Androgen insensitivity syndrome pathophysiology: Difference between revisions

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__NOTOC__
__NOTOC__
{{Androgen insensitivity syndrome}}
{{Androgen insensitivity syndrome}}
{{CMG}}; {{AE}}
{{CMG}}; {{AE}} {{ARK}}


==Overview==
==Overview==
Androgen insensitivity syndrome results from [[mutations]] of the gene encoding the [[Androgen receptors|androgen receptor]]. AIS involves variable degree of [[undervirilization]] and/or [[infertility]] in genetically male person.
Androgen insensitivity syndrome is due to [[hormone]] resistance which may be due to defective [[androgen receptor]] ([[Androgen receptor|AR]]) function by either abnormal [[androgen receptor]] ([[Androgen receptor|AR]]) binding, decreased receptor binding, or impaired [[androgen receptor]] ([[Androgen receptor|AR]]) binding. AIS is an [[X linked]] disorder. The development of androgen insensitivity syndrome is a result of [[genetic mutations]] of the [[androgen receptor]] ([[Androgen receptor|AR]]) gene located on the chromosome Xq11-12. Associated conditions include [[primary amenorrhea]], [[infertility]] and [[dyspareunia]].


==Pathophysiology==
==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.
*Androgen resistance may develop during fetal development and after birth.
*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.
*The hormone resistance may be due to defective [[androgen receptor]] ([[Androgen receptor|AR]]) function by either abnormal [[androgen receptor]] ([[Androgen receptor|AR]]) binding, decreased receptor binding, or impaired [[androgen receptor]] ([[Androgen receptor|AR]])  binding. <ref name="FlierUnderhill1992">{{cite journal|last1=Flier|first1=Jeffrey S.|last2=Underhill|first2=Lisa H.|last3=Griffin|first3=James E.|title=Androgen Resistance — The Clinical and Molecular Spectrum|journal=New England Journal of Medicine|volume=326|issue=9|year=1992|pages=611–618|issn=0028-4793|doi=10.1056/NEJM199202273260906}}</ref><ref name="BrownMaes1982">{{cite journal|last1=Brown|first1=Terry R.|last2=Maes|first2=Marc|last3=Rothwell|first3=Stephen W.|last4=Migeon|first4=Claude J.|title=Human Complete Androgen Insensitivity with Normal Dihydrotestosterone Receptor Binding Capacity in Cultured Genital Skin Fibroblasts: Evidence for a Qualitative Abnormality of the Receptor*|journal=The Journal of Clinical Endocrinology & Metabolism|volume=55|issue=1|year=1982|pages=61–69|issn=0021-972X|doi=10.1210/jcem-55-1-61}}</ref><ref name="Griffin1979">{{cite journal|last1=Griffin|first1=James E.|title=Testicular Feminization Associated with a Thermolabile Androgen Receptor in Cultured Human Fibroblasts|journal=Journal of Clinical Investigation|volume=64|issue=6|year=1979|pages=1624–1631|issn=0021-9738|doi=10.1172/JCI109624}}</ref>
*A spectrum of [[phenotypes]] may be caused due to [[missense mutations]] in the [[androgen receptor]] ([[Androgen receptor|AR]]) [[protein]]. The two important domains of the [[receptor protein]] namely DBD and LDB domains are the ones wherein the most frequent [[missense mutations]] are found.<ref name="pmid24339553">{{cite journal |vauthors=Kota SK, Gayatri K, Kota SK, Jammula S |title=Genetic analysis of a family with complete androgen insensitivity syndrome |journal=Indian J Hum Genet |volume=19 |issue=3 |pages=355–7 |year=2013 |pmid=24339553 |pmc=3841565 |doi=10.4103/0971-6866.120820 |url=}}</ref><ref name="pmid2626022">{{cite journal |vauthors=Brinkmann AO, Faber PW, van Rooij HC, Kuiper GG, Ris C, Klaassen P, van der Korput JA, Voorhorst MM, van Laar JH, Mulder E |title=The human androgen receptor: domain structure, genomic organization and regulation of expression |journal=J. Steroid Biochem. |volume=34 |issue=1-6 |pages=307–10 |year=1989 |pmid=2626022 |doi= |url=}}</ref>
*The [[phenotype|phenotypic]] variability impacts and translates the degree to which ligand-binding and [[receptor]] functions are disrupted by different substitutions.<ref name="pmid24339553">{{cite journal |vauthors=Kota SK, Gayatri K, Kota SK, Jammula S |title=Genetic analysis of a family with complete androgen insensitivity syndrome |journal=Indian J Hum Genet |volume=19 |issue=3 |pages=355–7 |year=2013 |pmid=24339553 |pmc=3841565 |doi=10.4103/0971-6866.120820 |url=}}</ref><ref name="pmid1752359">{{cite journal |vauthors=McPhaul MJ, Marcelli M, Tilley WD, Griffin JE, Wilson JD |title=Androgen resistance caused by mutations in the androgen receptor gene |journal=FASEB J. |volume=5 |issue=14 |pages=2910–5 |year=1991 |pmid=1752359 |doi= |url=}}</ref>
*The genetic background has an influence on the resulting [[phenotype]] as a result of the same [[mutation]] which may lead to different forms of AIS within a family.<ref name="pmid24339553">{{cite journal |vauthors=Kota SK, Gayatri K, Kota SK, Jammula S |title=Genetic analysis of a family with complete androgen insensitivity syndrome |journal=Indian J Hum Genet |volume=19 |issue=3 |pages=355–7 |year=2013 |pmid=24339553 |pmc=3841565 |doi=10.4103/0971-6866.120820 |url=}}</ref><ref name="pmid9245853">{{cite journal |vauthors=Evans BA, Hughes IA, Bevan CL, Patterson MN, Gregory JW |title=Phenotypic diversity in siblings with partial androgen insensitivity syndrome |journal=Arch. Dis. Child. |volume=76 |issue=6 |pages=529–31 |year=1997 |pmid=9245853 |pmc=1717223 |doi= |url=}}</ref>
*Mutations in the [[androgen receptor]] ([[Androgen receptor|AR]]) gene helps as a trusted tool for the diagnosis and molecular subclassification of AIS. The resulting [[phenotype]] is affected by the kind of amino acid substitution occurring due to [[mutation]].<ref name="pmid24339553">{{cite journal |vauthors=Kota SK, Gayatri K, Kota SK, Jammula S |title=Genetic analysis of a family with complete androgen insensitivity syndrome |journal=Indian J Hum Genet |volume=19 |issue=3 |pages=355–7 |year=2013 |pmid=24339553 |pmc=3841565 |doi=10.4103/0971-6866.120820 |url=}}</ref>
*Information regarding the mutation in the [[androgen receptor]] ([[Androgen receptor|AR]]) and its functional consequences helps in determining the genotype-phenotype correlation, to improve and better manage the cases of male [[pseudohermaphroditism]] pertaining to surgery of the [[genitalia]], gonadectomy and gender assignment. <ref name="pmid24339553">{{cite journal |vauthors=Kota SK, Gayatri K, Kota SK, Jammula S |title=Genetic analysis of a family with complete androgen insensitivity syndrome |journal=Indian J Hum Genet |volume=19 |issue=3 |pages=355–7 |year=2013 |pmid=24339553 |pmc=3841565 |doi=10.4103/0971-6866.120820 |url=}}</ref>
*The lack of virilization of external genitalia is due to the failure of genital folds to fuse and to form [[scrotum]] and [[penis]].
*The agenesis of the [[fallopian tubes]], [[uterus]], [[cervix]] and proximal [[vagina]] is due to the simultaneous [[testicular]] production of [[mullerian inhibiting factor]] which regresses the mullerian structures.
*In CAIS (complete androgen insensitivity syndrome), the development of the [[wolffian duct]] and the differentiation of male external [[genitalia]] do not occur correctly, and the [[Mullerian ducts]] regress due to the presence of anti-Mullerian hormone (AMH) produced by the [[sertoli cells]] of normally developed [[gonads]]. The residual [[Mullerian structures]] exist in approximately one third of patients. <ref name="pmid18930210">{{cite journal |vauthors=Nichols JL, Bieber EJ, Gell JS |title=Case of sisters with complete androgen insensitivity syndrome and discordant Müllerian remnants |journal=Fertil. Steril. |volume=91 |issue=3 |pages=932.e15–8 |year=2009 |pmid=18930210 |doi=10.1016/j.fertnstert.2008.09.027 |url=}}</ref> <ref name="pmid25191030">{{cite journal |vauthors=Ozdemir O, Sari ME, Akmut E, Selimova V, Unal T, Atalay CR |title=Complete androgen insensitivity syndrome with a large gonadal serous papillary cystadenofibroma |journal=J Hum Reprod Sci |volume=7 |issue=2 |pages=148–50 |year=2014 |pmid=25191030 |pmc=4150143 |doi=10.4103/0974-1208.138875 |url=}}</ref>
*The female [[phenotype]] along with [[breast]] development is a result of the peripheral [[aromatization]] of [[testosterone]] into [[estrogen]].<ref name="pmid17161333">{{cite journal |vauthors=Hughes IA, Deeb A |title=Androgen resistance |journal=Best Pract. Res. Clin. Endocrinol. Metab. |volume=20 |issue=4 |pages=577–98 |year=2006 |pmid=17161333 |doi=10.1016/j.beem.2006.11.003 |url=}}</ref>
*As a result of the defective [[androgen receptor]] ([[Androgen receptor|AR]]) due to imperfect feedback mechanism of [[testosterone]] at the [[pituitary]] and [[hypothalamus]] there are elevated levels of serum [[testosterone]], [[FSH]] and [[LH]] observed.
*[[Testosterone]] biosynthetic defects are ruled out by the normal serum 17α hydroxyprogesterone, [[DHEA]] and [[androstenedione]] levels.<ref name="pmid9389232">{{cite journal |vauthors=Viner RM, Teoh Y, Williams DM, Patterson MN, Hughes IA |title=Androgen insensitivity syndrome: a survey of diagnostic procedures and management in the UK |journal=Arch. Dis. Child. |volume=77 |issue=4 |pages=305–9 |year=1997 |pmid=9389232 |pmc=1717340 |doi= |url=}}</ref>
*Sufficient peripheral conversion of [[testosterone]] is indicative of normal [[estradiol]] level.


===Early developmental/embryological aspect===
[[Image:Androgen_dependencies_of_male_genital_tissues.png|thumb|600px|left|By Jonathan.Marcus (Own work) [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], via Wikimedia Commons]]
*In 8th to 10th week of gestation, male gonads start to produce testosterone, [[dihydrotestosterone]](DHT), and Mullerian inhibiting factor(MIF), the hormones important for the male development.  
[[Image:Human_sexual_differentiation.gif|thumb|600px|center|By Jonathan.Marcus (Own work) [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], via Wikimedia Commons]]
*Normal production of the hormone levels occurs, but improper functioning of androgen receptors for testosterone and dihydrotestosterone(DHT) is observed.
*Concurrently, when exposed to the Mullerian inhibiting factor, it causes internal male development, while unopposed testicular estrogen results in the development of external female genitalia.
 
====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]], 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 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 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===
===Genetics===
*AIS is an [[X linked]] disorder. <ref name="pmid28670533">{{cite journal |vauthors=Akella RR |title=Mutational Analysis of Androgen Receptor Gene in Two Families with Androgen Insensitivity |journal=Indian J Endocrinol Metab |volume=21 |issue=4 |pages=520–523 |year=2017 |pmid=28670533 |pmc=5477437 |doi=10.4103/ijem.IJEM_345_16 |url=}}</ref>
*A high proportion of [[De novo mutation|De novo mutations]] arise after the [[zygote]] stage which occur at a high rate within the [[androgen receptor]] ([[Androgen receptor|AR]]) gene.<ref name="pmid28670533">{{cite journal |vauthors=Akella RR |title=Mutational Analysis of Androgen Receptor Gene in Two Families with Androgen Insensitivity |journal=Indian J Endocrinol Metab |volume=21 |issue=4 |pages=520–523 |year=2017 |pmid=28670533 |pmc=5477437 |doi=10.4103/ijem.IJEM_345_16 |url=}}</ref>
*Spontaneous [[mutations]] in the [[androgen receptor]] ([[Androgen receptor|AR]]) gene results in androgen insensitivity syndrome even without any family history.<ref name="pmid28670533">{{cite journal |vauthors=Akella RR |title=Mutational Analysis of Androgen Receptor Gene in Two Families with Androgen Insensitivity |journal=Indian J Endocrinol Metab |volume=21 |issue=4 |pages=520–523 |year=2017 |pmid=28670533 |pmc=5477437 |doi=10.4103/ijem.IJEM_345_16 |url=}}</ref>
*The development of androgen insensitivity syndrome is a result of [[genetic mutations]] of the [[androgen receptor]] ([[Androgen receptor|AR]]) gene located on the chromosome Xq11-12.<ref name="pmid24339553">{{cite journal |vauthors=Kota SK, Gayatri K, Kota SK, Jammula S |title=Genetic analysis of a family with complete androgen insensitivity syndrome |journal=Indian J Hum Genet |volume=19 |issue=3 |pages=355–7 |year=2013 |pmid=24339553 |pmc=3841565 |doi=10.4103/0971-6866.120820 |url=}}</ref><ref name="pmid28670533">{{cite journal |vauthors=Akella RR |title=Mutational Analysis of Androgen Receptor Gene in Two Families with Androgen Insensitivity |journal=Indian J Endocrinol Metab |volume=21 |issue=4 |pages=520–523 |year=2017 |pmid=28670533 |pmc=5477437 |doi=10.4103/ijem.IJEM_345_16 |url=}}</ref>
*Different [[mutations]] in the [[androgen receptor]] ([[Androgen receptor|AR]]) gene leads to varied clinical [[phenotypes]].<ref name="pmid26806084">{{cite journal |vauthors=Li L, Liu WM, Liu MX, Zheng SQ, Zhang JX, Che FY, Liu SG |title=A missense mutation in the androgen receptor gene causing androgen insensitivity syndrome in a Chinese family |journal=Asian J. Androl. |volume=19 |issue=2 |pages=260–261 |year=2017 |pmid=26806084 |pmc=5312231 |doi=10.4103/1008-682X.172647 |url=}}</ref><ref name="Brinkmann2001">{{cite journal|last1=Brinkmann|first1=Albert O.|title=Molecular basis of androgen insensitivity|journal=Molecular and Cellular Endocrinology|volume=179|issue=1-2|year=2001|pages=105–109|issn=03037207|doi=10.1016/S0303-7207(01)00466-X}}</ref>
*There have been more than 800 [[mutations]] in  the [[androgen receptor]] [[Androgen receptor|(]][[Androgen receptor|AR]][[Androgen receptor|)]] gene reported in AIS patients. <ref name="pmid23044881">{{cite journal| author=Hughes IA, Werner R, Bunch T, Hiort O| title=Androgen insensitivity syndrome. | journal=Semin Reprod Med | year= 2012 | volume= 30 | issue= 5 | pages= 432-42 | pmid=23044881 | doi=10.1055/s-0032-1324728 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23044881  }} </ref>


*Family history of other affected individuals related to each other in a pattern consistent with X-linked inheritance. “Other affected family members” refers to: <ref name="pmid20301602">{{cite journal |vauthors=Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, Gottlieb B, Trifiro MA |title= |journal= |volume= |issue= |pages= |year= |pmid=20301602 |doi= |url=}}</ref>
[[Image:XlinkRecessiveAIS.png|thumb|600px|center|By U.S. National Library of Medicine; David-Sarah Hopwood (Originally from http://ghr.nlm.nih.gov/) [Public domain], via Wikimedia Commons]]
**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.
 
[[Image:aisdiag.png|thumb|left|300px|Schematic of AIS affecting an Androgen Receptor]]
*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 ''AR'', the gene for the human Androgen Receptor, 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. 
 
[[Image:XlinkRecessive.jpg|thumb|center|300px|X-linked recessive inheritance.]]
*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 [[underarm hair|axillary]] and [[pubic hair]], and reduced normal adolescent [[Acne vulgaris|acne]].


==Associated Conditions==
==Associated Conditions==
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*[[Infertility]]
*[[Infertility]]
*[[Dyspareunia]]
*[[Dyspareunia]]
*Common [[Testicular tumor|testicular tumors]] seen in the Androgen insensitivity syndrome are: <ref name="pmid25395750">{{cite journal |vauthors=Bhaskararao G, Himabindu Y, Nayak SR, Sriharibabu M |title=Laparoscopic gonedectomy in a case of complete androgen insensitivity syndrome |journal=J Hum Reprod Sci |volume=7 |issue=3 |pages=221–3 |year=2014 |pmid=25395750 |pmc=4229800 |doi=10.4103/0974-1208.142498 |url=}}</ref>
:*[[Germ cell tumors]]
:*Sex cord tumors ([[seminoma]])
:*[[Sertoli Cell Tumor|Sertoli cell tumors]]
:*[[Leydig cell tumor|Leydig cell tumors]]
:*[[Hamartomas]]


==Gross Pathology==
==Gross Pathology==
*Complete androgen insensitivity syndrome in a 30 years old woman who presented primary amenorrhea.<ref name="pmid28270903">{{cite journal |vauthors=Souhail R, Amine S, Nadia A, Tarik K, Khalid EK, Abdellatif K, Ahmed A |title=Complete androgen insensitivity syndrome or testicular feminization: review of literature based on a case report |journal=Pan Afr Med J |volume=25 |issue= |pages=199 |year=2016 |pmid=28270903 |pmc=5326263 |doi=10.11604/pamj.2016.25.199.10758 |url=}}</ref>. <ref name="pmid26301004">{{cite journal |vauthors=Lachiri B, Hakimi I, Boudhas A, Guelzim K, Kouach J, Oukabli M, Rahali DM, Dehayni M |title=[Complete androgen insensitivity syndrome: report of two cases and review of literature] |language=French |journal=Pan Afr Med J |volume=20 |issue= |pages=400 |year=2015 |pmid=26301004 |pmc=4524922 |doi=10.11604/pamj.2015.20.400.6760 |url=}}</ref>
*Complete androgen insensitivity syndrome in a 30 years old woman presenting with [[primary amenorrhea]].<ref name="pmid28270903">{{cite journal |vauthors=Souhail R, Amine S, Nadia A, Tarik K, Khalid EK, Abdellatif K, Ahmed A |title=Complete androgen insensitivity syndrome or testicular feminization: review of literature based on a case report |journal=Pan Afr Med J |volume=25 |issue= |pages=199 |year=2016 |pmid=28270903 |pmc=5326263 |doi=10.11604/pamj.2016.25.199.10758 |url=}}</ref>. <ref name="pmid26301004">{{cite journal |vauthors=Lachiri B, Hakimi I, Boudhas A, Guelzim K, Kouach J, Oukabli M, Rahali DM, Dehayni M |title=[Complete androgen insensitivity syndrome: report of two cases and review of literature] |language=French |journal=Pan Afr Med J |volume=20 |issue= |pages=400 |year=2015 |pmid=26301004 |pmc=4524922 |doi=10.11604/pamj.2015.20.400.6760 |url=}}</ref>


<gallery>
<gallery>
Image: AIS_-_Front and side view of the patient.jpg|Front and side view of the patient
 
Image: AIS_-_absence of pubic and axillary hair.jpg| Normal female morphotype but absence of pubic and axillary hair
Image: AIS_-_Front and side view of the patient.jpg|Front and side view of the patient by Regragui Souhail et al from The Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). <ref name="pmid28270903">{{cite journal| author=Souhail R, Amine S, Nadia A, Tarik K, Khalid EK, Abdellatif K et al.| title=Complete androgen insensitivity syndrome or testicular feminization: review of literature based on a case report. | journal=Pan Afr Med J | year= 2016 | volume= 25 | issue=  | pages= 199 | pmid=28270903 | doi=10.11604/pamj.2016.25.199.10758 | pmc=5326263 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28270903  }} </ref>
Image: AIS_-_Clinical aspect of the vagina.jpg|Clinical aspect of the vagina
 
Image: AIS_-_Intra- abdominal testes - laparoscopic aspect.jpg|Intra- abdominal testes - Laparoscopic aspect
Image: AIS_-_Clinical aspect of the vagina.jpg|Clinical aspect of the vagina by Regragui Souhail et al from The Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). <ref name="pmid28270903">{{cite journal| author=Souhail R, Amine S, Nadia A, Tarik K, Khalid EK, Abdellatif K et al.| title=Complete androgen insensitivity syndrome or testicular feminization: review of literature based on a case report. | journal=Pan Afr Med J | year= 2016 | volume= 25 | issue=  | pages= 199 | pmid=28270903 | doi=10.11604/pamj.2016.25.199.10758 | pmc=5326263 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28270903  }} </ref>
Image: AIS_-_The excised testis - Macroscopic aspect.jpg|The excised testis - Macroscopic aspect
 
Image: AIS_-_Intra- abdominal testes - laparoscopic aspect.jpg|Intra- abdominal testes - Laparoscopic aspect by Regragui Souhail et al from The Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). <ref name="pmid28270903">{{cite journal| author=Souhail R, Amine S, Nadia A, Tarik K, Khalid EK, Abdellatif K et al.| title=Complete androgen insensitivity syndrome or testicular feminization: review of literature based on a case report. | journal=Pan Afr Med J | year= 2016 | volume= 25 | issue=  | pages= 199 | pmid=28270903 | doi=10.11604/pamj.2016.25.199.10758 | pmc=5326263 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28270903  }} </ref>
 
Image: AIS_-_The excised testis - Macroscopic aspect.jpg|The excised testis - Macroscopic aspect by Regragui Souhail et al from The Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). <ref name="pmid28270903">{{cite journal| author=Souhail R, Amine S, Nadia A, Tarik K, Khalid EK, Abdellatif K et al.| title=Complete androgen insensitivity syndrome or testicular feminization: review of literature based on a case report. | journal=Pan Afr Med J | year= 2016 | volume= 25 | issue=  | pages= 199 | pmid=28270903 | doi=10.11604/pamj.2016.25.199.10758 | pmc=5326263 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28270903  }} </ref>
</gallery>
</gallery>


==Microscopic Pathology==
==Microscopic Pathology==


*Histopathology shows two testes with atrophic seminiferous tubules containing only Sertoli cells, associated to a Leydig cells hyperplasia.<ref name="pmid26301004">{{cite journal| author=Lachiri B, Hakimi I, Boudhas A, Guelzim K, Kouach J, Oukabli M et al.| title=[Complete androgen insensitivity syndrome: report of two cases and review of literature]. | journal=Pan Afr Med J | year= 2015 | volume= 20 | issue=  | pages= 400 | pmid=26301004 | doi=10.11604/pamj.2015.20.400.6760 | pmc=4524922 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26301004  }} </ref>
*Histopathology of testes shows atrophic [[seminiferous tubules]] containing only [[sertoli cells]], associated to a [[leydig cells]] [[hyperplasia]].<ref name="pmid26301004">{{cite journal| author=Lachiri B, Hakimi I, Boudhas A, Guelzim K, Kouach J, Oukabli M et al.| title=[Complete androgen insensitivity syndrome: report of two cases and review of literature]. | journal=Pan Afr Med J | year= 2015 | volume= 20 | issue=  | pages= 400 | pmid=26301004 | doi=10.11604/pamj.2015.20.400.6760 | pmc=4524922 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26301004  }} </ref>
*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. <ref name="pmid28270903">{{cite journal| author=Souhail R, Amine S, Nadia A, Tarik K, Khalid EK, Abdellatif K et al.| title=Complete androgen insensitivity syndrome or testicular feminization: review of literature based on a case report. | journal=Pan Afr Med J | year= 2016 | volume= 25 | issue=  | pages= 199 | pmid=28270903 | doi=10.11604/pamj.2016.25.199.10758 | pmc=5326263 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28270903  }} </ref>
*The well-limited nodule presents as a circumscribed structure with a thin capsule consisting 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]]. <ref name="pmid28270903">{{cite journal| author=Souhail R, Amine S, Nadia A, Tarik K, Khalid EK, Abdellatif K et al.| title=Complete androgen insensitivity syndrome or testicular feminization: review of literature based on a case report. | journal=Pan Afr Med J | year= 2016 | volume= 25 | issue=  | pages= 199 | pmid=28270903 | doi=10.11604/pamj.2016.25.199.10758 | pmc=5326263 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28270903  }} </ref>
*The gonads on histopathological examination show the following: <ref name="pmid25395750">{{cite journal |vauthors=Bhaskararao G, Himabindu Y, Nayak SR, Sriharibabu M |title=Laparoscopic gonedectomy in a case of complete androgen insensitivity syndrome |journal=J Hum Reprod Sci |volume=7 |issue=3 |pages=221–3 |year=2014 |pmid=25395750 |pmc=4229800 |doi=10.4103/0974-1208.142498 |url=}}</ref>
:*Thickened [[tunica albuginea]]
:*[[Seminiferous tubules]] with primary and secondary spermatogonia and [[sertoli cells]]
:*Intertubular leydig cells were seen along with peritubular fibrosis


<gallery>
<gallery>
Image: AIS_-_Testes_-_atrophy of the seminiferous tubules - Histopathological aspect, HE staining.jpg| Testes - Atrophy of the seminiferous tubules - Histopathological aspect, HE staining.<ref name="pmid28270903">{{cite journal| author=Souhail R, Amine S, Nadia A, Tarik K, Khalid EK, Abdellatif K et al.| title=Complete androgen insensitivity syndrome or testicular feminization: review of literature based on a case report. | journal=Pan Afr Med J | year= 2016 | volume= 25 | issue=  | pages= 199 | pmid=28270903 | doi=10.11604/pamj.2016.25.199.10758 | pmc=5326263 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28270903  }} </ref>
Image:AIS_-_Testes_-_atrophy_of_the_seminiferous_tubules_-_Histopathological_aspect,_HE_staining.jpg|Testes - Atrophy of the seminiferous tubules - Histopathological aspect, HE staining by Regragui Souhail et al from The Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). <ref name="pmid28270903">{{cite journal| author=Souhail R, Amine S, Nadia A, Tarik K, Khalid EK, Abdellatif K et al.| title=Complete androgen insensitivity syndrome or testicular feminization: review of literature based on a case report. | journal=Pan Afr Med J | year= 2016 | volume= 25 | issue=  | pages= 199 | pmid=28270903 | doi=10.11604/pamj.2016.25.199.10758 | pmc=5326263 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28270903  }} </ref>
Image: AIS_-_testicular parenchyma.jpg| 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.<ref name="pmid26301004">{{cite journal| author=Lachiri B, Hakimi I, Boudhas A, Guelzim K, Kouach J, Oukabli M et al.| title=[Complete androgen insensitivity syndrome: report of two cases and review of literature]. | journal=Pan Afr Med J | year= 2015 | volume= 20 | issue=  | pages= 400 | pmid=26301004 | doi=10.11604/pamj.2015.20.400.6760 | pmc=4524922 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26301004  }} </ref>
 
Image:AIS_-_testicular_parenchyma.jpg|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 by Boutaina Lachiri et al from the Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2015;20:400. CC BY-NC 3.0, Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0). <ref name="pmid26301004">{{cite journal| author=Lachiri B, Hakimi I, Boudhas A, Guelzim K, Kouach J, Oukabli M et al.| title=[Complete androgen insensitivity syndrome: report of two cases and review of literature]. | journal=Pan Afr Med J | year= 2015 | volume= 20 | issue=  | pages= 400 | pmid=26301004 | doi=10.11604/pamj.2015.20.400.6760 | pmc=4524922 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26301004  }} </ref>
</gallery>
</gallery>


Latest revision as of 14:04, 19 October 2017

Androgen insensitivity syndrome Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2]

Overview

Androgen insensitivity syndrome is due to hormone resistance which may be due to defective androgen receptor (AR) function by either abnormal androgen receptor (AR) binding, decreased receptor binding, or impaired androgen receptor (AR) binding. AIS is an X linked disorder. The development of androgen insensitivity syndrome is a result of genetic mutations of the androgen receptor (AR) gene located on the chromosome Xq11-12. Associated conditions include primary amenorrhea, infertility and dyspareunia.

Pathophysiology

Pathogenesis

By Jonathan.Marcus (Own work) [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], via Wikimedia Commons
By Jonathan.Marcus (Own work) [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) or GFDL (http://www.gnu.org/copyleft/fdl.html)], via Wikimedia Commons

Genetics

By U.S. National Library of Medicine; David-Sarah Hopwood (Originally from http://ghr.nlm.nih.gov/) [Public domain], via Wikimedia Commons

Associated Conditions

Gross Pathology

  • Front and side view of the patient by Regragui Souhail et al from The Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). [17]

    Front and side view of the patient by Regragui Souhail et al from The Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). [17]

  • Clinical aspect of the vagina by Regragui Souhail et al from The Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). [17]

    Clinical aspect of the vagina by Regragui Souhail et al from The Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). [17]

  • Intra- abdominal testes - Laparoscopic aspect by Regragui Souhail et al from The Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). [17]

    Intra- abdominal testes - Laparoscopic aspect by Regragui Souhail et al from The Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). [17]

  • The excised testis - Macroscopic aspect by Regragui Souhail et al from The Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). [17]

    The excised testis - Macroscopic aspect by Regragui Souhail et al from The Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). [17]

Microscopic Pathology

  • Testes - Atrophy of the seminiferous tubules - Histopathological aspect, HE staining by Regragui Souhail et al from The Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). [17]

    Testes - Atrophy of the seminiferous tubules - Histopathological aspect, HE staining by Regragui Souhail et al from The Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2016;25:199. Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). [17]

  • 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 by Boutaina Lachiri et al from the Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2015;20:400. CC BY-NC 3.0, Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0). [18]

    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 by Boutaina Lachiri et al from the Pan African Medical Journal - ISSN 1937-8688. Pan Afr Med J. 2015;20:400. CC BY-NC 3.0, Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0). [18]

References

  1. ↑ Flier, Jeffrey S.; Underhill, Lisa H.; Griffin, James E. (1992). "Androgen Resistance — The Clinical and Molecular Spectrum". New England Journal of Medicine. 326 (9): 611–618. doi:10.1056/NEJM199202273260906. ISSN 0028-4793.
  2. ↑ Brown, Terry R.; Maes, Marc; Rothwell, Stephen W.; Migeon, Claude J. (1982). "Human Complete Androgen Insensitivity with Normal Dihydrotestosterone Receptor Binding Capacity in Cultured Genital Skin Fibroblasts: Evidence for a Qualitative Abnormality of the Receptor*". The Journal of Clinical Endocrinology & Metabolism. 55 (1): 61–69. doi:10.1210/jcem-55-1-61. ISSN 0021-972X.
  3. ↑ Griffin, James E. (1979). "Testicular Feminization Associated with a Thermolabile Androgen Receptor in Cultured Human Fibroblasts". Journal of Clinical Investigation. 64 (6): 1624–1631. doi:10.1172/JCI109624. ISSN 0021-9738.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Kota SK, Gayatri K, Kota SK, Jammula S (2013). "Genetic analysis of a family with complete androgen insensitivity syndrome". Indian J Hum Genet. 19 (3): 355–7. doi:10.4103/0971-6866.120820. PMC 3841565. PMID 24339553.
  5. ↑ Brinkmann AO, Faber PW, van Rooij HC, Kuiper GG, Ris C, Klaassen P, van der Korput JA, Voorhorst MM, van Laar JH, Mulder E (1989). "The human androgen receptor: domain structure, genomic organization and regulation of expression". J. Steroid Biochem. 34 (1–6): 307–10. PMID 2626022.
  6. ↑ McPhaul MJ, Marcelli M, Tilley WD, Griffin JE, Wilson JD (1991). "Androgen resistance caused by mutations in the androgen receptor gene". FASEB J. 5 (14): 2910–5. PMID 1752359.
  7. ↑ Evans BA, Hughes IA, Bevan CL, Patterson MN, Gregory JW (1997). "Phenotypic diversity in siblings with partial androgen insensitivity syndrome". Arch. Dis. Child. 76 (6): 529–31. PMC 1717223. PMID 9245853.
  8. ↑ Nichols JL, Bieber EJ, Gell JS (2009). "Case of sisters with complete androgen insensitivity syndrome and discordant Müllerian remnants". Fertil. Steril. 91 (3): 932.e15–8. doi:10.1016/j.fertnstert.2008.09.027. PMID 18930210.
  9. ↑ Ozdemir O, Sari ME, Akmut E, Selimova V, Unal T, Atalay CR (2014). "Complete androgen insensitivity syndrome with a large gonadal serous papillary cystadenofibroma". J Hum Reprod Sci. 7 (2): 148–50. doi:10.4103/0974-1208.138875. PMC 4150143. PMID 25191030.
  10. ↑ Hughes IA, Deeb A (2006). "Androgen resistance". Best Pract. Res. Clin. Endocrinol. Metab. 20 (4): 577–98. doi:10.1016/j.beem.2006.11.003. PMID 17161333.
  11. ↑ Viner RM, Teoh Y, Williams DM, Patterson MN, Hughes IA (1997). "Androgen insensitivity syndrome: a survey of diagnostic procedures and management in the UK". Arch. Dis. Child. 77 (4): 305–9. PMC 1717340. PMID 9389232.
  12. ↑ 12.0 12.1 12.2 12.3 Akella RR (2017). "Mutational Analysis of Androgen Receptor Gene in Two Families with Androgen Insensitivity". Indian J Endocrinol Metab. 21 (4): 520–523. doi:10.4103/ijem.IJEM_345_16. PMC 5477437. PMID 28670533.
  13. ↑ Li L, Liu WM, Liu MX, Zheng SQ, Zhang JX, Che FY, Liu SG (2017). "A missense mutation in the androgen receptor gene causing androgen insensitivity syndrome in a Chinese family". Asian J. Androl. 19 (2): 260–261. doi:10.4103/1008-682X.172647. PMC 5312231. PMID 26806084.
  14. ↑ Brinkmann, Albert O. (2001). "Molecular basis of androgen insensitivity". Molecular and Cellular Endocrinology. 179 (1–2): 105–109. doi:10.1016/S0303-7207(01)00466-X. ISSN 0303-7207.
  15. ↑ Hughes IA, Werner R, Bunch T, Hiort O (2012). "Androgen insensitivity syndrome". Semin Reprod Med. 30 (5): 432–42. doi:10.1055/s-0032-1324728. PMID 23044881.
  16. ↑ 16.0 16.1 Bhaskararao G, Himabindu Y, Nayak SR, Sriharibabu M (2014). "Laparoscopic gonedectomy in a case of complete androgen insensitivity syndrome". J Hum Reprod Sci. 7 (3): 221–3. doi:10.4103/0974-1208.142498. PMC 4229800. PMID 25395750.
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 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.
  18. ↑ 18.0 18.1 18.2 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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