Androgen insensitivity syndrome

Synonyms

4

Overview

Androgen insensitivity syndrome (AIS) is a condition that affects sexual development before birth and during puberty. People with this condition are genetically male, with one X chromosome and one Y chromosome in each cell. Because their bodies are unable to respond to certain male sex hormones (called androgens), they may have mostly female sex characteristics or signs of both male and female sexual development.

Complete androgen insensitivity syndrome occurs when the body cannot use androgens at all. People with this form of the condition have the external sex characteristics of females, but do not have a uterus and therefore do not menstruate and are unable to conceive a child (infertile). They are typically raised as females and have a female gender identity. Affected individuals have male internal sex organs (testes) that are undescended, which means they are abnormally located in the pelvis or abdomen. Undescended testes can become cancerous later in life if they are not surgically removed. People with complete androgen insensitivity syndrome also have sparse or absent hair in the pubic area and under the arms.

The partial and mild forms of androgen insensitivity syndrome result when the body's tissues are partially sensitive to the effects of androgens. People with partial androgen insensitivity (also called Reifenstein syndrome) can have normal female sex characteristics, both male and female sex characteristics, or normal male sex characteristics. They may be raised as males or as females, and may have a male or a female gender identity. People with mild androgen insensitivity are born with male sex characteristics, but are often infertile and tend to experience breast enlargement at puberty.

Symptoms

AIS is broken down into three classes based on phenotype: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), and mild androgen insensitivity syndrome (MAIS).

A supplemental system of phenotypic grading that uses seven classes instead of the traditional three was proposed by pediatric endocrinologist Charmian A. Quigley et al. in 1995.

The first six grades of the scale, grades 1 through 6, are differentiated by the degree of genital masculinization;

grade 1 is indicated when the external genitalia is fully masculinized, grade 6 is indicated when the external genitalia is fully feminized, and grades 2 through 5 quantify four degrees of decreasingly masculinized genitalia that lie in the interim.

Grade 7 is indistinguishable from grade 6 until puberty, and is thereafter differentiated by the presence of secondary terminal hair; grade 6 is indicated when secondary terminal hair is present, whereas grade 7 is indicated when it is absent.

The Quigley scale can be used in conjunction with the traditional three classes of AIS to provide additional information regarding the degree of genital masculinization, and is particularly useful when the diagnosis is PAIS.

  • Abnormal hair quantity
  • Abnormality of female internal genitalia
  • Cryptorchidism
  • Decreased fertility
  • Male pseudohermaphroditism

Causes

Androgen insensitivity syndrome is caused by mutations in the AR gene and is inherited in an X-linked recessive pattern.

Diagnosis

The phenotypes that result from the insensitivity to androgens are not unique to AIS, and thus the diagnosis of AIS requires thorough exclusion of other causes.

Clinical findings indicative of AIS include the presence of a short vagina or undermasculinized genitalia, partial or complete regression of M├╝llerian structures, bilateral nondysplastic testes, and impaired spermatogenesis and / or virilization.

Laboratory findings include a 46,XY karyotype  and normal or elevated postpubertal testosterone, luteinizing hormone, and estradiol levels. The androgen binding activity of genital skin fibroblasts is typically diminished, although exceptions have been reported. Conversion of testosterone to dihydrotestosterone may be impaired.

The diagnosis of AIS is confirmed if androgen receptor gene sequencing reveals a mutation, although not all individuals with AIS (particularly PAIS) will have an AR mutation

Treatment

Hormone replacement therapy o HRT is the first and less complex aspect.

All patients with CAIS and most patients with all but the mildest forms of PAIS undergo gonadectomy at some point in their treatment (see Surgical Care). Adolescent and adult patients with AIS require hormone replacement.

For patients with CAIS, 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 PAIS, traditional therapy has mirrored therapy for individuals with CAIS. Patients with PAIS who have a male gender identity, however, may be treated with testosterone and/or DHT. The advantage of DHT is that it cannot be aromatized to estrogen. No medical consensus has been reached about this therapy; no dosage schedules have been established. Therapy may vary depending on the nature of the gene defect.

Resources

  • NIH
  • Genetics Home Reference