Androgen insensitivity syndrome pathophysiology: Difference between revisions

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Revision as of 15:24, 23 August 2017

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: ^[1]
- 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

Associated Conditions

Gross Pathology

Complete androgen insensitivity syndrome in a 30 years old woman who presented primary amenorrhea.^[2]. ^[3]

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.^[3]
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. ^[2]

Testes - Atrophy of the seminiferous tubules - Histopathological aspect, HE staining.^[2]
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.^[3]

References

↑ Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean L, Bird TD, Ledbetter N, Mefford HC, Smith R, Stephens K, Gottlieb B, Trifiro MA. PMID 20301602. Vancouver style error: initials (help); Missing or empty |title= (help)
↑ ^2.0 ^2.1 ^2.2 Souhail R, Amine S, Nadia A, Tarik K, Khalid EK, Abdellatif K, Ahmed A (2016). "Complete androgen insensitivity syndrome or testicular feminization: review of literature based on a case report". Pan Afr Med J. 25: 199. doi:10.11604/pamj.2016.25.199.10758. PMC 5326263. PMID 28270903.
↑ ^3.0 ^3.1 ^3.2 Lachiri B, Hakimi I, Boudhas A, Guelzim K, Kouach J, Oukabli M, Rahali DM, Dehayni M (2015). "[Complete androgen insensitivity syndrome: report of two cases and review of literature]". Pan Afr Med J (in French). 20: 400. doi:10.11604/pamj.2015.20.400.6760. PMC 4524922. PMID 26301004.

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[pmid20301602-1] Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean L, Bird TD, Ledbetter N, Mefford HC, Smith R, Stephens K, Gottlieb B, Trifiro MA. PMID 20301602. Vancouver style error: initials (help); Missing or empty |title= (help)

[pmid28270903-2] 2.0 ^2.1 ^2.2 Souhail R, Amine S, Nadia A, Tarik K, Khalid EK, Abdellatif K, Ahmed A (2016). "Complete androgen insensitivity syndrome or testicular feminization: review of literature based on a case report". Pan Afr Med J. 25: 199. doi:10.11604/pamj.2016.25.199.10758. PMC 5326263. PMID 28270903.

[pmid26301004-3] 3.0 ^3.1 ^3.2 Lachiri B, Hakimi I, Boudhas A, Guelzim K, Kouach J, Oukabli M, Rahali DM, Dehayni M (2015). "[Complete androgen insensitivity syndrome: report of two cases and review of literature]". Pan Afr Med J (in French). 20: 400. doi:10.11604/pamj.2015.20.400.6760. PMC 4524922. PMID 26301004.

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[2]

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@@ Line 7: / Line 7: @@
 ==Pathophysiology==
-*Androgen insensitivity syndrome results from [[mutation]]s of the gene encoding the [[androgen]] [[receptor (biochemistry)|receptor]]. It has also been called androgen resistance in the medical literature.
+===Pathogenesis===
-*The nature of the resulting problem varies according to the structure and sensitivity of the abnormal receptor.
+*The exact pathogenesis of [disease name] is not fully understood.
-*Most of the forms of AIS involve variable degrees of [[virilization|undervirilization]] and/or [[infertility]] in [[XY sex-determination system|XY]] persons of either sex. A woman with complete androgen insensitivity syndrome (CAIS) has a nearly normal female body despite a 46XY [[karyotype]] and undescended  [[testis|testes]], a condition termed [[testicular feminization]] in the past.
+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].
-===Early developmental/embryological aspect===
+*[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
-*In 8th to 10th week of gestation, male gonads start to produce [[testosterone]], [[dihydrotestosterone]]([[Dihydrotestosterone|DHT]]), and [[Mullerian inhibiting factor deficiency|Mullerian inhibiting factor]](MIF), the hormones important for the male development.
+*Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
-*Normal production of the hormone levels occurs, but improper functioning of [[androgen receptors]] for [[testosterone]] and [[dihydrotestosterone]]([[Dihydrotestosterone|DHT]]) is observed.
+*[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
-*Concurrently, when exposed to the [[Anti-Müllerian hormone|Mullerian inhibiting factor]], it causes internal male development, while unopposed [[testicular]] [[estrogen]] results in the development of external [[female genitalia]].
+*The progression to [disease name] usually involves the [molecular pathway].
+*The pathophysiology of [disease/malignancy] depends on the histological subtype.
-====Prenatal effects of testosterone in 46,XY fetus====
-*In a normal fetus with a [[46,XY]] karyotype, the presence of the [[SRY]] gene induces testes to form on the [[genital ridge]]s in the fetal [[abdomen]] a few weeks after [[conception]]. By 6 weeks of gestation, [[genitalia|genital]] anatomies of XY and XX fetuses are still indistinguishable, consisting of a tiny underdeveloped [[genital tubercle|button]] of tissue able to become a [[Phallus (embryology)|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 [[Dihydrotestosterone|DHT]], [[testosterone]] acts on the skin and tissues of the genital area and by 12 weeks of [[gestation]], has produced a recognizable male, with a growing [[penis]] with a [[urethra]]l 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 [[Dihydrotestosterone|DHT]] is continued growth of the penis and internal [[wolffian ducts|wolffian]] derivatives (part of [[prostate]], [[epididymis]], [[seminal vesicle]]s, and [[vas deferens]]).
-====Early postnatal effects of testosterone in 46,XY infants====
-*[[Testosterone]] levels are low at birth but rise within weeks, remaining at normal male [[puberty|pubertal]] levels for about 2 months before declining to the low, barely detectable childhood levels. The biological function of this rise is unknown. Animal research suggests a contribution to brain differentiation.
-====Pubertal effects of testosterone in 46,XY children====
-*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]], [[Underarm 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, [[epiphysis|epiphyseal closure]], termination of growth, and (if it occurs) [[gynecomastia]].
 ===Genetics===