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Androgen insensitivity syndrome (AIS) is a set of disorders of sexual differentiation that results from mutations of the gene encoding the androgen receptor. It has also been called androgen resistance in the medical literature. The nature of the resulting problem varies according to the structure and sensitivity of the abnormal receptor. Most of the forms of AIS involve variable degrees of undervirilization and/or infertility in XY persons of either sex. A woman with complete androgen insensitivity syndrome (CAIS) has a nearly normal female body despite a 46XY karyotype and testes, a condition termed testicular feminization in the past.
Major changes in the understanding and management of the various forms of AIS have occurred since 1990. Laboratory research has greatly expanded our understanding of the molecular mechanisms of the clinical features, including a rare neuromuscular disorder. More importantly, patient advocacy groups for AIS and other intersex conditions have increased public awareness of these disorders, helped revise our understanding of gender identity, emphasized the value of accurate and sophisticated information for patients, and induced physicians to re-evaluate the effectiveness of the surgical corrections attempted in past decades. Surgery is increasingly seen as a very elective option even for the more ambiguous conditions.
The gene, AR, for the human androgen receptor is located within the Xq11-12 area of the X chromosome. Effects of the AIS mutations behave as sex-linked recessive traits, causing no effects in 46,XX women. In other words, since 46,XX women have two X chromosomes, and hence two copies of the gene for the androgen receptor, no problems occur if one of the genes is defective. Since a 46,XY person has only a single X chromosome, a mutation of the single androgen receptor gene may cause a problem if it produces a receptor with reduced ability to respond to androgens.
Except in the rare instance of a new mutation, a 46,XY person affected with AIS has inherited his/her single X chromosome with the defective gene from his/her mother, who may have an affected sibling. Generally the condition caused by a familial mutation will affect family members similarly, though differing degrees of severity occasionally occur in different relatives with apparently the same mutation. Carrier testing is now available for relatives at risk when a diagnosis of AIS is made in a family member.
Over 100 AR mutations causing various forms of AIS have been reported. In general, the milder types of AIS (4 and 5 in the list below) are caused by simple missense mutations with single codon/single amino acid difference, while CAIS and the nearly complete forms result from mutations that more severely affect the shape and structure of the protein. About one third of cases of AIS are new mutations rather than familial. A single case of CAIS attributed to an abnormality of the AF-1 coactivator (rather than AR itself) has been reported (OMIM 300274).
Incidence of complete AIS is about in 1 in 20,000. The incidence of milder degrees may be lower but is not well established because of greater ascertainment uncertainty.
Understanding the effects of androgen insensitivity begins with an understanding of the normal effects of testosterone in male and female development. The principal mammalian androgens are testosterone and its more potent metabolite, dihydrotestosterone (DHT).
The androgen receptor (AR) is a large protein of at least 910 amino acids. Each molecule consists of a portion which binds the androgen, a zinc-finger portion that binds to DNA in steroid sensitive areas of nuclear chromatin, and an area that controls transcription.
Testosterone diffuses from the circulation into the cytoplasm of a target cell. Some is metabolized to estradiol, some reduced to DHT, and some remains as testosterone (T). Both T and DHT can bind and activate the androgen receptor, though DHT does so with more potent and prolonged effect. As DHT (or T) binds to the receptor, a portion of the protein is cleaved. The AR-DHT combination dimerizes by combining with a second AR-DHT, both are phosphorylated, and the entire complex moves into the nucleus and binds to androgen response elements on the promoter region of androgen-sensitive target genes. The transcription effect is amplified or inhibited by coactivators or corepressors.
Although testosterone can be produced directedly and indirectly from ovaries and adrenals later in life, the primary source of testosterone in early fetal life is the testes, and it plays a major role in human sexual differentiation. Before birth, testosterone induces the primary sex characteristics of males. At puberty, testosterone is primarily responsible for the secondary sex characteristics of males.
In a normal fetus with a 46,XY karyotype, the presence of the SRY gene induces testes to form on the genital ridges in the fetal abdomen a few weeks after conception. By 6 weeks of gestation, genital anatomies of XY and XX fetuses are still indistinguishable, consisting of a tiny underdeveloped button of tissue able to become a phallus, and a urogenital midline opening flanked by folds of skin able to become either labia or scrotum. By the 7th week, fetal testes begin to produce testosterone and release it into the blood.
Directly and as DHT, testosterone acts on the skin and tissues of the genital area and by 12 weeks of gestation, has produced a recognizable little boy, with a growing penis with a urethral opening at the tip, and a perineum fused and thinned into a scrotum, ready for the testes. Evidence suggests that this "remodelling" of the genitalia can only occur during this period of fetal life; if not complete by about 13 weeks, no amount of testosterone later will move the urethral opening or close a vagina-like opening.
For the remainder of gestation the principal known effect of testosterone and DHT is continued growth of the penis and internal wolffian derivatives (part of prostate, epidydimis, seminal vesicles, vas).
Testosterone levels are low at birth but rise within weeks, remaining at normal male pubertal levels for about 2 months before declining to the low, barely detectable childhood levels. We do not know the biological function of this rise. Animal research suggests a contribution to brain differentiation.
At puberty, many of the early physical changes in both sexes are androgenic (adult-type body odor, increased oiliness of skin and hair, acne, pubic hair, axillary hair, fine upper lip and sideburn hair).
As puberty progresses, later secondary sex characteristics in males are nearly entirely due to androgens (continued growth of the penis, maturation of spermatogenic tissue and fertility, beard, deeper voice, masculine jaw and musculature, body hair, heavier bones). In males, the major pubertal changes attributable to estradiol are growth acceleration, epiphyseal closure, termination of growth, and (if it occurs) gynecomastia.
Although many distinct mutations have been discovered, the clinical manifestations have been divided into six phenotypes, which roughly correspond to increasing amounts of androgen effect due to increasing tissue responsiveness. It should be emphasized that the disorders of androgen sensitivity represent a spectrum rather than 6 discrete diseases, and some affected persons will have features that fall between the phenotypes described.
1. Complete AIS (CAIS): completely female body except no uterus; testes in the abdomen; minimal androgenic hair at puberty. OMIM .
2. Partial or incomplete AIS (PAIS): female body, with slightly virilized genitalia; testes in the abdomen; sparse to normal androgenic hair. Variant of OMIM .
3. Reifenstein syndrome: obviously ambiguous genitalia; small testes may be in abdomen or scrotum; sparse to normal androgenic hair; gynecomastia at puberty. OMIM .
4. Infertile male syndrome: normal male body internally and externally; normal virilization and androgenic hair; reduced sperm production; reduced fertility. OMIM .
5. Undervirilized fertile male syndrome: male internal and external genitalia with small penis; testes in scrotum; normal androgenic hair; sperm count and fertility normal or reduced. Variant of OMIM .
6. X-linked spinal and bulbar muscular atrophy: normal or nearly normal male body and fertility; exaggerated adolescent gynecomastia; adult onset degenerative muscle disease. OMIM .
OMIM numbers are a genetic disease classification system available at (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM)
People with CAIS are girls or women with internal testes, 46,XY karyotypes, and normal female bodies except for shallow vaginas and lack of ovaries, uterus, menses or fertility. Gender identity is female.
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 antimullerian hormone (AMH) by the testes, and suppression of mullerian 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. 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 normal girl, with no reason to suspect an incongruous karyotype, male testosterone level, and 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 closer to the average time of male puberty, slightly later than her friends. As the hypothalamus and pituitary signal the testes to produce testosterone, male amounts begin to appear in the blood. Some of the testosterone is converted (as normally occurs in boys) 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, though no teenage girl ever complains of this to her doctor. Acne is rare as well.
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 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 normal 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 (approximately male height), primarily because of their later timing of puberty. Breast development is said to be average to above average. Lack of responsiveness to androgen prevents even normal 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 normally before puberty if not removed, the testes in adults with CAIS become increasingly abnormal, with abnormal spermatogenic cells and no spermatogenesis.
By clinical reports and information from support groups, women with CAIS are at least as likely as those in the general population to feel a normal female gender identity and to be attracted sexually to men.
Most cases of CAIS are diagnosed in the following circumstances.
Accurate, sensitive explanation
Counseling, referral to support network
Vaginal enlargement
Gonadectomy decision
Estrogen replacement
When a person is diagnosed with CAIS or PAIS, referral to a genetic counselor may be warranted to explain the implications of the X-linked recessive inheritance.
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.
Whether called CAIS or testicular feminization, this condition intrigues the imagination when people first learn of it. Inevitably, when CAIS is discussed or taught, someone will mention that they have heard from a reliable source that insert name of voluptuous female movie star or celebrity has AIS, as if offering some titillating scandal or memorable illustration. Lack of corroborative evidence never stops a good rumor. Experience learns that the names change with the decades, but not the story. The Talk page for this article provides an unplanned but perfect example.
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 impolite or impolitic.
As with CAIS, girls and women with PAIS also have a 46,XY karyotype, testes, and a female body lacking a uterus, ovaries and full vagina. However, the mutations associated with PAIS do not entirely eliminate all responsiveness to androgens, and mild testosterone effects occur.
The most obvious testosterone effect seen in PAIS is pubic and axillary hair, which are usually normal. The clitoris may be enlarged, and the labia partially fused, though these features are usually not pronounced enough to cause noticeable ambiguity of the genitalia at birth, or may be subtle enough to be ascribed to normal anatomic variation. Internally, traces of undeveloped wolffian structures (epididymis, vas deferens, seminal vesicles, ejaculatory ducts) may be present.
Circumstances of diagosis tend to be similar to those listed for CAIS, with the additional possibility that the mild differences of genital structure may elicit evaluation.
Management issues for PAIS are virtually the same as for CAIS. Most women with PAIS do not seek genital reconstructive surgery for anatomic differences.
In a biological sense, all other conditions (2,3,4,5,6) resulting from any degree of reduced but not absent androgen sensitivity might accurately be termed "partial" or "incomplete" AIS. However, it was not understood until the 1980s that Reifenstein syndrome and the other male problems described below were also due to androgen receptor mutations, and the term incomplete or partial androgen insensitivity syndrome (PAIS) had already been used for decades for the condition "almost" like CAIS.
Androgen receptor mutations associated with more intermediate degrees of androgen responsiveness can result in more intermediate degrees of masculinization before birth and obvious ambiguity of the genitalia. Of the five clinical forms of AIS described here, this is the only one likely to result in uncertainty about a baby's sex at birth, and the most likely to be diagnosed in infancy. The clinical diagnostic and management problems are those common to many other intersex disorders. Puberty can produce secondary sex characteristics of both sexes, though not fertility as the spermatogenic tissue requires androgen support as well as scrotal location. The amounts of androgenic body hair and breast development are variable.
As described above, the testes of a 46,XY fetus produce AMH and testosterone. In Reifenstein syndrome, as in CAIS, PAIS, and normal males, the AMH suppresses development of a uterus, fallopian tubes, and upper vagina. However, unlike CAIS and PAIS, fetal testosterone has a significant effect on the external genitalia, producing a phallus smaller than a typical penis but larger than a typical clitoris. The labioscrotal folds are almost but not completely fused in the midline of the perineum, producing a small perineal pouch termed a "pseudovagina". Instead of being on the tip of the phallus, the urethra remains in this pseudovagina of the perineum (a position termed a 3rd degree hypospadias). The labioscrotal skin flanking the pseudovagina remains less prominent than labia but less thinned, rugated, and fused than a scrotum. The testes usually remain in the abdomen but occasionally can be felt in the inguinal canal. This genital configuration has traditionally been referred to as a pseudovaginal perineoscrotal hypospadias (PPSH) and can occur in other intersex conditions.
Variants of Reifenstein syndrome occur with greater or less androgen sensitivity and correspondingly more or less genital masculinization. The common feature is that they have enough ambiguity that they are not simply assumed to be normal female infants, as is usual in CAIS and PAIS.
This most obvious birth defect, somewhat midway between male and female, nearly always leads to referral to a pediatric endocrinologist and a full genetic, anatomic, and hormonal evaluation.
Evaluation of neonatal ambiguity is described in more detail in the intersex article. It typically consists of pelvic ultrasound to determine presence or absence of uterus and gonads, karyotype, and measurement of testosterone, DHT, AMH, and one or more adrenal steroids.
Commercial androgen receptor assays have recently become available:
AIS is one of the more common forms of male undervirilization. Even after absence of the uterus and a 46,XY karyotype have been demonstrated, a number of other conditions, including Leydig cell hypoplasia, several uncommon defects of testosterone synthesis, and 5α-reductase deficiency which can produce similar genital anatomy must be excluded.
One of the most important aspects of evaluation of suspected AIS is the potential tissue responsiveness to testosterone, since future growth of the penis and other male secondary sex characteristics are dependent on it. After one or more injections of testosterone are given to the infant, measurable growth of the penis and noticeably increased erection frequency over the next two weeks suggests (though not infallibly) a capacity for further growth and virilization at puberty.
The first major management decision is the sex of assignment: will the baby be a boy or girl? Assignment depends partly on predicting likely pubertal development, potential response of the phallus to testosterone, and likely outcome of surgical reconstruction attempts. The Reifenstein form of AIS can present one of the most challenging sets of decisions imaginable as parents and physicians try to choose the "least bad" of several undesirable options.
Over the last 40-50 years, the second path, female assignment with reconstructive surgery in infancy, has been the course most often chosen by parents and physicians, and the hazards of this course are most familiar. Since 1997, male assignment with early surgery is increasing in popularity, and even the third course of delaying surgery is sometimes followed. Advantages and disadvantages of this course will become apparent over the next two decades. See the intersex article for more detail on this important management shift.
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.
Androgen receptor mutations have also been discovered in men with normal internal and external genitalia but infertility due to absence of sperm (azoospermia). Androgenic body hair is normal and gynecomastia uncommon. Some have mildly elevated testosterone and LH levels but this is not invariable. Several surveys suggest that androgen receptor mutations can be found in 30-40% of men with infertility due to otherwise unexplained oligospermia or azoospermia. AIS may also explain most cases of a rarer form of male infertility, the Del Castillo or Sertoli-cell-only syndrome.
Some AR mutations with mildly reduced sensitivity cause mild undervirilization. These men have normally formed internal and external genitalia but a small penis. Androgenic body hair may be sparser than unaffected relatives. Ejaculate volume may be reduced, though sperm density is normal. Few examples of this variant of AIS have been reported, but unlike the previously listed phenotypes, many of these men are fertile.
Kennedy disease is an X-linked spinal-bulbar muscle atrophy syndrome associated with mutations of the androgen receptor.
Since the neuromuscular disease was first described in 1968 many kindreds have been reported. Ages of onset and severity of manifestations in affected males vary from adolescence to old age, but most commonly develop in middle adult life. Early signs often include weakness of tongue and mouth muscles, fasciculations, and gradually increasing weakness of proximal limb muscles. In some cases, premature muscle exhaustion began in adolescence. Neuromuscular management is supportive, and the disease progresses very slowly and often does not lead to extreme disability.
Endocrine manifestations of this disorder are variable and rarely include underdevelopment of internal or external genitalia. Fertility has been normal in most. However, exaggerated and persistent adolescent gynecomastia is common, and many affected men have the mildly high LH, testosterone, and estradiol levels characteristic of AIS.
The distinctive AR mutation, 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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