Androgen Insensitivity Syndrome

Updated: Dec 16, 2015
  • Author: Christian A Koch, MD, PhD, FACP, FACE; Chief Editor: Stephen Kemp, MD, PhD  more...
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Androgen insensitivity syndrome (AIS), formerly known as testicular feminization, is an X-linked recessive condition resulting in a failure of normal masculinization of the external genitalia in chromosomally male individuals. This failure of virilization can be either complete androgen insensitivity syndrome (CAIS) or partial androgen insensitivity syndrome (PAIS), depending on the amount of residual receptor function. [1]

Both individuals with partial androgen insensitivity syndrome and individuals with complete androgen insensitivity syndrome have 46,XY karyotypes. Individuals with complete androgen insensitivity syndrome have female external genitalia with normal labia, clitoris, and vaginal introitus. [2, 3, 4, 5, 6] The phenotype of individuals with partial androgen insensitivity syndrome may range from mildly virilized female external genitalia (clitorimegaly without other external anomalies) to mildly undervirilized male external genitalia (hypospadias and/or diminished penile size).

See the image below.

Penoscrotal hypospadias is shown. Note the associa Penoscrotal hypospadias is shown. Note the associated ventral chordee and true urethral meatus located at the scrotal level.

In either case, affected individuals have normal testes with normal production of testosterone and normal conversion to dihydrotestosterone (DHT), which differentiates this condition from 5-alpha reductase deficiency. Because the testes produce normal amounts of müllerian-inhibiting factor (MIF), also known as müllerian-inhibiting substance (MIS) or anti-müllerian hormone/factor (AMH/AMF), affected individuals do not have fallopian tubes, a uterus, or a proximal (upper) vagina.



The basic etiology of androgen insensitivity syndrome is a loss-of-function mutation in the androgen receptor (AR) gene. This AR gene has been localized to the long arm of the X chromosome (ie, Xq11-13). Over 1,000 such mutations have been described, including complete and partial gene deletions, point mutations, and small insertions/deletions. These mutations can cause a variety of functional defects, ranging from a complete loss of receptors on the cell surface because of incomplete protein synthesis to alterations in substrate binding affinity. Altered substrate binding affinity causes a signal transmission loss, despite normal cell surface receptor numbers.

While the genotypes causing complete androgen insensitivity syndrome are fairly consistent in phenotypic presentation, the genotype/phenotype relationships for the mutations causing partial androgen insensitivity syndrome remain unclear. The N-terminal domain encoded by exon 1 of the AR gene contains a substantial number of mutations. Within exon 1, CAG and and GGN repeat regions are polymorphic in length. [7, 8] Molecular phenotyping based on 5 different functional assays matched the clinical phenotype in most (70%) cases. [9]

Loss of AR function means that, despite normal levels of androgen synthesis, the typical postreceptor events that mediate the effects of hormones on tissues do not occur. This results in the phenotype of prenatal undervirilization of external genitalia, absence of pubic and axillary hair, lack of acne, and absence of voice changes at puberty.

In patients with Kennedy disease, a neurologic disorder characterized by bulbar and spinal muscular atrophy, androgen insensitivity appears later in life with postpubertal gynecomastia being the most common sign. Muscular weakness (amyotrophic, proximal or distal) usually occurs after the appearance of gynecomastia. Occasional sensory disturbances can occur, as well as reduced fertility. There is an expansion (>40) of a polymorphic CAG tandem-repeat in exon 1 of the androgen-receptor. Mild elevation of creatine kinase may exist. [10] Pituitary glands in patients with Kennedy disease are larger than in those without androgen insensitivity. [11]




United States

Data are currently not available on the specific incidence of complete androgen insensitivity syndrome and partial androgen insensitivity syndrome.


The best available data suggest an androgen insensitivity syndrome incidence of approximately 1 case per 20,400 liveborn males. This statistic is based on analysis of a Danish patient registry that included only hospitalized cases; thus, the true incidence of androgen insensitivity syndrome may be higher. Complete androgen insensitivity syndrome appears more common than partial androgen insensitivity syndrome, although exact figures are unavailable. In the international disorders of sex development registry, of 649 accessible cases, 170 cases had suspected androgen insensitivity syndrome. Of these 170 cases, 19 (11%) had reported anomalies and 9 of these had confirmed androgen receptor mutations. [12]


No racial differences in incidence or presentation of androgen insensitivity syndrome have been described.


All patients with androgen insensitivity syndrome are chromosomally and gonadally male. However, separating the concepts of sex and gender is crucial with these patients. The term sex is usually based on physical attributes, whereas the concept of gender is based on an individual's self-concept and self-identification as well as the role an individual assumes in society.

Most patients with complete androgen insensitivity syndrome have a female gender. This may be due, in part, to the patient's role assignment and upbringing before the diagnosis or to the patient's choice of female "sex/gender" at diagnosis. The significance of the androgen effect's absence is increasingly recognized for its influence on the maturing brain (and other systems) in terms of developing adult gender identity. The Endocrine Society has developed guidelines to assist healthcare providers to take better care of patients with gender identity disorder. [13]

Partial androgen insensitivity syndrome is a more complicated problem for gender identity. Just as the genitalia may be highly varied in the degree of virilization, gender identity may be either female or male. At present, no reliable predictors of eventual gender identity have been identified, including genotype or degree of genital virilization at birth.