Androgen Insensitivity Syndrome Treatment & Management

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.

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.

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.

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%. 

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.