Androgen Insensitivity Syndrome 

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

Overview

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]

Pathophysiology

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]

Epidemiology

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.

Prognosis

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]

 

Presentation

History

The basic etiology of androgen insensitivity syndrome is a loss-of-function mutation in the AR gene.[22, 23]  Most cases of androgen insensitivity syndrome (AIS) are identified in the newborn period by the presence of inguinal masses, which later are identified as testes during surgery. Some patients are first seen in the teenage years for evaluation of primary amenorrhea. Many of these patients have a history of surgery for hernias and/or the presence of gonads in the inguinal canals, which were considered ovaries and returned to the abdomen. Adults with partial androgen insensitivity syndrome often have gynecomastia and impaired phallic growth in association with elevated circulating concentrations of testosterone, estradiol, and luteinizing hormone in puberty, while follicle-stimulating hormone levels are normal.[24]

Patients with Kennedy disease have partial androgen resistance and are often underdiagnosed or misdiagnosed as having amyotrophic lateral sclerosis.[13] They usually have gynecomastia and may develop tremor, muscle cramps, and sensory disturbances and slowly lose the ability to walk. Gynecomastia is postpubertal and men often do not have to shave daily.

Physical

In newborns with complete androgen insensitivity syndrome (CAIS), the most frequent initial finding is unilateral or bilateral masses in the inguinal canals that are found to be testes during surgery. Associated hernias may or may not be present.[25]

In adolescent patients, notable findings include inguinal masses. As with newborns, these masses may or may not be associated with hernias. In addition, adolescent patients have no pubic and axillary hair, with otherwise scanty body hair, and lack acne, although breasts are normal as a result of conversion of testosterone to estradiol. Women with complete androgen insensitivity syndrome often have reduced mean clitoral length compared with controls but are just as satisfied with sexual function as controls/healthy females.[26, 27]

Newborns with partial androgen insensitivity syndrome (PAIS) can have a highly variable genital appearance. Adolescents may have pubic hair, although usually less than normal, and may have progressive clitoral enlargement and other signs of masculinization.

Postpubertal gynecomastia is present in most patients with Kennedy disease.

 

DDx

Diagnostic Considerations

46,XY complete gonadal dysgenesis (46,XY CGD) differs from androgen insensitivity syndrome by the presence of streak gonads and functioning Müllerian structures.[28]  

There is normal production of testosterone and normal conversion to dihydrotestosterone (DHT) in androgen insensitivity syndrome, which differentiates this condition from 5-alpha reductase deficiency.   

Kennedy Disease

The diagnostic criteria of Kennedy disease (spinal and bulbar muscular atrophy [SBMA]) include progressive proximal weakness, medullary involvement, asymmetrical muscle weakness, muscle atrophy, gynecomastia, and sexual dysfunction. Polymyositis and Kennedy disease have overlapping clinical manifestations which include elevated CK levels and progressive proximal weakness. Polymyositis should be suspected in the presence of subacute to chronic symmetric proximal muscle weakness, occasional bulbar signs but no facial weakness and normal motor and sensory nerve conduction studies.[29]  

 

Differential Diagnoses

 

Workup

Laboratory Studies

The studies described below may be indicated in patients with androgen insensitivity syndrome (AIS).

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. These offer a much quicker turnaround time than conventional karyotypes.

Levels of testosterone and dihydrotestosterone (DHT) establish the presence of normal steroidogenesis. If the testosterone level is low for age, obtain levels of dehydroepiandrosterone (DHEA), androstenedione, and their precursors, 17-hydroxypregnenolone and 17-hydroxyprogesterone. These levels allow identification of errors in the steroid biosynthetic pathways. An elevated ratio of testosterone to DHT indicates a 5-alpha reductase deficiency, a possible differential for patients with partial androgen insensitivity syndrome but usually not for complete androgen insensitivity syndrome. Low levels of testosterone in the absence of evidence of defective steroidogenesis suggest testicular dysgenesis or Leydig cell aplasia/hypoplasia.

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. The analysis is performed on DNA obtained from buccal swabs. However, the testing is slow (about 6 wk for results) and expensive (not covered by some insurance companies).

For patients with Kennedy disease, an elevated testosterone level can be found in approximately 70% of cases. More than 40 CAG tandem repeats in exon 1 of the AR are diagnostic.[13]

Imaging Studies

A pelvic ultrasound examination is frequently useful. Identification of any müllerian structures, such as uterus or fallopian tubes, is inconsistent with a diagnosis of complete androgen insensitivity syndrome or partial androgen insensitivity syndrome.

Histologic Findings

Histologic examination of the testes in patients with complete androgen insensitivity syndrome or partial androgen insensitivity syndrome should show fairly normal testicular structure, although the numbers of spermatogonia and/or sperm may be reduced markedly in postpubertal patients.

Given current management recommendations, a histologic examination may be impossible to perform until the patient is in late adolescence or early adulthood.

 

Treatment

Medical Care

Medical care for a patient with androgen insensitivity syndrome (AIS) has 2 aspects: hormone replacement therapy (HRT) and psychological support.[5, 7, 8]

Hormone replacement therapy

HRT is the first and less complex aspect. All patients with complete androgen insensitivity syndrome (CAIS) and most patients with all but the mildest forms of partial androgen insensitivity syndrome (PAIS) undergo gonadectomy at some point in their treatment. Adolescent and adult patients with androgen insensitivity syndrome require hormone replacement.

For patients with complete androgen insensitivity syndrome, hormone therapy almost always consists of estrogen replacement. The general belief is that these women do not require progesterone because they have no uterus. Some evidence suggests that progesterone therapy combined with estrogen replacement may lessen the long-term risk of breast cancer, although this type of therapy is debatable. More recent meta-analyses suggest progesterone administration may have little or no advantage for patients without a uterus. Therapy usually is initiated with a low dose of estrogen alone, then is increased to routine adult dosing. Progesterone is added, if considered appropriate, after maintenance therapy with estrogen is established.

For individuals with partial androgen insensitivity syndrome, traditional therapy has mirrored therapy for individuals with complete androgen insensitivity syndrome. Patients with partial androgen insensitivity syndrome who have a male gender identity, however, may be treated with testosterone and/or dihydrotestosterone (DHT). The advantage of DHT is that it cannot be aromatized to estrogen. No medical consensus has been reached about this therapy, and no dosage schedules have been established. Therapy may vary depending on the nature of the gene defect.[30]

Patients with Kennedy disease cannot receive causal therapy. Trials have been done with testosterone replacement. Animal data suggest worsening of the neurologic symptoms, but this has not yet been confirmed in humans. In this context, nongenomic testosterone effects have to be considered.[31]

Psychological support

Psychological support is probably the most important aspect of medical care from the patient's point of view. In a family with an affected infant, the parents are the primary clients. Parents need genetic counseling to understand the nature of the condition and the risk of recurrence (25% for each subsequent pregnancy), as well as to identify other potential carriers. In addition, parents often benefit from the services of a pediatric psychologist or child and adolescent psychiatrist to help adjust to their child's condition, including support on how to inform the child, over time and in an age-appropriate manner, about the condition. Genetic counselors do not provide this type of ongoing family support.

In a family with an affected older child, the patient is the primary client, although family members also may require psychological services. In these cases, too, pediatric psychologists or child and adolescent psychiatrists are the preferred clinicians because of their medical background and ability to help address medical, emotional, and psychological issues or questions. If at all possible, the therapist also should have experience dealing with patients who have intersex conditions, even if this experience is not specific to androgen insensitivity syndrome. The patient needs to establish a long-term relationship with the therapist to discuss new issues that arise as the child matures. (At times, these visits will be infrequent.) For adults with androgen insensitivity syndrome and other intersex conditions, lack of emotional and psychological support has been a major criticism of the medical care system.

The primary care practitioner can coordinate medical care for a child with androgen insensitivity syndrome, or coordination may be performed by a pediatric endocrinologist, especially as part of a multidisciplinary team. Carefully maintain communication and coordination among primary care, genetic, endocrinologic, and surgical services to avoid trauma to the child and family.

Contact with other individuals who have androgen insensitivity syndrome is another source of psychological and emotional support for the patient. The Androgen Insensitivity Syndrome Support Group (AISSG) has constituent organizations in the United States, United Kingdom, and Australia, as well as contacts and/or smaller groups in many European countries. AISSG maintains an excellent Web site at www.aissg.org that provides a large amount of medical information, AISSG contact points, and patients' accounts of their experiences with AIS. This type of contact can markedly decrease feelings of "freakishness" and "being the only one," which patients and families frequently experience.

Surgical Care

For individuals with androgen insensitivity syndrome, the standard of care is an orchidectomy to prevent possible malignant degeneration of the testes.[9] The timing of such surgery has been debated. The finding of the majority of tumors in the postpubertal age group argues for later surgery,[32] while the treatment of associated inguinal hernia and psychological issues related to the gonad may warrant prepubertal surgery. Later orchidectomy allows pubertal development to occur spontaneously with the production of estrogen from the aromatization of the high levels of testosterone normally produced. The advantage of natural hormone production by the testes aiding in development of secondary sex characteristics is theorized though not substantiated by research trials.[18]  

Low bone mineral density (BMD) has been reported in complete androgen insensitivity syndrome (AIS), but the impact of timing of gonadectomy is not known. In a retrospective analysis of pre- and post-gonadectomy parameters in 113 women with complete AIS, no relationship between age of gonadectomy and BMD was found, nor was a drop in BMD seen during follow-up after gonadectomy.[33]

In addition, many women with androgen insensitivity syndrome require vaginal lengthening procedures. Orchidectomy and vaginal lengthening procedures may be performed concurrently if surgery is postponed until the patient matures. Ultrasound examination of the gonads can monitor potential tumor development.

Vaginal lengthening procedures have stirred ongoing debate. In the past, many vaginal lengthening procedures were performed before or at onset of puberty. Many patient advocates now support delaying these procedures until the patient is sufficiently mature to participate actively in treatment decisions (ie, whether to undergo surgery, what type of procedure).

Similarly, in female gender patients with partial androgen insensitivity syndrome who have some degree of masculinization of the genitalia at birth, cosmetic reconstructive surgery traditionally has been performed in infancy. Patient advocates, including medical ethicists and intersex advocates, now endorse delaying this reconstructive surgery until children are old enough to decide for themselves. Medical practice and court decisions appear to be moving in this direction as the new standard of care.

Consultations

Initial consultation for the child with androgen insensitivity syndrome should include a geneticist and a pediatric endocrinologist. These individuals order and interpret the tests required to confirm the diagnosis. Additionally, these clinicians can provide appropriate information about the child's condition. An endocrinologist helps set the future course for medical and surgical therapy.

Because this is a particularly stressful diagnostic possibility for many families, consult an appropriate mental health professional to provide psychological and emotional support. Part of the mental health professional's role is to facilitate communication between the medical team and the family.

Complications

Osteoporosis and psychological sequelae are the 2 major complications of androgen insensitivity syndrome, and their risk can be decreased significantly by appropriate therapeutic intervention. These interventions involve HRT with estrogen to prevent osteoporosis and early and continuing involvement with an appropriate mental health professional for psychological and emotional support.

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%. 

Prevention

Androgen insensitivity syndrome prevention revolves around the identification of women who may carry the gene. Provide appropriate nondirective counseling, including information about the condition and the woman's risk of having an affected child, so that she can make an informed decision about whether to have children.

 

Medication

Medication Summary

Hormone replacement therapy (HRT) with estrogens has been the standard of practice for postorchidectomy patients with androgen insensitivity syndrome (AIS). Although most physicians prescribe estrogen alone, some physicians have begun adding progesterone to the regimen, based upon a relatively small amount of data that suggests progesterone may lower the risk of breast cancer, have a role in the ductal development of the breast, or have some role in bone mineral accretion. (These potential benefits are hypothetical.)

Administration of androgens in more masculinized patients with partial androgen insensitivity syndrome (PAIS) has been suggested but remains highly controversial. Because some patients now are assigned male gender and are identifying as males in adulthood, this treatment probably will be described more extensively soon. No data currently describe dosage, administration, benefits, or adverse effects of androgen administration to patients with androgen insensitivity syndrome. Dosage and response likely depends on the severity of the receptor defect. Dihydrotestosterone (DHT) or androgen analogues that cannot be aromatized to estrogen appear to be the treatments of choice.

Estrogens

Class Summary

These agents are used as hormone replacement for women with androgen insensitivity syndrome who are postgonadectomy to support development and maintenance of secondary sexual characteristics and to prevent osteoporosis.

Conjugated estrogens (Premarin)

Conjugated estrogens represent the average composition of estrogens in pregnant mare urine. They are composed of estrone, equilin, 17-alpha estradiol, equilenin, and 17-alpha dihydroequilenin (in small amount). It is rapidly biotransformed after administration.