- Incidence: 1 in 20,000 live births in genetic male individuals (46,XY)
- Androgen insensitivity syndrome (AIS) is the 3rd most common cause of primary amenorrhea in phenotypic female individuals.
- Karyotype: 46,XY
- Inheritance: X-linked recessive
- Mutation in the coding region of the gene for androgen receptor (AR) protein
- Mutations often lead to amino-acid substitutions and varying levels of loss of androgen function, and are responsible for the wide range of clinical phenotypes.
- In 30%–40% of cases, AIS is owing to the spontaneous de novo mutation of a germ cell.
- ARs are required for cells to respond appropriately to androgens, including testosterone.
- Androgens (and their receptors) are required for normal sexual development in both men and women.
- Testosterone synthesis is normal in AIS, but typical post-receptor events mediating hormonal effects in tissues are altered or absent.
- Any of the steps involved in androgenization, from the synthesis of the AR protein through the transcriptional ability of the androgen-AR complex, may be affected.
- Alterations in any of the above steps result in varying levels of resistance to androgens either through impairment in androgen binding or impaired ability to respond to androgens.
Sexual characteristics of affected individuals can vary and lead to 1 of the 3 classification types:
- Complete AIS (CAIS): characterized by feminization (phenotypic female) in an individual with a male genotype
- Partial AIS (PAIS): characterized by undervirilization of a phenotypic male or virilization of a phenotypic female in an individual with a male genotype
- Mild AIS (MAIS): characterized by a phenotypic and genotypic male individual with infertility
Complete androgen insensitivity syndrome
- Phenotypic female at birth with male genotype
- Female external genitalia appear normal.
- Short, blind-ended vagina
- Female internal genitalia (ovaries, uterus, and fallopian tubes) are absent.
- Male internal genitalia are absent, with the exception of testes.
- Primary amenorrhea
- Sparse or absent pubic- and axillary-hair development
- Breast development occurs
- Pubertal growth spurt occurs
- Normal-appearing female body habitus
Partial androgen insensitivity syndrome
- Presentation may vary depending on the response of external genitalia to androgens.
- Male phenotype:
- Hypospadias (urethral opening on the underside of the penis)
- Micropenis or macroclitoris
- Bifid scrotum (deep midline cleft dividing the scrotum), which may contain testes
- May have complete failure of fusion of scrotum with a pseudovagina
- Gynecomastia begins at puberty and persists.
- Facial- and body-hair development decreased or absent
- Infertility (impaired spermatogenesis)
- Virilized female phenotype:
- Complete or incomplete (partial) fusion of labioscrotal folds
- Short, blind-ended vagina
- May have incompletely developed male urogenital structures internally
- Sparse axillary and pubic hair
Mild androgen insensitivity syndrome
- Male external genitalia appear normal.
- Normal internal urogenital structures
- History and physical examination
- Lab tests:
- Testosterone levels:
- Infancy: basal levels possibly low, but ↑ with administration of hCG
- Prepubertal: ↑ testosterone concentration
- Post puberty: normal or ↑ slightly
- If low, rule out other abnormalities in the steroidogenesis pathway.
- Luteinizing hormone (LH) levels:
- Infancy: may be low but ↑ with stimulation of gonadotropin-releasing hormone (GnRH)
- Puberty: ↑ concentration (due to impaired feedback secondary to androgen resistance)
- Normal follicle-stimulating hormone (FSH) levels
- Androstenedione, dihydrotestosterone (DHT), anti-Müllerian hormone (AMH), and inhibin B levels may be determined to help exclude other diagnoses.
- Testosterone levels:
- Imaging: abdominal or pelvic ultrasound
- To determine the presence of reproductive organs
- If female reproductive organs are identified, the diagnosis should be reconsidered.
- Genetic testing:
- Confirms diagnosis
- Karyotype analysis to determine genotypic sex: FISH to confirm presence of Y chromosome
- Histopathology of testes: normal architecture of testes with markedly reduced spermatogonia and/or sperm in post-pubertal individuals
- May be diagnosed incidentally in utero during antenatal ultrasonography. Diagnosis is confirmed by subsequent karyotype analysis, chorionic villus sampling, or amniotic fluid sampling.
- Management depends on receptor status, phenotype, and gender identity of the affected individual.
- All individuals:
- Offer psychological counseling.
- Calcium and vitamin D supplementation for optimal bone health
- Hormone-replacement therapy:
- Female phenotype: estrogen replacement after gonadectomy
- Male phenotype (PAIS): high-dose androgen therapy
- Tamoxifen therapy may be considered for phenotypic males with gynecomastia.
- Reconstructive and/or reassignment surgery of genitalia if necessary, after expert evaluation
- Orchiopexy (moving and permanently fixing the position of testes) or orchiectomy (removal of testes) in cases of abnormally located testes (intra-abdominal or intra-labial locations)
- Vaginal dilatation and/or vaginoplasty to prevent dyspareunia
- Mastectomy may be indicated for gynecomastia.
- Hypospadias repair
All disorders affecting sexual development must be considered. The following are select conditions that are part of the differential diagnoses for AIS:
- Müllerian agenesis: also known as Mayer-Rokitansky-Küster-Hauser syndrome or vaginal agenesis. Müllerian agenesis is a congenital condition of uncertain etiology, in which the Müllerian ducts fail to develop properly in genotypic female individuals (46,XX). Normal female external genitalia and functioning ovaries are present, but the vagina and uterus may be absent or underdeveloped. Women present with primary amenorrhea, but the remainder of secondary sexual characteristics develop normally. Hormone levels are typically normal. Management involves surgery for anatomical abnormalities.
- 46,XY complete gonadal dysgenesis: a rare genetic disorder of sexual development with varying inheritance patterns, also known as Swyer’s syndrome. Infants present with female external genitalia and streak gonads (ovaries or testes). Women experience primary amenorrhea and infertility. Diagnosis is made based on imaging studies and genetic testing. Management includes hormone-replacement therapy and removal of the streak gonads.
- Mixed gonadal dysgenesis: a condition with asymmetric gonadal development involving both male and female gonads and respective internal and external reproductive anatomy. Mixed gonadal dysgenesis is associated with Turner syndrome mosaicism with a 45,X0/46,XY karyotype. Additional features of Turner syndrome may be present. Karyotyping and biopsy of gonadal tissue help in the diagnosis.
- Steroid 5-alpha-reductase deficiency: an autosomal recessive genetic condition affecting individuals with the 46,XY karyotype. External genitalia most often appears female but may appear male or ambiguous. Affected individuals have testes and normal testosterone production; however, there is impaired conversion of testosterone to DHT, causing undervirilization. Hormonal and genetic testing help make the diagnosis. Management depends on phenotype and gender identity, and may involve hormone replacement and/or surgery.
The following condition is related to AIS in that it involves the AR gene and impairs androgen receptivity:
Spinobulbar muscular atrophy: an X-linked genetic condition, also known as Kennedy disease. Spinobulbar muscular atrophy is caused by abnormal expansion repeat in the AR gene, resulting in AR impairment. Spinobulbar muscular atrophy is characterized by a progressive deterioration of anterior motor neurons and is associated with the development of gynecomastia, infertility, and hormonal profiles, similar to that seen in AIS.
- Androgen Insensitivity Syndrome. (2020). MedlinePlus. Retrieved January 13, 2020, from https://medlineplus.gov/genetics/condition/androgen-insensitivity-syndrome/
- Hiort, O. (2020). Pathogenesis and clinical features of disorders of androgen action. UpToDate. Retrieved January 13, 2021, from https://www.uptodate.com/contents/pathogenesis-and-clinical-features-of-disorders-of-androgen-action
- Hiort, O. (2020). Diagnosis and treatment of disorders of the androgen receptor. UpToDate. Retrieved January 13, 2021, from https://www.uptodate.com/contents/diagnosis-and-treatment-of-disorders-of-the-androgen-receptor