Fact Sheet: Complete AIS

Complete AIS

People with CAIS are generally girls or women with internal testes, 46,XY karyotypes, and normal female bodies by external appearance except for 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

If a 46,XY fetus cannot respond to testosterone or DHT, only the non-androgenic aspects of male development begin to take place: formation of testes, production of testosterone and anti-müllerian hormone (AMH) by the testes, and suppression of müllerian ducts. The testes usually remain in the abdomen, or occasionally move into the inguinal canals but can go no further because there is no scrotum. AMH prevents the uterus and upper vagina from forming. The testes make male amounts of testosterone and DHT but no androgenic sexual differentiation occurs. Most of the prostate and other internal male genital ducts fail to form because of lack of testosterone action. A shallow vagina forms, surrounded by normally formed labia. Phallic tissue remains small and becomes a clitoris. At birth, a child with CAIS appears to be a typical girl, with no reason to suspect an incongruous karyotype and testosterone level, or lack of uterus.

Childhood growth is normal and the karyotypic incongruity remains unsuspected unless an inguinal lump is discovered to be a testis during surgical repair of an inguinal hernia, appendectomy, or other coincidental surgery.

Puberty tends to begin slightly later than the average for girls. As the hypothalamus and pituitary signal the testes to produce testosterone, amounts more often associated with boys begin to appear in the blood. Some of the testosterone is converted into estradiol, which begins to induce normal breast development. Normal reshaping of the pelvis and redistribution of body fat occurs as in other girls. Little or no pubic hair or other androgenic hair appears, sometimes a source of worry or shame. Acne is rare.

As menarche typically occurs about two years after breast development begins, no one usually worries about lack of menstrual periods until a girl reaches 14 or 15 years of age. At that point, an astute physician may suspect the diagnosis just from the breast/hair discrepancy. Diagnosis of complete AIS is confirmed by discovering an adult male testosterone level, 46,XY karotype, and a shallow vagina with no cervix or uterus.

Hormone measurements in pubertal girls and women with CAIS and PAIS are similar, and are characterized by total testosterone levels in the upper male rather than female range, estradiol levels mildly elevated above the female range, mildly elevated LH levels, normal FSH levels, sex hormone binding globulin levels in the female range, and possibly mild elevation of AMH. DHT levels are in the normal male range in CAIS but reportedly in the lower male range in PAIS. Interpretation of hormone levels in infancy is more complex and cannot be as easily summarized for this article. Androgen receptor testing has become available commercially but is rarely needed for diagnosis of CAIS and PAIS.

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.
• Prenatal amniocentesis discovers male karyotype not matched by ultrasound or obvious female appearance at birth.
• A lump in the inguinal canal is discovered to be a testis.
• Abdominal surgery done for repair of inguinal hernia, appendicitis or other reason discovers testes or lack of uterus and ovaries. Even in the absence of a visible inguinal lump, perhaps 1% of girls operated on for inguinal hernia are found to have AIS.
• Karyotype performed for unrelated purposes is found to be XY.
• The girl or family seeks evaluation for delayed menarche (primary amenorrhea).
• The woman seeks explanation for difficulty with sexual intercourse.
• The woman seeks explanation for infertility.
• 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

• The need for explicit mention of such an obvious first step in the care of any disease reflects the difficulty felt by physicians in explaining testes to an adolescent girl, as well as the dissatisfactions with past medical care expressed by many women with CAIS.
• 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

For women for whom vaginal shallowness is a problem, enlargement can be achieved by a prolonged course of self-dilation. Surgical construction of a vagina is sometimes performed for adults but carries its own potential problems.

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 preserved in some way. 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

Once testes have been removed, estrogen needs to be taken in order to support pubertal development, bone development, and completion of growth. Among estrogen preparations available, transdermal patches are gaining in popularity. Since there is no uterus, progesterone is not considered necessary.

Osteoporosis

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 counseling information

When a woman is diagnosed with CAIS or PAIS, referral to a genetic counselor may be warranted to explain the implications of the X-linked recessive inheritance.

The mother of the woman with AIS is likely to be an unaffected carrier of the gene on one of her X chromosomes.

A mother who carries the defect will, on average, pass it to 50% of her children, whether XX or XY. Those who are XX will be similarly unaffected carriers who can pass it to succeeding generations. Those who are XY will have the condition but, being infertile, cannot pass it.

If the family is large, other members can be found who have or carry AIS. Many women with AIS will be able to identify affected maternal relatives such as aunts or great aunts.

Carrier detection by gene testing is now possible.

A small percentage of new cases of AIS are due to new, spontaneous mutations, and the above information about the family is not applicable. See the section above for more genetic details.

A note on history and terminology

Case reports compatible with CAIS date back to the 19th century, when hermaphroditism was the technical term for intersex conditions. In 1950, Lawson Wilkins hypothesized that this condition might be explained by resistance to testosterone but hormones could not be easily measured, and even chromosomes were just beginning to be understood. In 1953 J.C. Morris suggested the term testicular feminization, and by 1963 most of the essential pathophysiology of complete AIS was suspected. However, as the relationship with the partial forms became worked out in the 1980s, physicians began to prefer the less confusing and more comprehensive term androgen insensitivity. In the 1990s, patient advocacy groups also supported abandoning the term "testicular feminization," and it is now considered inaccurate, stigmatising and archaic.

In an outcome study from one of the institutions (Johns Hopkins Hospital) with the greatest experience with this condition. Of 20 adult women seen in the clinic over the last 40 years with CAIS, 14 agreed to participate in a questionnaire and examination to assess long-term outcome. Most of the women agreed with delay of vaginal surgery until adolescence or later, and many felt inadequately informed about the details of their condition.

*For more information search AIS in Wikipedia