Complete Androgen Insensitivity Syndrome

Androgen Insensitivity Syndrome (AIS) is the most common form of Variation of Sex Characteristics (VSC)/Difference of Sex Development (DSD) in individuals with XY chromosomes.
It is caused by a genetic mutation of the androgen receptor (AR), resulting in a reduced masculinizing action of testosterone (i.e., reduced virilization) in various stages of a person's life. The different forms of AIS depend on the level of response to androgens: CAIS (Complete Androgen Insensitivity Syndrome), PAIS (partial AIS), or MAIS (mild AIS). People with complete androgen resistance have a 46,XY genetic makeup, and their gonads (testes) can produce both anti-Müllerian hormone (AMH) and testosterone, but the latter fails to act. In general, the production of AMH by the testicles causes the structures that lead to the formation of the uterus and part of the vagina (upper third) to regress, while testosterone stimulates the differentiation of the male genital system. In CAIS, a typically male development of genitals is thwarted by missing action of testosterone. The external genitalia will therefore develop in a typically female line, but only the lower portion of the vagina will take form. The vagina may be as long as approximately two thirds of the vagina in persons without complete resistance to androgens. Breast development, however, may occur due to the action of oestrogens resulting from the peripheral transformation of testosterone (aka “aromatization”).

Genetic traits
The gene for the androgen receptor (AR) is located on the X chromosome; therefore CAIS is a hereditary “X-linked” condition, even though in about a third of cases it occurs in the newborn without the mother carrying the genetic anomaly (de novo mutation).
Identification Suspicion of CAIS generally occurs in adolescence in people assigned female at birth because of their typically female external genitalia, when their first menstrual cycle (menarche) fails to occur. During puberty, there is usually breast development, as well as a typically female distribution of adipose tissue. However, there is little or no pubic or underarm hair. On physical examination, the vagina is “blind”, and its length varies from a few millimetres to 7–13 centimetres. The gonads, composed of testicular tissue, can be located in the abdomen, in the inguinal canal or, more rarely, in the labia majora. Testicle location and size can be determined by MRI. The absence of the uterus can be ascertained by pelvic ultrasound. The genetic analysis of the karyotype and the identification of the androgen receptor (AR) gene mutations will confirm the suspicion and diagnosis of CAIS.

Medical options
The management of CAIS symptoms needs a multidisciplinary approach to establish a correct assessment, and direct to adequate counselling. People with CAIS may require medical therapy, so it is necessary to provide psychological support and discuss therapeutic timing.

Hormone Therapy
Owing to the aromatization of testosterone, during puberty most people with CAIS may have insufficient oestrogen to achieve an adequate level of bone mineral density. Hormone therapy is needed not only for people undergoing gonadectomy before puberty, but also for those undergoing surgery during or after adolescence to complete or maintain female secondary sex characteristics. This will prevent bone loss and neurocognitive disorders, as well as ensure cardiovascular health. Hormone therapy should be continued at least until the age of 50–51, the average age of menopause onset.
Hormone therapy consists in the administration of oestrogens; however, there are no specific guidelines on hormone formulations, administration, dosage, and monitoring parameters. The most suitable formulations are probably micronized 17-beta-estradiol or estradiol valerate taken orally or transdermally (gel or patch). During counselling, it is important to clarify that long-term adherence to treatment is a fundamental aspect of health. It is therefore the doctor's task to explain in detail the indications and advantages of taking hormone therapy correctly.

Surgery
International scientific research suggests that the risk of gonadal cancer in people with CAIS is low and remains relatively low until adulthood, after which it starts increasing over the years. In particular, the risk of gonadal cancer is estimated to be 3.6% at 25 years and 33% at 50 years. Consequently, the choice to remove the gonads (gonadectomy) can be postponed until adulthood; this allows the person to make an independent decision, as well as to optimize growth in height and bone maturation. However, accurate counseling on possible risks and the need for careful follow-up is essential in this regard. Another important aspect to deal with, when the person feels ready to have sexual intercourse, is the treatment of vaginal agenesis (partial or total absence of the vagina) through vaginal dilations or surgical techniques.

Bibliography
Barros BA, Oliveira LR, Surur CRC, Barros-Filho AA, Maciel-Guerra AT, Guerra-Junior G. Complete androgen insensitivity syndrome and risk of gonadal malignancy: systematic review. Ann Pediatr Endocrinol Metab. 2021;26(1):19-23
Bertelloni S et al. Bone Mineral Density in Women Living with Complete Androgen Insensitivity Syndrome and Intact Testes or Removed Gonads. Sexual Development. 2017;11(4):182-189
Chaudhry S et al. Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): A retrospective case-series analysis [Abstract]. Journal of pediatric urology. 2017 Oct;13(5):498.e1-498.e6
Cools M, Drop SL, Wolffenbuttel KP, Oosterhuis JW, Looijenga LH. Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers. Endocr Rev. 2006;27(5):468-484
Gava G et al. Bone mineral density, body composition and metabolic profiles in adult women with complete androgen insensitivity syndrome and removed gonads using oral or transdermal estrogens [Abstract]. European Journal of Endocrinology. 2019 Dec;181(6):711-718
Lanciotti L et al. Presentations and Management in Complete Androgen Insensitivity Syndrome (CAIS). International Journal of Environmental Research and Public Health. 2019 Apr 9;16(7):1268
Mongan NP et al. Androgen insensitivity syndrome [Abstract]. Best practice & research. Clinical endocrinology & metabolism. 2015 Aug;29(4):569-80
Tyutyusheva N et al. Complete Androgen Insensitivity Syndrome: From Bench to Bed. International Journal of Molecular Sciences. 2021 Jan 27;22(3):1264

Further Links
NHS. Androgen insensitivity syndrome
Orphanet. Complete androgen insensitivity syndrome