Androgen insensitivity syndrome

Overview

Androgen Insensitivity Syndrome (AIS) is a rare genetic condition in which a person who is genetically male (46,XY chromosomes) is resistant to male sex hormones called androgens. As a result, individuals with AIS may have female external genitalia or ambiguous genitalia despite having male chromosomes and internal testes. AIS exists on a spectrum, ranging from complete to partial forms depending on the degree of androgen insensitivity.

The condition affects sexual development and gender characteristics, often not being diagnosed until puberty or during investigations for infertility or amenorrhea (absence of menstruation).

Causes

AIS is caused by mutations in the AR gene (androgen receptor gene) located on the X chromosome. This gene provides instructions for making androgen receptors, which allow the body to respond to androgens like testosterone. When these receptors are faulty, cells can't respond properly to male hormones, leading to feminized or ambiguous development despite the presence of XY chromosomes.

The condition is inherited in an X-linked recessive pattern, typically passed from a carrier mother to her genetically male child.

Symptoms

The symptoms of AIS vary based on the degree of insensitivity and are generally classified into two main forms:

1. Complete Androgen Insensitivity Syndrome (CAIS):

• Typical female external genitalia

• No uterus or upper vagina (a shallow vaginal pouch)

• Undescended testes (often in the abdomen or inguinal canal)

• No menstruation (primary amenorrhea)

• Normal breast development at puberty

• Little or no pubic and underarm hair

2. Partial Androgen Insensitivity Syndrome (PAIS):

• Ambiguous genitalia (e.g., micropenis, enlarged clitoris, hypospadias)

• Varying degrees of breast development

• Small or undescended testes

• Infertility in many cases

Diagnosis

Diagnosis is typically made through a combination of clinical evaluation, hormone testing, imaging, and genetic analysis:

• Physical examination: Especially in newborns with ambiguous genitalia or girls with delayed puberty or amenorrhea

• Karyotype testing: Reveals a 46,XY chromosome pattern

• Hormone levels: Normal or high testosterone levels, but unresponsive target tissues

• Pelvic ultrasound or MRI: Shows absence of uterus and presence of undescended testes

• Genetic testing: Confirms mutations in the AR gene

Treatment

Treatment for AIS focuses on medical, psychological, and surgical care tailored to the individual’s needs and gender identity. A multidisciplinary team approach is essential:

Gonad Management:

• In CAIS, removal of undescended testes is typically recommended after puberty due to risk of malignancy

• In PAIS, timing and necessity of surgery depend on individual presentation and preferences

Hormone Therapy:

• Estrogen replacement therapy may be needed after gonad removal to support bone and sexual health

Genital and Reconstructive Surgery:

• In PAIS, may be considered for functional or cosmetic reasons

• Vaginal lengthening or creation (vaginoplasty) in some CAIS cases if needed

Psychological Support:

• Counseling for individuals and families to address gender identity, fertility, and body image issues

Genetic Counseling:

• For affected families to understand inheritance risks and reproductive options

Prognosis

The overall prognosis for individuals with AIS is good. Those with CAIS generally have normal female gender identity, normal sexual function, and a healthy life expectancy, though they are infertile. Individuals with PAIS may face more challenges related to genital ambiguity, gender identity, and fertility, but many lead fulfilling lives with appropriate care and support.

Early diagnosis, open communication, and supportive care are key to promoting physical and psychological well-being.