Androgen insensitivity syndrome

Androgen insensitivity syndrome (AIS), also referred to as androgen resistance syndrome, is a set of disorders of sexual differentiation caused by mutations of the gene encoding the androgen receptor. The nature of the resulting problem varies according to the structure and sensitivity of the abnormal receptor. Most forms of AIS involve variable degrees of undervirilization and/or infertility in XY persons of either gender. A person with complete androgen insensitivity syndrome (CAIS) has a female external appearance despite a 46XY karyotype and undescended testes, a condition termed "testicular feminization" in the past.


Incidence and genetics

The incidence of complete AIS is about in 1 in 20,000. The incidence of milder degrees of androgen resistance is not known and it has been suggested by various authorities that it might be both more common or less common than CAIS. Evidence suggests many cases of unexplained male infertility may be due to the mildest forms of androgen resistance.

Because the Androgen Insensitivity Syndrome gives rise to ambiguity between the genetic and the phenotypic gender, we will use the convention 46,XY to designate a genotypic male, and 46,XX to designate a genotypic female. By this convention, a person with Androgen Insensitivity Syndrome is a 46,XY but a phenotypic female.


However, 46,XX women with a single mutated copy of the AR gene can be carriers of AIS, and their 46,XY children (male) will have a 50% chance of having the syndrome. As in some other X-linked recessive conditions, carrier mothers may display some minor traits of the condition: AIS carriers often have reduced axillary and pubic hair, and reduced normal adolescent acne.



Normal function of androgens and the androgen receptor






Defects in the androgen receptor


Prenatal effects of testosterone in 46,XY fetus




Early postnatal effects of testosterone in 46,XY infants


Pubertal effects of testosterone in 46,XY children



Problems produced by androgen insensitivity








OMIM (Online Mendelian Inheritance in Man) numbers are a genetic disease classification system available at the NCBI

1. Complete AIS

People with CAIS are generally girls or women with internal testes, 46,XY karyotypes, and normal female bodies by external appearance with some exceptions. The vagina is not as deep, and there are no ovaries or uterus— hence no menses or fertility. Gender identity is almost always female.

Natural history of CAIS






Adult women with CAIS tend to be taller than average, primarily because of their later timing of puberty. Breast development is said to be average to above average. Lack of responsiveness to androgen prevents some usual female adult hair development, including pubic, axillary, upper lip. In contrast, head hair remains fuller than average, without recession of scalp or thinning with age. Shallowness of the vagina varies and may or may not lead to mechanical difficulties during coitus. Although the testes develop fairly unexceptionally before puberty if not removed, the testes in adults with CAIS become increasingly distinctive, with unusual spermatogenic cells and no spermatogenesis.

By clinical reports and information from support groups, women with CAIS are at least as likely as other women to have a female gender identity and to be attracted sexually to men.

Diagnostic circumstances of CAIS

Most cases of CAIS are diagnosed in the following circumstances.

  6. The woman seeks explanation for difficulty with sexual intercourse.
  7. The woman seeks explanation for infertility.
  8. Diagnosis of androgen insensitivity syndrome (AIS) is confirmed by identification of a novel homozygous nonsense mutation predicted to negatively impact androgen receptor (AR) gene function.

Aspects of medical treatment of CAIS

The ethical aspects of diagnostic disclosure are: (1) the history of withholding information from patients with disorders of sex development (DSD) based on the assumption that physicians were better able to determine what was in the patient’s best interest; (2) the principle of informed consent asserts an ethical imperative to disclose such a diagnosis to the patient; in the case of minors, participation in decision-making is guided by the concept of “assent” commensurate with developmental capacity; and (3) the extent to which a physician has the dual responsibility to maintain confidentiality and to inform other members of the family that they may be at risk for being affected by a condition or for transmitting it to their offspring.

Others include: Accurate, sensitive explanation


Counseling, referral to support network

"Counseling" should be included in published recommendations for CAIS management. Many women with CAIS find value in making connections with others similarly affected. The internet now provides the simplest method of connecting with such support (AIS Support Group (AISSG)).

Vaginal enlargement

''' Gonadectomy decision
Optimal timing of removal of the testes has been the management issue most often debated by physicians, though whether it is necessary has been questioned as well. The advantage of retaining the (usually intra-abdominal) testes until after puberty is that pubertal changes will happen "naturally," without hormone replacement. This happens because the testosterone produced by the testes gets converted to oestrogen in the body tissues (a process known as aromatisation).

The primary argument for removal is that testes remaining in the abdomen throughout life may develop benign or malignant tumors and confer little benefit. The testicular cancer risk in CAIS appears to be higher than that which occurs with men whose testes have remained in the abdomen, and rare cases of testicular cancer occurring in adolescents with CAIS have been reported. Unfortunately the uncommonness of CAIS and the small numbers of women who have not had testes removed make cancer risk difficult to quantify. The best evidence suggests that women with CAIS and PAIS retaining their testes after puberty have a 25% chance of developing benign (harmless) tumors and a 4-9% chance of malignancy. It should be noted, however, that the risk of breast cancer in women as a whole is around 1 in 8 and yet clinicians do not remove the breasts of young girls/women on the off chance that they might develop cancer.

There is also the issue of whether medical advances might enable tissue from testes in situ to be used with a donor egg to produce a child via IVF that is genetically related to the XY woman. This chance is lost for ever if the testes have been removed, unless they are in some way preserved. Apart from this, a significant number of CAIS women say that they never felt the same after gonadectomy as a young adult, that they lose their libido etc. Another benefit provided by testes in CAIS is the estradiol produced from testosterone. Although this can be provided pharmaceutically post-gonadectomy, many CAIS women have trouble adjusting to artificial HRT and regret losing their natural source of oestrogen.

Estrogen replacement



CAIS women appear to have a higher than average risk of thinning of the bones (osteoporosis) but possibly not with an associated tendency to increased fracture. The low bone density does not always relate to poor compliance with an HRT regimen or to the timing of gonadectomy. It has been speculated that the lack of androgen action might be a contributing factor since women with the partial form (PAIS) seem to fare better in this respect. More research is needed in this area.

Genetic counselling information


  • The mother of the woman with AIS is likely to be an unaffected carrier of the gene on one of her X chromosomes.
  • Carrier detection by gene testing is now possible.


A note on history and terminology



3. Reifenstein syndrome


Neonatal manifestations




Diagnostic issues




Aspects of management


  • Male assignment is usually followed by one or more operations in infancy by a pediatric urologist to completely repair the hypospadias, close the midline pouch, and (if possible) place the testes in the scrotum. Gonadal status and potential testosterone responsiveness is reassessed around age 12. Breast tissue can be removed surgically in adolescence if excessive. Gonads should be removed if scrotal placement is impossible. High dose testosterone replacement will sometimes achieve further virilization. An advantage of this choice commonly cited by parents is consistency with karyotype. A survey of adults brought up this way reported that nearly all were comfortable with the gender assignment made at birth and the sexual function of their genitalia, but many were dissatisfied with the size.
  • Female assignment is usually followed by gonadectomy in childhood to prevent further masculinization, especially at puberty; sometimes by surgery to enlarge the vaginal opening and reduce clitoral size. Estrogen is replaced at puberty. This course has the advantage that future tissue sensitivity to testosterone is irrelevant for a girl. This course may involve fewer surgical procedures than male assignment and surgery, and may produce a better cosmetic outcome, but a higher percentage of women raised with early surgical repair describe impairment of sexual sensation or function.
  • A third option has been advocated in the last decade by some: to tentatively assign male or female sex but postpone all surgery until early adolescence. This approach is intended to make it easier for an adolescent to reject or confirm the gender assigned in infancy by parents and doctors, and to choose or refuse reconstructive surgery.


Yet another note on history and terminology

One might fairly call Reifenstein syndrome "even more partial" AIS, but when E.C. Reifenstein described the features of a new syndrome of male "familial hypogonadism" in 1947, it was not known that this condition was due to an abnormal androgen receptor and related to the female conditions of CAIS or PAIS. Additional familial intersex and hypogonadal conditions described by Lubs, Gilbert, Dreyfus, Rosewater, Walker, and others are now considered variants of the Reifenstein syndrome form of AIS.

4. Infertile male syndrome


5. Undervirilized fertile male syndrome (Mild Androgen Insensitivity Syndrome)


6. X-linked spinal and bulbar atrophy syndrome



Endocrine manifestations of this disorder are variable and only rarely include undervirilization of internal or external genitalia. In the majority evidence of altered androgen sensitivity is restricted to exaggerated or persistent adolescent gynecomastia, and the mildly high LH, testosterone, and estradiol levels characteristic of other forms of AIS. In other words, most people affected with Kennedy disease are relatively normal XY men with normal fertility and normal or minimally reduced virilization.

The distinctive AR mutation of Kennedy disease, reported in 1991, involves multiplied CAG repeats in the first exon. The mechanism by which this type of mutation causes neuromuscular disease, while complete insensitivity does not, is not yet understood.


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