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's 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. Sometimes, a mild virilization (clitoral enlargement, body hair) develops (Quigley stage 6). Synonyms: testicular feminization, Goldberg-Maxwell-Morris-Syndrome,

**Table clinical classification of androgen insensitivity syndromes (Quigley, 2005):** MAIS: mild androgen insensitivity syndrome. PAIS: partial androgen insensitivity syndrome. CAIS: complete androgen insensitivity syndrome.
Grading	Genital appearance and clinical features
1 (MAIS)	Normal male phenotype, possibly gynecomastia or mild impairment of virilization
2 (PAIS)	Male phenotype, but small penis, penoscrotal hypospadia
3 (PAIS)	Predominantly male phenotype with micropenis, perineal hypospadia, cryptorchidism and possibly bifid scrotum
4 (PAIS)	Ambiguity of the external genitalia: very large clitoris, urogenital sinus with perineal opening and labioscrotal folds
5 (PAIS)	Predominantly female phenotype: large clitoris, separate openings of the urethra and vagina
6 (PAIS)	Female phenotype, androgen-induced pubic and axillar hair growth at the time of puberty. 50% inguinal hernia.
7 (CAIS)	Normal female phenotype. Lack of androgen-induced pubic and axillar hair growth at the time of puberty. 50% inguinal hernia.

Etiology (Causes) of the Androgen Insensitivity Syndrome

Different mutations of the androgen receptor gene, located on the X chromosome, lead to a reduced (partial) androgen response or complete lack of androgen response (PAIS or CAIS). Many different types of mutations with different effects have been reported, but molecular alterations cannot predict the resulting phenotype. 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 Work-Up 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)

Causal treatment of MAIS is not possible. The substitution to supranormal levels of testosterone may alleviate symptoms or may improve the spermatogenesis, close monitoring of breast and prostate due to possible tumor growth is necessary.

Treatment of the Partial Androgen Insensitivity Syndrome (MAIS)

Gender role is defined depending on the phenotype of the external genitalia; the decision should take place early in childhood in specialized multidisciplinary centers. The majority of patients will be assigned to the male gender role. If in doubt, a therapeutic trial with testosterone during infancy may test virilization at puberty. The commitment to a male gender role usually includes early surgical correction of hypospadia and cryptorchidism.

If a female gender role is assigned, the timing and scope of a feminizing genitoplasty are controversial. Surgical corrections are usually recommended after puberty. Some authors recommend early bilateral orchiectomy to avoid further virilization at puberty.

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.

Testicular diseases

Index

5αReductase deficiency

Index: 1–9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

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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

Deutsche Version: Androgeninsensitivitätssyndrom (testikuläre Feminisierung)

Last update

Dr. med. Dirk Manski
man...@urologielehrbuch.de