Androgen Insensitivity Syndrome

Enter an AIS diagnostic pathway for a newborn with 46,XY undermasculinization or genital atypia, an adolescent with primary amenorrhea and absent or limited Müllerian structures, or an adult with gynecomastia, infertility, or otherwise unexplained androgen resistance. AIS spans complete, partial, and mild phenotypes according to residual androgen receptor activity. The Lancet+3The LancetAndrogen insensitivity syndromePubMedAndrogen Insensitivity Syndrome - StatPearls - NCBI BookshelfPubMedAndrogen Insensitivity Syndrome - GeneReviews - NCBI - NIHPubMedThe challenges of androgen insensitivity syndrome - PMC

In a phenotypic female with primary amenorrhea, an inguinal mass should prompt pelvic and inguinal imaging to identify testes and assess for Müllerian structures while obtaining chromosome analysis. CAIS is characterized by a typical female phenotype in an individual with XY chromosomes; primary amenorrhea and inguinal swelling are high-yield clinical prompts. The Lancet+1The LancetAndrogen insensitivity syndromePubMedThe challenges of androgen insensitivity syndrome - PMC

In a newborn with ambiguous genitalia, do not label PAIS from appearance alone. Parallel evaluation must exclude alternative 46,XY DSD mechanisms, particularly defects in testosterone synthesis, before attributing undermasculinization to androgen resistance. PubMed+2PubMedAndrogen Insensitivity Syndrome - StatPearls - NCBI BookshelfPubMedAndrogen Insensitivity Syndrome - GeneReviews - NCBI - NIHpublications aapThe Newborn With a Suspected Difference of Sex ...

Confirm a 46,XY karyotype, document external genital phenotype and gonadal location, obtain hormone testing appropriate to age and pubertal stage, and exclude testosterone-synthesis defects. The diagnosis of CAIS or PAIS rests on this combined assessment rather than any single hormone result or genital finding. PubMed+1PubMedAndrogen Insensitivity Syndrome - StatPearls - NCBI BookshelfPubMedAndrogen Insensitivity Syndrome - GeneReviews - NCBI - NIH

Order molecular testing of the X-linked AR gene when CAIS or PAIS is suspected. AR pathogenic variants cause impaired androgen receptor function and support the diagnosis; testing is specifically recommended in suspected complete or partial androgen insensitivity. PubMed+2PubMedAndrogen Insensitivity Syndrome - StatPearls - NCBI BookshelfPubMedConsensus in Guidelines for Evaluation of DSD by the Texas ...PubMedGenetic Testing Registry (GTR) - NCBI - NIH

Interpret an identified AR variant in the context of phenotype because androgen receptor function and clinical expression vary substantially, particularly in PAIS. If AR sequencing does not identify an explanatory variant but clinical and biochemical findings continue to favor PAIS, consider a genital-skin biopsy for androgen-binding studies at a specialized center. The Lancet+1The LancetUse of clinical and functional androgen receptor indicesPubMedAndrogen Insensitivity Syndrome - GeneReviews - NCBI - NIH

Use imaging to establish the presence and location of gonads and to assess internal reproductive anatomy. Imaging informs counseling about gonad retention or removal and operative planning, but does not replace molecular and endocrine characterization. PubMed+2PubMedAndrogen Insensitivity Syndrome - GeneReviews - NCBI - NIHPubMedMolecular pathogenesis, diagnosis, and management challenges in complete androgen insensitivity syndromePubMedDisorders of Sexual Development in Adult Women - PMC - NIH

For CAIS, counsel about gonadal management, anticipated spontaneous pubertal feminization from aromatization of testicular androgens, sexual function, vaginal length concerns when present, and the consequences of gonadectomy for lifelong sex-steroid replacement. Bilateral gonadectomy has historically been used to reduce later gonadal tumor risk, but timing should be individualized rather than treated as automatic at diagnosis. The Lancet+3The LancetSupplemental Materials for Androgen insensitivity syndromeNatureCaring for individuals with a difference of sex development (DSD): a Consensus Statement | Nature Reviews EndocrinologyPubMedAndrogen Insensitivity Syndrome - GeneReviews - NCBI - NIHPubMedDisorders of Sexual Development in Adult Women - PMC - NIH

For PAIS, management must not be extrapolated from CAIS. The range of genital development, pubertal virilization, gynecomastia, gonadal position, urogenital anatomy, gender-related goals, and potential androgen responsiveness should determine whether observation, endocrine treatment planning, gonadal surgery, or genital reconstruction is considered. The Lancet+3The LancetUse of clinical and functional androgen receptor indicesOxford AcademicManagement of 46,XY Differences/Disorders of Sex ...PubMedCentral precocious puberty in partial androgen insensitivity syndrome: a 9-year follow-upPubMedAndrogen Insensitivity Syndrome - GeneReviews - NCBI - NIH

For MAIS, focus on the presenting complication—gynecomastia, infertility, or both—and assess for hypogonadism and treatment adherence where testosterone replacement is used. Men with 46,XY DSD who have irregular testosterone replacement or androgen insensitivity warrant cardiometabolic monitoring. Oxford Academic+2Oxford AcademicManagement of 46,XY Differences/Disorders of Sex ...PubMedAndrogen Insensitivity Syndrome - StatPearls - NCBI BookshelfPubMedThe challenges of androgen insensitivity syndrome - PMC

Do not pursue genital surgery solely because a diagnosis is established. In PAIS, define anatomy, expected function, and patient or family goals in an experienced DSD setting; repeated hypospadias repairs can create long-term infection and surgical morbidity. PubMed+2PubMedCentral precocious puberty in partial androgen insensitivity syndrome: a 9-year follow-upPubMedAndrogen Insensitivity Syndrome - GeneReviews - NCBI - NIHPubMedConsensus statement on management of intersex disorders - PMC

At each developmental transition, review pubertal progression, gonadal status, sex-steroid exposure, gynecomastia or virilization concerns, genital or urinary symptoms, sexual function, fertility goals, and mental health. Long-term follow-up is particularly important in PAIS because clinical issues can emerge from infancy through adulthood. PubMed+1PubMedCentral precocious puberty in partial androgen insensitivity syndrome: a 9-year follow-upPubMedAndrogen Insensitivity Syndrome - GeneReviews - NCBI - NIH

After gonadectomy, monitor adequacy of hormone replacement and skeletal health because loss of endogenous testicular hormone production changes long-term bone risk. Bone mineral density has been specifically studied in CAIS in relation to intact testes, gonadectomy timing, and hormone replacement. Nature+2NatureCaring for individuals with a difference of sex development (DSD): a Consensus Statement | Nature Reviews EndocrinologyOxford AcademicBone density and skeletal turnover in complete androgen ...PubMedAndrogen Insensitivity Syndrome - GeneReviews - NCBI - NIH

Offer genetic counseling to affected individuals and families because AIS is an X-linked condition caused by AR variants. Molecular confirmation improves counseling regarding inheritance and enables targeted testing options in relatives when appropriate. PubMed+2PubMedAndrogen Insensitivity Syndrome - GeneReviews - NCBI - NIHPubMedGenetic Testing Registry (GTR) - NCBI - NIHPubMedClinical outcomes and genotype-phenotype correlations in ...

Integrate psychology or psychiatry into care when distress, gender-related concerns, sexual-function concerns, stigma, or treatment decision conflict is present. DSD consensus guidance identifies psychosocial support and peer or parent support as important components of longitudinal care. PubMed+1PubMedAndrogen Insensitivity Syndrome - GeneReviews - NCBI - NIHPubMedConsensus statement on management of intersex disorders - PMC