Androgen Insensitivity Syndrome

Updated: Oct 16, 2017
  • Author: Christian A Koch, MD, PhD, FACP, MACE; Chief Editor: Robert P Hoffman, MD  more...
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Practice Essentials

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 of hypospadias 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). 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.

A karyotype is essential to differentiate an undermasculinized male from a masculinized female. Alternatively, the presence of a Y chromosome can be confirmed by fluorescent in situ hybridization (FISH) probes for either the SRY region of the Y chromosome or a subtelomeric Y chromosome probe. Mutation analysis of the androgen receptor gene is now commercially available. It detects upwards of 95% of the mutations for complete androgen insensitivity syndrome and partial androgen insensitivity syndrome.

Medical care for a patient with androgen insensitivity syndrome (AIS) has 2 aspects: hormone replacement therapy (HRT) and psychological support. [5, 7, 8]  For individuals with androgen insensitivity syndrome, the standard of care is an orchidectomy to prevent possible malignant degeneration of the testes. [9]



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. [10, 11] Molecular phenotyping based on 5 different functional assays matched the clinical phenotype in most cases (70%). [12]

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 Kennedy disease (spinal and bulbar muscular atrophy [SBMA]), a motor neuron disease caused by a CAG expansion in the AR gene, 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. [13] Pituitary glands in patients with Kennedy disease are larger than those in persons without androgen insensitivity. [14]



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. [15] 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. [16]

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. [17]

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.



The medical and psychological prognosis for a woman with androgen insensitivity syndrome is excellent if she has appropriate support and counseling.

Androgen insensitivity syndrome, either complete or partial, has little medical morbidity or mortality. Complete AIS increases the risk of testicular malignancy if the testes are not removed, with risk estimated at 3.6% at 25 years and 33% at 50 years.  Prepubertal malignancy in complete AIS is extremely rare. The risk of germ cell tumors (GCT) in partial AIS with untreated undescended testes is significantly greater, with estimates as high as 50%. [18]  Not much documentation on the morbidity or mortality of these tumors specifically in individuals with androgen insensitivity syndrome is available. The tumor is considered cured without need for further therapy if it is removed while still limited to the interior of the testes capsule. The tumor is considered curable in most patients even when undetected at this early state. The use of a magnetic resonance imaging before surgery appears to be helpful in localizing and planning for removal of the gonads for malignancy risk reduction and preventing injury to other structures. [19]

In contrast to medical morbidity, psychological morbidity is common. Phenotypic females who are discovered to be genetic males may have psychosocial problems. These females require sensitive psychological support. Their psychosocial problems range from identity issues to problems dealing with the gender perceptions of the outside world and the style and sensitivity (or lack thereof) they encounter within the medical system.

Most affected individuals report psychological trauma at diagnosis. Their reactions to the diagnosis frequently are compounded by their interactions with the medical care system, in which they often are treated as oddities and forced to undergo multiple examinations and interviews with students and residents for teaching purposes. Even in nonteaching situations, women with androgen insensitivity syndrome report difficulties identifying offices where physicians and staff are familiar with their condition. Many of these patients have been told that they really are not women but actually are men because of the presence of a Y chromosome and testes. These difficulties and doubts often cause shame and self-doubt, as well as anger and frustration with a medical system they had expected to take care of them. There is far-reaching lack of sexual confidence and sexual satisfaction in individuals with complete androgen insensitivity syndrome.


Patient Education

Educate patients and families about the full nature of androgen insensitivity syndrome. Information for children can be provided in an age-appropriate format, taking care to be as accurate and understandable as possible. As the child matures, education should include information about issues such as vaginal hypoplasia and osteoporosis.

Encourage patient participation in decisions about medical and surgical alternatives. All questions must be answered completely before informed consent can be granted for irreverisble surgery involving reproductive organs. [20]

Patient-oriented educational materials are available through the AISSG Web site. [21]