft C, Otten BJ, Verleun-Mooijman MC, et al. Genotype versus phenotype in families with androgen insensitivity syndrome. J Clin Endocrinol Metab. 2001;86(9):4151-60. PMID: .
• Hughes IA, Davies JD, Bunch TI, Pasterski V, Mastroyannopoulou K, MacDougall J. Androgen insensitivity syndrome. Lancet. 2012;380(9851):1419-28. PMID: .