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Mild, Partial, or Complete Androgen Insensitivity Syndromes

Definition and Symptoms of the Androgen Insensitivity Syndrome

A defective androgen receptor causes androgen insensitivity syndrome (AIS) in men (46, XY, leading to infertility and, to a varying degree, a male or female phenotype. The production of androgens is not disturbed. The extent of the disease depends on the severity of the androgen receptor dysfunction [Table clinical classification of AIS] (Galani et al., 2008).

Epidemiology

The prevalence of complete androgen insensitivity syndrome is 2–5/100000, the prevalence of partial and minimal androgen insensitivity syndrome is estimated to be similarly high.

Minimal Androgen Insensitivity Syndrome (MAIS)

Patients with minimal androgen insensitivity syndrome (MAIS) are phenotypically male; the most common symptom is infertility. Mild gynecomastia or mild impairment of virilization may be present.

Partial Androgen Insensitivity Syndrome (PAIS)

Patients with partial androgen insensitivity syndrome (PAIS) are phenotypically male, female or indifferent. Depending on the extent of androgen receptor dysfunction, cryptorchidism, micropenis, proximal hypospadias, urogenital sinus, vagina, lack of virilization, gynecomastia, and azoospermia may be present [Table clinical classification of AIS]. Synonyms: Reifenstein syndrome, Gilbert-Dreyfus Syndrome.

Complete Androgen Insensitivity Syndrome (CAIS)

Patients with complete androgen insensitivity syndrome (CAIS) are phenotypically female and are almost always raised as girls. Prenatal diagnosis is possible if amniocentesis reveals 46,XY karyotype despite a female phenotype. 1–2% of girls with inguinal hernia have CAIS; a pelvic exam (Cervix?) or karyotype may be helpful. During puberty, secondary female sexual characteristics develop, but without menstruation and pubic hair growth. The pelvic examination shows normal female external genitals. The vagina is short and ends blindly; the uterus and ovaries are missing. The testicles are located inguinal or labial. Puberty causes sometimes a mild virilization (clitoral enlargement, hirsutism). Synonyms: testicular feminization, Goldberg-Maxwell-Morris-Syndrome,

Etiology (Causes) of the Androgen Insensitivity Syndrome

Different mutations of the androgen receptor gene on the X chromosome lead to a minimal impairment, partial response, or complete lack of androgen response (androgen resistance). Different mutations with various effects are known, but molecular alterations cannot predict the resulting phenotype (MAIS, PAIS, or CAIS). Some mutations inhibit the binding of testosterone or DHT to the receptor; some impede the binding of the activated androgen-receptor complex to the DNA. If there is a complete loss of the androgen receptor gene, complete androgen insensitivity syndrome (CAIS) is certain.

Diagnostic Workup for suspected Androgen Insufficiency Syndrome

• Clinical examination and ultrasonography for localization of the testes.
• Laboratory tests: before puberty, normal concentrations of testosterone and gonadotropins are common. hCG stimulation leads to a rising testosterone. After puberty, testosterone is normal or elevated, and gonadotropins are elevated.
• Genetic testing: 46,XY karyotype, DNA analysis of the androgen receptor gene region. Androgen insensitivity syndrome is inherited in an X-linked recessive manner.

Treatment of Androgen Insensitivity Syndromes

Treatment of the Mild Androgen Insensitivity Syndrome (MAIS)

Testosterone substitution to supranormal levels may improve virilization or fertility. Mammoplasty for treatment of gynecomastia is often required.

Treatment of the Partial Androgen Insensitivity Syndrome (PAIS)

An early prognosis and, thus, determination of the future sex role is not possible and is not recommended. The tumor risk of the immature intra-abdominal gonads is estimated to be higher than in CAIS (see below). Still, bilateral orchiectomy should only be offered to patients capable of giving consent. Close monitoring is necessary, however, and the gonads should be sonographically visible for this purpose. From puberty onwards, patients can decide on their gender role and accept appropriate aligning surgery, prophylactic gonad removal, and hormone therapy if necessary.

Treatment of the Complete Androgen Insensitivity Syndrome (CAIS)

All studies implicate a female identity in complete androgen insensitivity syndrome since the brain tissue is androgen resistant as well. The diagnosis should be addressed to the growing child with the help of psychologists. The testes produce estradiol, enough to induce and complete puberty. Due to the risk of germ cell tumors in the testes (4% at 25 years, 33% at 50 years), bilateral orchiectomy is recommended after puberty. Hormonal replacement therapy with estrogens is necessary after orchiectomy. If orchiectomy is done in childhood, puberty has to be induced with hormones. A hypoplastic vagina can be treated after puberty with self-dilatation or, if insufficient, with vaginoplasty using ileum, colon, or skin flaps.

References

Galani, A.; Kitsiou-Tzeli, S.; Sofokleous, C.; Kanavakis, E. & Kalpini-Mavrou, A. Androgen insensitivity syndrome: clinical features and molecular defects.
Hormones (Athens), 2008, 7, 217-229

Quigley, C. A.; Bellis, A. D.; Marschke, K. B.; el-Awady, M. K.; Wilson, E. M. & French, F. S. Androgen receptor defects: historical, clinical, and molecular perspectives.
Endocr Rev, 1995, 16, 271-321

C. Radmayr, G. Bogaert, H. S. Dogan, and Tekg&uuml, “EAU Guidelines: Paediatric Urology,” 2022. [Online]. Available: https://uroweb.org/guidelines/paediatric-urology/.

  Deutsche Version: Androgeninsensitivitätssyndrom (testikuläre Feminisierung)