Androgen insensitivity syndrome pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

Androgen insensitivity syndrome results from mutations of the gene encoding the androgen receptor. AIS involves variable degree of undervirilization and/or infertility in genetically male person. Family history of other affected individuals related to each other in a pattern consistent with X linked inheritance. Androgen insensitivity syndrome is associated with conditions such as primary amenorrhea, infertility, and dyspareunia.

Pathophysiology

Pathogenesis

• The exact pathogenesis of [disease name] is not fully understood.

OR

• It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
• [Pathogen name] is usually transmitted via the [transmission route] route to the human host.
• Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
• [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
• The progression to [disease name] usually involves the [molecular pathway].
• The pathophysiology of [disease/malignancy] depends on the histological subtype.

Genetics

• Family history of other affected individuals related to each other in a pattern consistent with X linked inheritance. “Other affected family members” refers to:
  • Affected 46,XY individuals
  • Manifesting heterozygous females (46,XX).
• About 10% of heterozygous females have asymmetric distribution and sparse or delayed growth of pubic and/or axillary hair.
• Absence of a family history of AIS or suggestive features of AIS does not preclude the diagnosis.

• Because the Androgen Insensitivity Syndrome gives rise to ambiguity between the genetic and the phenotypic gender, we will use the convention 46,XY to designate a genotypic male, and 46,XX to designate a genotypic female. By this convention, a person with Androgen Insensitivity Syndrome is a 46,XY but a phenotypic female.

• The Androgen Insensitivity Syndrome has been linked to mutations in Androgen receptor (AR), the gene for the human Androgen receptor (AR), located at Xq11-12 (i.e. on the X chromosome). Thus, it is an X-linked recessive trait, causing minimal or no effects in 46,XX people.

• However, 46,XX women with a single mutated copy of the AR gene can be "carriers" of AIS, and their 46,XY children (male) will have a 50% chance of having the syndrome. As in some other X-linked recessive conditions, carrier mothers may display some minor traits of the condition: AIS carriers often have reduced axillary and pubic hair, and reduced normal adolescent acne.

Schematic of AIS affecting an Androgen Receptor

X-linked recessive inheritance

Associated Conditions

• Primary amenorrhea
• Infertility
• Dyspareunia

Gross Pathology

• Complete androgen insensitivity syndrome in a 30 years old woman who presented primary amenorrhea..

• 
  Front and side view of the patient
• 
  Normal female morphotype but absence of pubic and axillary hair
• 
  Clinical aspect of the vagina
• 
  Intra- abdominal testes - Laparoscopic aspect
• 
  The excised testis - Macroscopic aspect

Microscopic Pathology

• Histopathology shows two testes with atrophic seminiferous tubules containing only Sertoli cells, associated to a Leydig cells hyperplasia.
• On histological examination, the well-limited nodule circumscribed by a thin capsule consists of atrophic Servolian tubes with a very small interstitial tissue with rare Leydig cells. This nodule corresponds to a well differentiated tumor with Sertoli-Leydig cells.

• 
  Testes - Atrophy of the seminiferous tubules - Histopathological aspect, HE staining.
• 
  testicular parenchyma of lobulated architecture, made of seminiferous tubes of atrophic appearance; these tubes are lined with Sertolia cells, with no obvious signs of spermatogenesis the interstitium is fibrous with rare clusters of Leydig cells.