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Mild, Partial or Complete Androgen Insensitivity Syndrome

Definition and Symptoms of the Androgen Insensitivity Syndrome

The androgen insensitivity syndrome (AIS) leads among men (46, XY) to infertility and to a varying degree of male or female phenotype. AIS is caused by a defective androgen receptor, 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

• Incidence 1:20000 to 1:60000

Mild Androgen Insensitivity Syndrome (MAIS)

Patients with a 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 a partial androgen insensitivity syndrome (PAIS) are phenotypically male, female or indifferent. Depending on the extent of androgen receptor dysfunction, cryptorchidism, micropenis, penoscrotal hypospadia, 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 a complete androgen insensitivity syndrome (CAIS) are phenotypically female and are almost always raised as a girl. Prenatal diagnosis is possible if amniocentesis reveals 46,XY karyotype despite of 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 menstruation and pubic hair growth does not occur. 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, hirsuitism). Synonyms: testicular feminization, Goldberg-Maxwell-Morris-Syndrome,

Etiology (Causes) of the Androgen Insensitivity Syndrome

Different mutations of the androgen receptor gene, located on the X chromosome, lead to a minimal impairment, partial response or complete lack of androgen response (androgene resistance). Many different types of mutations with different effects have been reported, 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 inhibit 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 a normal concentration of testosterone and normal gonadotropins are common, there is a rising testosterone after hCG stimulation. After puberty: normal or elevated testosterone, elevated LH.
• 46,XY karyotype
• DNA analysis of the androgen receptor gene

Treatment of Androgen Insensitivity Syndromes

Treatment of the Mild Androgen Insensitivity Syndrome (MAIS)

Testosterone substitution to supranormal levels may improve virilization or spermiogram.se monitoring of breast and prostate due to possible tumor growth is necessary.

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), but 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 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 neovaginoplasty using ileum, colon or skin flaps.

References

  Deutsche Version: Androgeninsensitivitätssyndrom (testikuläre Feminisierung)