Complete Androgen Insensitivity Syndrome

Complete androgen insensitivity syndrome (CAIS) is a type of AIS condition where the cell cannot respond to androgens. This insensitivity is clinically relevant when individuals are exposed to significant testosterone levels during their lifetime. The cell's unresponsiveness to androgenic hormones hinders the masculinization of male genitalia in the developing fetus and the development of male secondary sexual characteristics during puberty, yet it permits normal female genital and sexual development in affected individuals.

All human fetuses initially develop similarly, with both the Müllerian duct system (female) and the Wolffian duct system (male) forming. Sex differentiation starts with the gonads, which become ovaries in XX individuals, and typically form testicles in XY individuals (including those with CAIS) due to the Y chromosome. In the seventh week of gestation, the bodies of non-CAIS XY individuals begin masculinization: the Wolffian duct system is promoted, and the Müllerian duct system is suppressed (the opposite occurs in typically developing females). This process is initiated by androgens from the testicles. The bodies of unaffected XY individuals masculinize by enlarging the genital tubercle into a penis, which becomes the clitoris in females, while the area that becomes labia in females fuses to form the scrotum in males (where the testicles will later descend).

XY individuals with CAIS develop a normal external female habitus, despite having a Y chromosome, but internally, they lack a uterus, and the vaginal cavity is shallow, while the gonads, which differentiated into testes due to the Y chromosome, remain undescended. This leads to infertility in CAIS individuals and increases the risk of gonadal cancer later in life.

CAIS is one of three types of androgen insensitivity syndrome (AIS), categorized by the degree of genital masculinization: complete androgen insensitivity syndrome (CAIS) when external genitalia appear typically female, mild androgen insensitivity syndrome (MAIS) when they appear typically male, and partial androgen insensitivity syndrome (PAIS) when the external genitalia are partially but not fully masculinized.

Androgen insensitivity syndrome is the most common cause of 46, XY undermasculinization.

Signs and Symptoms

Physical

Individuals with complete androgen insensitivity syndrome (grades 6 and 7 on the Quigley scale) are born with an external female phenotype and show no signs of genital masculinization, despite having a 46,XY karyotype. CAIS is typically identified during puberty, which may be slightly delayed but is otherwise normal except for the absence of menses and reduced or absent secondary terminal hair. Axillary hair (armpit hair) does not develop in one-third of cases. The vulva appears normal, though the labia and clitoris may be underdeveloped. Vaginal depth varies significantly in CAIS, often being shorter than average; a study of eight individuals with CAIS found the average vaginal depth to be 5.9 cm (compared to 11.1 ± 1.0 cm in unaffected women). In some extreme cases, the vagina is reported to be aplastic (resembling a "dimple"), though the exact frequency of this is unknown.

The gonads in individuals with CAIS are testes; during the embryonic stage of development, testes form through an androgen-independent process influenced by the SRY gene on the Y chromosome. They may be located intra-abdominally, at the internal inguinal ring, or may herniate into the labia majora, often leading to the condition's discovery. Testes in affected individuals have been found to be atrophic upon gonadectomy.

The testosterone produced by the testes cannot be directly utilized due to the mutant androgen receptor characteristic of CAIS; instead, it is aromatized into estrogen, which effectively feminizes the body and results in the normal female phenotype seen in CAIS. However, up to 5% of individuals with CAIS do not have an AR mutation. The receptor is encoded by the AR gene located on the X chromosome at Xq11–12. At least 15 different mutations were known in 2003, all of which are recessive, making the condition follow X-linked recessive inheritance.

Immature sperm cells in the testes do not mature beyond an early stage, as androgen sensitivity is necessary for spermatogenesis to complete. The risk of germ cell malignancy, once considered relatively high, is now thought to be approximately 2%. Wolffian structures (the epididymides, vasa deferentia, and seminal vesicles) are usually absent, but will develop at least partially in about 30% of cases, depending on the mutation causing the CAIS. The prostate, like the external male genitalia, cannot masculinize in the absence of androgen receptor function, and thus remains in the female form.

The Müllerian system typically regresses in the same manner as in unaffected male fetuses due to the anti-Müllerian hormone produced by the Sertoli cells of the testes. Therefore, individuals with CAIS, despite having a vagina due to androgen insensitivity, are born without fallopian tubes, a cervix, or a uterus, and the vagina ends in a "blind" pouch. Müllerian regression does not fully complete in some CAIS cases, leading to Müllerian "remnants". Although rare, a few cases of individuals diagnosed with CAIS having Müllerian structures have been reported. In one exceptional case, a 22-year-old with CAIS was found to have a cervix, uterus, and fallopian tubes. In an unrelated instance, an almost fully developed uterus was found in a 22-year-old adult with CAIS.

Other subtle differences reported include slightly longer limbs and larger hands and feet due to a proportionally greater stature than unaffected women, larger teeth, minimal or no acne, well developed breasts, a higher incidence of meibomian gland dysfunction (such as dry eye syndromes and light sensitivity), and dry skin and hair due to a lack of sebum production.

Endocrine

Several studies have documented hormone levels in gonadally intact individuals with CAIS. These levels are comparable to those found in males, characterized by elevated testosterone and relatively low estradiol. However, luteinizing hormone (LH) levels are higher, while sex hormone-binding globulin (SHBG) levels align more closely with those of females. Individuals with CAIS have low progesterone levels, similar to males. The production rates of testosterone, estradiol, and estrone are reported to be higher in gonadally intact individuals with CAIS than in men.

Comorbidity

All types of androgen insensitivity, including CAIS, are linked with infertility, although exceptions have been noted in mild and partial forms.

CAIS is linked to a reduction in bone mineral density. Some suggest that the reduced bone mineral density observed in women with CAIS may be related to the timing of gonadectomy and insufficient estrogen supplementation. However, recent studies indicate that bone mineral density is similar whether gonadectomy occurs before or after puberty, and remains decreased despite estrogen supplementation, suggesting that the deficiency may be directly due to the role of androgens in bone mineralization.

CAIS also carries a higher risk for gonadal tumors (e.g., germ cell malignancy) in adulthood if gonadectomy is not performed. The risk of malignant germ cell tumors in women with CAIS increases with age, estimated at 3.6% by age 25 and 33% by age 50. The occurrence of gonadal tumors in childhood is considered relatively low; a recent review of medical literature found only three cases of malignant germ cell tumors in prepubescent girls associated with CAIS in the last century. Some estimate the incidence of germ cell malignancy to be as low as 0.8% before puberty.

Vaginal hypoplasia, a common finding in CAIS and some forms of PAIS, is linked with sexual difficulties, including challenges with vaginal penetration and dyspareunia.

One study suggests that individuals with a DSD condition may be more susceptible to psychological challenges, partly due to parental attitudes and behaviors, recommending preventative long-term psychological counseling for both parents and affected individuals from the time of diagnosis.

AIS does not appear to affect lifespan.

Despite well-developed breasts in CAIS women, and for reasons not fully understood, breast cancer has never been reported in CAIS women and seems to be rare or nonexistent. Only one case of juvenile fibroadenoma has been documented. A few cases of breast cancer have been reported in individuals with partial androgen insensitivity syndrome.

Diagnosis

CAIS is typically not considered until menstruation does not occur at puberty, or an inguinal hernia appears before menarche. Up to 1–2% of prepubertal girls with an inguinal hernia may also have CAIS.

CAIS or Swyer syndrome can be diagnosed in utero by comparing a karyotype obtained through amniocentesis with the fetus's external genitalia during a prenatal ultrasound. Many infants with CAIS do not undergo the typical neonatal testosterone surge, which can be used diagnostically by measuring baseline luteinizing hormone and testosterone levels, followed by a human chorionic gonadotropin (hCG) stimulation test.

The primary differential diagnoses for CAIS include complete gonadal dysgenesis (Swyer syndrome) and Müllerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome or MRKH). Both CAIS and Swyer syndrome are linked to a 46,XY karyotype, whereas MRKH is not; MRKH can be excluded by checking for a Y chromosome, which can be done through fluorescence in situ hybridization (FISH) analysis or a full karyotype. Swyer syndrome is characterized by the presence of a uterus, underdeveloped breasts, and shorter stature. CAIS is confirmed when androgen receptor (AR) gene sequencing identifies a mutation, although up to 5% of individuals with CAIS do not have an AR mutation.

Until the 1990s, a CAIS diagnosis was often not disclosed to the affected person or their family. Currently, it is common practice to reveal the genotype at the time of diagnosis, especially when the individual is at least an adolescent. If the individual is a child or infant, the decision to disclose the diagnosis is typically made by the parents, often with the guidance of a psychologist.

Management

Currently, the management of AIS focuses on symptomatic management. There are no available methods to correct a defective androgen receptor protein caused by an AR gene mutation. Management strategies include sex assignment, genitoplasty, gonadectomy concerning tumor risk, hormone replacement therapy, as well as genetic and psychological counseling. Non-consensual interventions are still frequently performed, although awareness of the psychological trauma they may cause is increasing.

Sex assignment and sexuality

Most individuals with CAIS are raised as females. They are born with an external phenotype typical of females and are generally considered to be heterosexual with a female gender identity. However, some studies suggest that individuals with CAIS may have more diverse gender outcomes and a non-primarily heterosexual orientation compared to similar groups with MRKH syndrome and PCOS, challenging this belief. At least two case studies have noted a male gender identity in individuals with CAIS.

Dilation therapy

Most instances of vaginal hypoplasia related to CAIS can be treated with non-surgical pressure dilation techniques. The elastic nature of vaginal tissue, as shown by its capacity to adapt to the size differences between a tampon, a penis, and a baby's head, allows for dilation even when vaginal depth is significantly reduced. Treatment compliance is considered crucial for satisfactory outcomes. Dilation can also be accomplished through the Vecchietti procedure, which extends vaginal tissues into a functional vagina using a traction device anchored to the abdominal wall, subperitoneal sutures, and a mold placed against the vaginal dimple. Vaginal stretching occurs by daily increasing the tension on the sutures. The non-surgical pressure dilation method is currently recommended as the first option due to its non-invasive nature and high success rate. Vaginal dilation should not be performed before puberty.

Gonadectomy

Although it has often been advised that women with CAIS eventually undergo gonadectomy to reduce cancer risk, there are varying opinions on the necessity and timing of this procedure. The risk of malignant germ cell tumors in CAIS increases with age, estimated at 3.6% by age 25 and 33% by age 50. However, only three cases of malignant germ cell tumors in prepubescent girls with CAIS have been documented over the past century. The youngest of these was 14 years old. Individuals with CAIS naturally experience puberty through the aromatization of testosterone into estrogens. Thus, removing the gonads necessitates hormone replacement therapy. Gonadectomy is typically not advised before puberty to allow natural puberty to occur.

Some individuals with CAIS may opt for testosterone HRT instead of estrogen. Studies indicate that testosterone is at least as effective as estrogen replacement therapy and may enhance certain aspects of well-being.

If gonadectomy is done early, puberty must be induced artificially with gradually increasing doses of estrogen.

If gonadectomy is performed later, puberty will occur naturally due to the aromatization of testosterone into estrogen. At least one organization, the Australasian Paediatric Endocrine Group, considers the cancer risk in CAIS low enough to advise against gonadectomy, though it cautions that the cancer risk remains higher than in the general population, and ongoing cancer monitoring is crucial. Some choose to perform gonadectomy if an inguinal hernia occurs. Estrogen replacement therapy is vital to prevent bone mineral density deficiencies later in life.

Some individuals with CAIS may decide to keep their gonads. In this case, annual imaging of the gonads via MRI or ultrasound is recommended to monitor for malignancy. Diagnostic laparoscopy and biopsy should also be considered if imaging results are unclear.

Hormone replacement therapy

It has been suggested that higher-than-normal levels of estrogen might help mitigate the reduced bone mineral density linked to CAIS. Research has shown that women affected by CAIS who did not adhere to estrogen replacement therapy, or who experienced interruptions, faced a greater reduction in bone mineral density. Progestin replacement therapy is also rarely initiated. Androgen replacement has been noted to enhance well-being in individuals with CAIS who have undergone gonadectomy, although the exact mechanism for this benefit remains unclear.

Counseling

It is now uncommon to conceal a diagnosis of CAIS from the individual or their family. Parents of children with CAIS require significant support in planning and communicating the diagnosis to their child. For parents with young children, sharing this information is a continuous, collaborative process that needs a personalized approach, adapting as the child develops cognitively and psychologically. In all situations, consulting a psychologist with expertise in this area is advisable.

Neovaginal construction

Various surgical techniques have been created to construct a neovagina, though none are perfect. Surgical intervention should only be considered if non-surgical pressure dilation methods do not achieve satisfactory outcomes. Neovaginoplasty can be performed using skin grafts, segments of bowel, ileum, peritoneum, an absorbable adhesion barrier (Intercede, produced by Johnson & Johnson), buccal mucosa, amnion, dura mater, or with the aid of vaginal stents/expanders. The success of these methods should be evaluated based on sexual function, rather than solely on vaginal length, as was previously the case. Ileal or cecal segments may pose challenges due to a shorter mesentery, which can cause tension on the neovagina, leading to stenosis. The sigmoid neovagina is believed to be self-lubricating, without the excessive mucus production associated with small bowel segments.

Vaginoplasty may result in scarring at the introitus (the vaginal opening), necessitating further surgical correction. Vaginal dilators are needed post-surgery to prevent vaginal stenosis due to scarring. Inflatable vaginal stents are inserted deflated and then gently inflated. Other possible complications include injuries to the bladder and bowel. Annual examinations are necessary as neovaginoplasty carries a risk of carcinoma, although neovaginal carcinoma is rare. Neither neovaginoplasty nor vaginal dilation should be performed before puberty.

Prognosis

Individuals affected by this condition face challenges such as psychologically accepting the condition, issues with sexual function, and infertility. Long-term research shows that with proper medical and psychological care, those with CAIS can achieve satisfaction with their sexual function and psychosexual development. People with this condition can lead active lives and have a normal life expectancy.

Epidemiology

CAIS is estimated to occur in 1 in 20,400 to 1 in 99,000 individuals with a 46,XY karyotype.

Nomenclature

Historically, CAIS has been known by several other names in the literature, including testicular feminization [syndrome] (now outdated) and Morris syndrome. PAIS has also been called Reifenstein syndrome, which should not be confused with CAIS.