Androgen insensitivity syndrome (AIS)

Disease Description (Causes and Symptoms)

• Name: Androgen Insensitivity Syndrome (AIS)
• Cause and pathophysiology: Due to lesions in the AR (androgen receptor) gene (Xq11.2–12) on the long arm of the X chromosome, androgen receptor function is reduced or lost, preventing androgen-induced masculinization in 46,XY embryos. Because the testes secrete AMH (anti-Müllerian hormone), Müllerian structures such as the uterus and fallopian tubes do not develop. Male internal genitalia (Wolffian duct-derived structures) also fail to develop properly due to deficient androgen action.
• Inheritance pattern: X-linked recessive. Genetic counseling is recommended.
• Main symptoms (clinical spectrum):
  • Complete form (CAIS): External genitalia are typically female; a vagina is present but may be short or obstructed in its upper portion; breast development occurs at puberty; pubic, axillary, and body hair are sparse; amenorrhea (absence of the uterus); the testes are located in the abdominal cavity, inguinal region, or labia majora.
  • Partial form (PAIS): Ambiguous external genitalia (partial masculinization or a mixed form), with some possibility of male secondary sexual characteristics; pubic and body hair are sparse.
• Epidemiology: Depending on the report, it is known to occur in approximately 2–5 per 100,000 people.
• Main complications and related issues: Increased risk of tumors in undescended testes (such as germinoma and gonadoblastoma), and osteoporosis (especially when hormone management is inadequate after orchiectomy).

Treatment Methods and Precautions

• Basic principles: Integrated management through a multidisciplinary approach (endocrinology, medical genetics, pediatric urology, obstetrics and gynecology, and mental health), together with psychosocial support for the patient and family. Genetic counseling is essential.
• Surgical treatment
  • Management of the testes (undescended testes): Orchiectomy, taking tumor risk into account. For CAIS, it is often recommended after puberty (after natural breast development), with exceptions depending on tumor risk and the location of the testes. For PAIS, earlier surgery may be considered to prevent masculinization and because of cancer risk.
  • Vagina formation (genital reconstruction): Nonsurgical treatment (dilators) or surgical treatment (vaginoplasty) to create or enlarge the vagina. The decision should be individualized, taking sexual function and quality of life into account.
• Hormone therapy
  • Estrogen replacement therapy is necessary after orchiectomy to maintain bone density and secondary sexual characteristics. The dosage and starting time depend on the patient’s age and the timing of surgery.
  • Masculinizing treatment in PAIS should be determined on an individual basis.
• Monitoring and testing
  • Monitor for tumors by confirming testicular location (ultrasound and MRI) and performing tumor marker tests when necessary. The monitoring method and interval vary according to the patient’s circumstances.
  • Evaluate bone density (DEXA) and provide osteoporosis prevention and management (exercise, calcium and vitamin D, and medication when necessary).
• Psychosocial management
  • Sufficient counseling and an informed-consent process regarding gender identity, gender role, and decisions about surgery and hormone therapy.
• Precautions (including self-care)
  • After orchiectomy, take hormone therapy regularly to manage the risks of osteopenia and cardiovascular disease.
  • Follow instructions regarding sexual activity and postoperative recovery.
  • Regular tumor surveillance and bone density testing are recommended.
• Complications
  • Malignant tumors associated with undescended testes, osteoporosis, postoperative scarring, sensory changes, sexual-function problems, and psychosocial stress.

Checklist Before an Outpatient Visit (Including Preparation Items and Example Questions)

• Preparation items
  • List of medications and supplements currently being taken (including doses and administration times).
  • Copies of previous diagnostic documents and surgical and test results (hormone tests, imaging, and pathology).
  • Family history information (especially regarding X-linked diseases or sex chromosome abnormalities).
  • Symptom records: when amenorrhea began; changes in breast development and body hair; changes in the appearance of the external genitalia; pain or discomfort (in the groin or abdomen); and other symptoms.
  • The patient’s (or guardian’s) treatment goals and concerns (gender identity, wishes regarding pregnancy and reproduction, etc.).
• Examples of useful questions to ask during the outpatient visit (patients should write these down in advance)
  • Have there recently been any changes in the genitalia or any pain? (Specific date and condition)
  • What hormone tests (testosterone, LH/FSH, etc.) or imaging tests have been performed in the past? What were the results?
  • Does anyone in the family have a sex-related chromosomal abnormality or an AR gene variant?

Examples of General Questions to Ask the Doctor

• What are the exact diagnostic results for this condition (chromosome and genetic test results)?
• What is the risk of tumors developing in my (or my family member’s) testes? What monitoring methods are available?
• If orchiectomy is recommended, when should it be performed, and what is the plan for hormone therapy needed after surgery?
• What are the long-term side effects of surgery or hormone therapy (such as osteoporosis and cardiovascular risk), and how can they be prevented?
• What is the prognosis related to sexual function and sexual activity, and what supportive methods are available?
• Who provides genetic counseling, and what genetic risks may affect family members?

Examples of Condition-Specific Questions

• Where are my (or my child’s) testes located (abdominal cavity, inguinal region, or labia majora)? Do the tumor risk and timing of surgery vary depending on their location?
• Was a variant identified in genetic (AR) testing? If so, is testing recommended for family members (female carriers)?

(Additional information) It is important to establish an individualized treatment plan through detailed diagnostic testing (chromosome testing, AR gene testing, hormone testing, and imaging) and multidisciplinary counseling.