Editing Androgen insensitivity syndrome

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| name            = Androgen insensitivity syndrome
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| image           = Androgen_receptor_3-d_model.jpg
| caption         = AIS results when the function of the [[androgen receptor]] (AR) is impaired.  The AR protein (pictured) mediates the effects of androgens in the human body.
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| field           = [[Endocrinology]]
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'''Androgen insensitivity syndrome''' ('''AIS''') is a condition involving the inability to respond to androgens, typically due to [[androgen receptor]] dysfunction.<ref>{{Cite book|last=Legato|first=Marianne J.|url=https://books.google.com/books?id=khATDgAAQBAJ&q=androgen+insensitivity+syndrome|title=Principles of Gender-Specific Medicine: Gender in the Genomic Era|date=2017-05-15|publisher=Academic Press|isbn=978-0-12-803542-9|pages=34|language=en}}</ref>

It affects 1 in 20,000 to 64,000 XY ([[karyotype|karyotypically]] male) births. The condition results in the partial or complete inability of [[Animal cell|cells]] to respond to [[androgen]]s.<ref name="lead:1" /> This unresponsiveness can impair or prevent the [[Development of the reproductive system|development of male genitals]], as well as impairing or preventing the development of male [[Secondary sex characteristics|secondary sexual characteristics]] at [[puberty]]. It does not significantly impair female genital or sexual development.<ref name="1995 quigley 16" /><ref name="2002 giwercman 87" /> The insensitivity to androgens is therefore clinically significant only when it occurs in genetic males, (i.e. individuals with a [[Y chromosome|Y-chromosome]], or more specifically, an [[SRY|SRY gene]]).<ref name="2006 hughes 20" />  Clinical [[phenotypes]] in these individuals range from a typical [[body shape|male habitus]] with mild [[spermatogenesis|spermatogenic]] defect or reduced secondary [[terminal hair]], to a full [[Female body shape|female habitus]], despite the presence of a Y-chromosome.<ref name="lead:2" />

AIS is divided into three categories that are differentiated by the degree of [[Development of the reproductive system#External genitalia|genital masculinization]]:
*[[Mild androgen insensitivity syndrome]] (MAIS) is indicated when the external genitalia are those of a typical male (a [[Human penis|penis]] and a [[scrotum]])
*[[Partial androgen insensitivity syndrome]] (PAIS) is indicated when the external genitalia are partially, but not fully, masculinized<ref name="lead:3"/><ref name="lead:4"/>
*[[Complete androgen insensitivity syndrome]] (CAIS) is indicated when the external genitalia are those of a typical female (a [[vulva]])

Androgen insensitivity syndrome is the largest single entity that leads to 46,XY [[Intersexuality#Conditions|undermasculinized genitalia]].<ref name="1999 ahmed 80" />

Management of AIS is currently limited to [[symptomatic treatment|symptomatic management]]; no method is currently available to correct the malfunctioning androgen receptor proteins produced by ''AR'' gene mutations.  Areas of management include [[sex assignment]], [[genitoplasty]], [[gonadectomy]] to reduce [[germ cell tumor|tumor]] risk, [[Hormone replacement therapy (menopause)|hormone replacement therapy]], [[genetic counseling]], and [[psychotherapy|psychological counseling]].

==Genetics==
[[File:Functional domains of the human androgen receptor.svg|thumb|200px|Location and structure of the human androgen receptor: '''Top''', the AR gene is located on the proximal long arm of the X chromosome. '''Middle''', the eight exons are separated by introns of various lengths. '''Bottom''', illustration of the AR protein, with primary functional domains labeled (not representative of actual 3-D structure).<ref name="1995 quigley 16" />]]

The human [[androgen receptor]] (AR) is a protein encoded by a [[gene]] located on the [[Anatomical terms of location#Proximal and distal|proximal]] [[Locus (genetics)|long arm]] of the [[X chromosome]] ([[Locus (genetics)|locus]] Xq11-Xq12).<ref name="1989 brown 44" />  The [[Gene#Structure and function|protein coding region]] consists of approximately 2,757 [[nucleotides]] (919 [[codons]]) spanning eight [[exons]], designated 1-8 or A-H.<ref name="2006 hughes 20" /><ref name="1995 quigley 16" />  [[Introns]] vary in size between 0.7 and 26 [[Base pair#Length measurements|kb]].<ref name="1995 quigley 16" />  Like other nuclear receptors, the AR protein consists of several [[protein domain|functional domains]]: the [[transactivation]] domain (also called the transcription-regulation domain or the amino / [[N-terminus|NH2-terminal]] domain), the [[DNA-binding domain]], the hinge region, and the steroid-binding domain (also called the [[C-terminus|carboxyl-terminal]] [[Ligand (biochemistry)|ligand-binding]] domain).<ref name="2006 hughes 20" /><ref name="2008 galani 7" /><ref name="1995 quigley 16" /><ref name="2005 gottlieb 10" />  The transactivation domain is encoded by exon 1, and makes up more than half of the AR protein.<ref name="1995 quigley 16" />  Exons 2 and 3 encode the DNA-binding domain, while the [[Directionality (molecular biology)#5′-end|5']] portion of exon 4 encodes the hinge region.<ref name="1995 quigley 16" />  The remainder of exons 4 through 8 encodes the ligand binding domain.<ref name="1995 quigley 16" />

===Trinucleotide satellite lengths and AR transcriptional activity===
The AR gene contains two [[Polymorphism (biology)#Genetic polymorphism|polymorphic]] [[nucleotide|trinucleotide]] [[Microsatellite (genetics)|microsatellites]] in exon 1.<ref name="2008 galani 7" />  The first microsatellite (nearest the [[Directionality (molecular biology)#5′-end|5']] end) contains 8 <ref name="1999 kooy 85" /> to 60 <ref name="2002 dejager 87" /><ref name="1998 choong 21" /> repetitions of the [[glutamine]] [[codon]] "CAG" and is thus known as the [[polyglutamine tract]].<ref name="1995 quigley 16" />  The second microsatellite contains 4 <ref name="2010 audi 95" /> to 31<ref name="1997 lumbroso 101" /> repetitions of the [[glycine]] codon "GGC" and is known as the [[polyglycine tract]].<ref name="1999 gottlieb 89" />  The average number of repetitions varies by ethnicity, with Caucasians exhibiting an average of 21 CAG repeats, and Blacks 18.<ref name="1992 edwards 12" />  In men, disease states are associated with extremes in polyglutamine tract length; [[prostate cancer]],<ref name="2001 casella 58" /> [[hepatocellular carcinoma]],<ref name="2007 yeh 120" /> and [[intellectual disability]]<ref name="1999 kooy 85" /> are associated with too few repetitions, while [[spinal and bulbar muscular atrophy]] (SBMA) is associated with a CAG repetition length of 40 or more.<ref name="1991 la spada 352" />  Some studies indicate that the length of the polyglutamine tract is inversely correlated with [[Transcription (genetics)|transcriptional activity]] in the AR protein, and that longer polyglutamine tracts may be associated with [[infertility|male infertility]]<ref name="2003 casella 169" /><ref name="1999 dowsing 354" /><ref name="1997 tut 82" /> and [[Development of the reproductive system#External genitalia|undermasculinized genitalia]] in men.<ref name="2000 lim 9" />  However, other studies have indicated no such correlation exists.<ref name="2000 hiort 85" /><ref name="2002 kukuvitis 25" /> A comprehensive [[meta-analysis]] of the subject published in 2007 supports the existence of the correlation, and concluded these discrepancies could be resolved when [[sample size]] and study design are taken into account.<ref name="2007 davis-dao 92" />  Some studies suggest longer polyglycine tract lengths are also associated with genital masculinization defects in men.<ref name="2007 radpour 28" /><ref name="2004 aschim 89" />  Other studies find no such association.<ref name="2006 rajender 27" />

===AR mutations===
As of 2010, over 400 ''AR'' [[mutations]] have been reported in the ''AR'' mutation database, and the number continues to grow.<ref name="2008 galani 7" />  [[heredity|Inheritance]] is typically maternal and follows an [[X-linked recessive]] pattern;<ref name="2006 hughes 20" /><ref name="2001 gottlieb 17" /> individuals with a [[karyotype|46,XY karyotype]] always express the mutant gene since they have only one [[X chromosome]], whereas 46,XX carriers are minimally affected.  About 30% of the time, the ''AR'' mutation is a spontaneous result, and is not inherited.<ref name="2010 ozulker 24" />  Such [[de novo mutation|''de novo'' mutations]] are the result of a [[germ cell]] mutation or [[Mosaic (genetics)|germ cell mosaicism]] in the [[gonads]] of one of the parents, or a mutation in the [[zygote|fertilized egg]] itself.<ref name="2005 kohler 90" />  In one study,<ref name="1998 hiort 132" /> three of eight ''de novo'' mutations occurred in the postzygotic stage, leading to the estimate that up to one-third of ''de novo'' mutations result in somatic mosaicism.<ref name="2006 hughes 20" />  Not every mutation of the ''AR'' gene results in androgen insensitivity; one particular mutation occurs in 8 to 14% of [[karyotype|genetic males]],<ref name="1992 batch 1" /><ref name="1994 hiort 153" /><ref name="1996 lu 49" /><ref name="1993 macke 53" /> and is thought to adversely affect only a small number of individuals when other genetic factors are present.<ref name="1999 gottlieb 14" />

===Other causes===
Some individuals with CAIS or PAIS do not have any ''AR'' mutations despite clinical, hormonal, and [[histological]] features sufficient to warrant an AIS diagnosis; up to 5% of women with CAIS do not have an ''AR'' mutation,<ref name="2008 galani 7" /> as well as between 27<ref name="2006 ferlin 65" /><ref name="2003 melo 88" /> and 72%<ref name="2000 ahmed 85" /> of individuals with PAIS.

In one patient, the underlying cause for presumptive PAIS was a mutant [[steroidogenic factor 1|steroidogenic factor-1 (SF-1)]] protein.<ref name="2007 coutant 92" />  In another patient, CAIS was the result of a deficit in the transmission of a [[transactivation|transactivating]] signal from the [[N-terminus|N-terminal]] region of the androgen receptor to the [[Transcriptional regulation#Regulation of transcription machinery|basal transcription machinery]] of the cell.<ref name="2000 adachi 343" />  A [[coactivator]] protein interacting with the [[activation function 1]] (AF-1) [[transactivation]] domain of the androgen receptor may have been deficient in this patient.<ref name="2000 adachi 343" />  The signal disruption could not be corrected by supplementation with any coactivators known at the time, nor was the absent coactivator protein characterized, which left some in the field unconvinced that a mutant coactivator would explain the mechanism of androgen resistance in CAIS or PAIS patients with a typical ''AR'' gene.<ref name="2006 hughes 20" />

===XY karyotype===
Depending on the mutation, a person with a 46,XY karyotype and AIS can have either a male (MAIS) or female (CAIS) phenotype,<ref name="1999 ghadessy 103" /> or may have genitalia that are only partially masculinized (PAIS).{{needs source|date=October 2024}}  The gonads are testes regardless of phenotype due to the influence of the Y chromosome.<ref name="2006 achermann" /><ref name="1995 simpson" />  A 46,XY female, thus, does not have ovaries,<ref name="1996 brinkmann 61" /> and can not contribute an [[ovum|egg]] towards conception. In some cases, 46, XY females do form a vestigial [[uterus]] and have been able to [[gestate]] children. Such examples are rare and have required the use of an egg donor, hormone therapy, and IVF.<ref>{{Cite web |last=Stone |first=Jon |date=January 31, 2015 |title=Woman born with no womb gives birth to twins after treatment breakthrough |url=https://www.independent.co.uk/news/science/woman-born-with-no-womb-gives-birth-to-twins-after-treatment-breakthrough-10015506.html |access-date=July 7, 2022 |website=The Independent}}</ref>

Several case studies of fertile 46,XY males with AIS have been published,<ref name="1989 pinsky 32" /><ref name="2000 giwercman 85" /> although this group is thought to be a minority.<ref name="2005 gottlieb 10" />  In some cases, infertile males with MAIS have been able to conceive children after increasing their [[sperm count]] through the use of supplementary [[testosterone (medication)|testosterone]].<ref name="2006 hughes 20" /><ref name="1994 yong 344" />

A genetic male conceived by a man with AIS would not receive his father's [[X chromosome]],  thus would neither [[heredity|inherit]] nor carry the gene for the syndrome.  A genetic female conceived in such a way would receive her father's X chromosome, thus would become a [[X-linked recessive inheritance|carrier]].

===XX karyotype===
Genetic females (46,XX karyotype) have two X chromosomes, thus have two ''AR'' genes.  A mutation in one (but not both) results in a minimally affected, fertile, female carrier.  Some carriers have been noted to have slightly reduced body hair, delayed puberty, and/or tall stature, presumably due to skewed X-inactivation.<ref name="1995 quigley 16" /><ref name="2002 giwercman 87" />  A female carrier will pass the affected ''AR'' gene to her children 50% of the time.  If the affected child is a genetic female, she, too, will be a carrier.  An affected 46,XY child will have AIS.{{citation needed|date=May 2022}}

A genetic female with mutations in both ''AR'' genes could theoretically result from the union of a fertile man with AIS and a female carrier of the gene, or from ''de novo'' mutation.  However, given the scarcity of fertile AIS men and low [[Incidence (epidemiology)|incidence]] of ''AR'' mutation, the chances of this occurrence are small.  The [[phenotype]] of such an individual is a matter of speculation; as of 2010, no such documented case has been published.{{citation needed|date=May 2022}}

===Correlation of genotype and phenotype===
Individuals with partial AIS, unlike those with the complete or mild forms, present at birth with [[ambiguous genitalia]], and the decision to raise the child as male or female is often not obvious.<ref name="2006 hughes 20" /><ref name="2005 kohler 90" /><ref name="2006 bouvattier 91" />  Unfortunately,  little information regarding [[phenotype]] can be gleaned from precise knowledge of the ''AR'' mutation itself;  the same ''AR ''mutation may cause significant variation in the degree of masculinization in different individuals, even among members of the same family.<ref name="2001 boehmer 86" /><ref name="1997 evans 76" /> Exactly what causes this variation is not entirely understood, although factors contributing to it could include the lengths of the [[polyglutamine tract|polyglutamine]] and [[polyglycine tract|polyglycine]] tracts,<ref name="2006 werner 91" /> sensitivity to and variations in the [[intrauterine]] [[endocrine]] milieu,{{needs source|date=October 2024}} the effect of [[Transcription coregulator|coregulatory]] proteins active in [[Sertoli cells]],<ref name="1999 gottlieb 89" /><ref name="2002 zenteno 57" /> somatic mosaicism,<ref name="2006 hughes 20" /> expression of the [[5-alpha reductase|''5RD2'']] [[gene]] in genital skin [[fibroblasts]],<ref name="2001 boehmer 86" /> reduced ''AR'' [[Transcription (genetics)|transcription]] and [[Translation (genetics)|translation]] from factors other than mutations in the AR coding region,<ref name="2005 holterhus 83" /> an unidentified [[Coactivator (genetics)|coactivator]] protein,<ref name="2000 adachi 343" /> enzyme deficiencies such as [[21-hydroxylase deficiency]],<ref name="2002 giwercman 87" /> or other genetic variations such as a mutant [[steroidogenic factor 1|steroidogenic factor-1]] protein.<ref name="2007 coutant 92" />  The degree of variation, however, does not appear to be constant across all ''AR'' mutations, and is much more extreme in some.<ref name="2006 hughes 20" /><ref name="2002 giwercman 87" /><ref name="1999 gottlieb 14" />  [[Missense mutations]] that result in a single amino acid substitution are known to produce the most phenotypic diversity.<ref name="2008 galani 7" />

==Pathophysiology==
[[File:Human androgen receptor and androgen binding.svg|thumb|Normal function of the androgen receptor: Testosterone (T) enters the cell and, if 5-alpha-reductase is present, is converted into dihydrotestone (DHT). Upon steroid binding, the androgen receptor (AR) undergoes a conformational change and releases heat shock proteins (hsps). Phosphorylation (P) occurs before or after steroid binding. The AR translocates to the nucleus where dimerization, DNA binding, and the recruitment of coactivators occur. Target genes are transcribed (mRNA) and translated into proteins.<ref name="1995 quigley 16" /><ref name="2005 gottlieb 10" /><ref name="1998 choong 21" /><ref name="2003 meehan 8" />]]

===Androgens and the androgen receptor===
{{Main|Androgen receptor}}
The [[Androgen#Functions|effects]] that [[androgens]] have on the human body ([[Puberty#Physical changes in boys|virilization]], masculinization, [[anabolism]], etc.) are not brought about by androgens themselves, but rather are the result of androgens bound to androgen receptors; the androgen receptor mediates the effects of androgens in the human body.<ref name="1998 wang 83" />  Likewise, the androgen receptor itself is generally inactive in the cell until androgen binding occurs.<ref name="1995 quigley 16" />

The following series of steps illustrates how androgens and the androgen receptor work together to produce androgenic effects:<ref name="2006 hughes 20" /><ref name="2008 galani 7" /><ref name="1995 quigley 16" /><ref name="2005 gottlieb 10" />

{{ordered list
 | Androgen enters the cell.
  {{ordered list|type=lower-alpha
    | Only certain organs in the body, such as the [[gonads]] and the [[adrenal glands]], produce the androgen [[testosterone]].
    | Testosterone is converted into [[dihydrotestosterone]], a chemically similar androgen, in cells containing the [[enzyme]] [[5-alpha reductase]].
    | Both androgens exert their influence through binding with the androgen receptor.
  }}
 | Androgen binds with the androgen receptor.
  {{ordered list|type=lower-alpha
    | The androgen receptor is expressed ubiquitously throughout the tissues of the human body.
    | Before it binds with an androgen, the androgen receptor is bound to [[heat shock proteins]].
    | These heat shock proteins are released upon androgen binding.
    | Androgen binding induces a stabilizing, [[Chemical structure|conformational]] change in the androgen receptor.
    | The two [[zinc fingers]] of the [[DNA-binding domain]] are exposed as a result of this new conformation.
    | AR stability is thought to be aided by type II [[Transcription coregulator|coregulators]], which modulate [[protein folding]] and androgen binding, or facilitate NH2/carboxyl-terminal interaction.
  }}
 | The hormone-activated androgen receptor is [[Protein phosphorylation|phosphorylated]].
  {{ordered list|type=lower-alpha
    | Receptor phosphorylation can occur before androgen binding, although the presence of androgen promotes hyperphosphorylation.
    | The biological ramifications of receptor phosphorylation are unknown.
  }}
 | The hormone-activated androgen receptor [[Protein targeting#Protein translocation|translocates]] to the nucleus.
  {{ordered list|type=lower-alpha
    | Nucleocytoplasmic transport is in part facilitated by an [[amino acid]] [[Nucleic acid sequence|sequence]] on the [[androgen receptor|AR]] called the [[nuclear localization signal]].
    | The AR's nuclear localization signal is primarily encoded in the hinge region of the AR gene.
  }}
 | [[Protein dimer|Homodimerization]] occurs.
  {{ordered list|type=lower-alpha
    | Dimerization is mediated by the second (nearest the 3' end) [[zinc finger]].
  }}
 | DNA binding to regulatory [[Hormone response element|androgen response elements]] occurs.
  {{ordered list|type=lower-alpha
    | Target genes contain (or are flanked by) [[Transcription (genetics)|transcriptional]] enhancer nucleotide sequences that interact with the first zinc finger.
    | These areas are called androgen response elements.
  }}
 | [[Coactivator (genetics)|Coactivators]] are recruited by the AR.
  {{ordered list|type=lower-alpha
    | Type I coactivators (i.e., coregulators) are thought to influence AR transcriptional activity by facilitating DNA occupancy, [[chromatin remodeling]], or the recruitment of general [[transcription factor]]s associated with [[RNA polymerase II]] holocomplex.
  }}
 | Target [[gene transcription]] ensues.
}}

In this way, androgens bound to androgen receptors [[Regulation of gene expression|regulate the expression]] of target genes, thus produce androgenic effects.<ref>{{Cite journal |last1=Jin |first1=Hong-Jian |last2=Kim |first2=Jung |last3=Yu |first3=Jindan |date=September 2013 |title=Androgen receptor genomic regulation |url=https://tau.amegroups.com/article/view/2705 |journal=Translational Andrology and Urology |language=en |volume=2 |issue=3 |pages=15877–15177 |doi=10.3978/j.issn.2223-4683.2013.09.01 |issn=2223-4691 |pmc=4165347 |pmid=25237629}}</ref>

Theoretically, certain mutant androgen receptors can function without androgens; ''in vitro'' studies have demonstrated that a mutant androgen receptor protein can induce transcription in the absence of androgen if its steroid binding domain is deleted.<ref name="1991 jenster 5" /><ref name="1991 simental 266" />  Conversely, the steroid-binding domain may act to repress the AR [[transactivation]] domain, perhaps due to the AR's [[Ligand (biochemistry)|unliganded]] conformation.<ref name="1995 quigley 16" />

[[File:Human sexual differentiation.gif|thumb|Sexual differentiation: The human embryo has indifferent sex accessory ducts until the seventh week of development.<ref name="2000 gilbert" />]]

===Androgens in fetal development===
[[Human embryos]] develop similarly for the first six weeks, regardless of genetic sex (46,XX or 46,XY karyotype); the only way to tell the difference between 46,XX or 46,XY embryos during this time period is to look for [[Barr bodies]] or a Y chromosome.<ref name="2006 jones" />  The gonads begin as bulges of tissue called the [[gonadal ridge|genital ridges]] at the back of the [[abdominal cavity]], near the midline.  By the fifth week, the genital ridges [[sexual differentiation|differentiate]] into an outer [[Cortex (anatomy)|cortex]] and an inner [[wikt:medulla|medulla]], and are called [[Development of the gonads|indifferent gonads]].<ref name="2006 jones" />  By the sixth week, the indifferent gonads begin to differentiate according to genetic sex.  If the karyotype is 46,XY, testes develop due to the influence of the [[Y chromosome]]'s ''SRY'' gene.<ref name="2006 achermann" /><ref name="1995 simpson" />  This process does not require the presence of androgen, nor a functional androgen receptor.<ref name="2006 achermann" /><ref name="1995 simpson" />

Until around the seventh week of development, the embryo has indifferent [[Sex determination and differentiation (human)|sex accessory ducts]], which consist of two pairs of ducts: the [[Müllerian ducts]] and the [[Wolffian ducts]].<ref name="2006 jones" />  [[Sertoli cells]] within the testes secrete [[anti-Müllerian hormone]] around this time to suppress the development of the Müllerian ducts, and cause their degeneration.<ref name="2006 jones" />  Without this anti-Müllerian hormone, the Müllerian ducts develop into the [[Female reproductive system#Internal genitalia|female internal genitalia]] ([[uterus]], [[cervix]], [[fallopian tubes]], and [[Vagina#Gross anatomy|upper vaginal barrel]]).<ref name="2006 jones" />  Unlike the Müllerian ducts, the Wolffian ducts will not continue to develop by default.<ref name="2003 yong 9" />  In the presence of testosterone and functional androgen receptors, the Wolffian ducts develop into the [[epididymis|epididymides]], [[vas deferens|vasa deferentia]], and [[seminal vesicles]].<ref name="2006 jones" />  If the testes fail to secrete testosterone, or the androgen receptors do not function properly, the Wolffian ducts degenerate.<ref name="2004 hannema 89" />

[[File:Androgen dependencies of male genital tissues.png|thumb|Masculinization of the male genitalia is dependent on both testosterone and dihydrotestosterone.<ref name="2000 gilbert" />]]
Masculinization of the [[male external genitalia]] (the [[Human penis|penis]], penile [[urethra]], and [[scrotum]]), as well as the [[prostate]], are dependent on the androgen [[dihydrotestosterone]].<ref name="2008 oakes 21" /><ref name="1999 roy 55" /><ref name="1999 kokontis 55" /><ref name="2009 rajender 91" />  Testosterone is converted into dihydrotestosterone by the 5-alpha reductase enzyme.<ref name="2006 sobel 91" />  If this enzyme is absent or deficient, then dihydrotestosterone is not created, and the external male genitalia do not develop properly.<ref name="2008 oakes 21" /><ref name="1999 roy 55" /><ref name="1999 kokontis 55" /><ref name="2009 rajender 91" /><ref name="2006 sobel 91" />  As is the case with the [[Male reproductive system#Internal genitalia|internal male genitalia]], a functional androgen receptor is needed for dihydrotestosterone to regulate the [[gene transcription|transcription of target genes]] involved in development.<ref name="1998 wang 83" />

===Pathogenesis of AIS===
Mutations in the androgen receptor gene can cause problems with any of the steps involved in androgenization, from the synthesis of the androgen receptor protein itself, through the [[Transcription (genetics)|transcriptional ability]] of the [[Protein dimer|dimerized]], androgen-AR complex.<ref name="1995 quigley 16" />  AIS can result if even one of these steps is significantly disrupted, as each step is required for androgens to activate the AR successfully and [[regulation of gene expression|regulate gene expression]].<ref name="1995 quigley 16" />  Exactly which steps a particular mutation will impair can be predicted, to some extent, by identifying the area of the AR in which the mutation resides.  This predictive ability is primarily retrospective in origin; the different [[protein domain|functional domains]] of the AR gene have been elucidated by analyzing the effects of specific mutations in different regions of the AR.<ref name="1995 quigley 16" />  For example, mutations in the steroid binding domain have been known to affect [[Ligand (biochemistry)#Receptor/ligand binding affinity|androgen binding affinity or retention]], mutations in the hinge region have been known to affect [[Protein targeting#Protein translocation|nuclear translocation]], mutations in the [[DNA-binding domain]] have been known to affect dimerization and binding to target DNA, and mutations in the [[transactivation]] domain have been known to affect target gene transcription regulation.<ref name="1995 quigley 16" /><ref name="2003 yong 9" />  Unfortunately, even when the affected functional domain is known, predicting the [[phenotype|phenotypical]] consequences of a particular mutation (see [[#Correlation of genotype and phenotype|Correlation of genotype and phenotype]]) is difficult.{{citation needed|date=September 2021}}

Some mutations can adversely impact more than one functional domain.  For example, a mutation in one functional domain can have deleterious effects on another by altering the way in which the domains interact.<ref name="2003 yong 9" />  A single mutation can affect all [[Upstream and downstream (DNA)|downstream]] functional domains if a [[nonsense mutation|premature stop codon]] or [[frameshift mutation|framing error]] results; such a mutation can result in a completely unusable (or unsynthesizable) androgen receptor protein.<ref name="1995 quigley 16" />  The steroid binding domain is particularly vulnerable to the effects of a premature stop codon or framing error, since it occurs at the end of the gene, and its information is thus more likely to be truncated or misinterpreted than other functional domains.<ref name="1995 quigley 16" />

Other, more complex relationships have been observed as a consequence of mutated ''AR''; some mutations associated with male phenotypes have been linked to [[male breast cancer]], [[prostate cancer]], or in the case of [[spinal and bulbar muscular atrophy]], disease of the [[central nervous system]].<ref name="2003 lund 79" /><ref name="2001 casella 58" /><ref name="1992 wooster 2" /><ref name="1996 evans 28" /><ref name="1993 lobaccaro 2" />  The form of breast cancer seen in some men with PAIS is caused by a mutation in the AR's DNA-binding domain.<ref name="1992 wooster 2" /><ref name="1993 lobaccaro 2" />  This mutation is thought to cause a disturbance of the AR's target gene interaction that allows it to act at certain additional targets, possibly in conjunction with the [[estrogen receptor]] protein, to cause [[neoplasm|cancerous growth]].<ref name="1995 quigley 16" /> The [[pathogenesis]] of spinal and bulbar muscular atrophy (SBMA) demonstrates that even the mutant AR protein itself can result in [[pathology]].  The [[trinucleotide repeat disorder|trinucleotide repeat expansion]] of the [[polyglutamine tract]] of the AR gene that is associated with SBMA results in the synthesis of a [[misfolded]] AR protein that the cell fails to [[Proteolysis|proteolyze]] and disperse properly.<ref name="1999 stenoien 8" />  These misfolded AR proteins form aggregates in the cell [[cytoplasm]] and [[Cell nucleus|nucleus]].<ref name="1999 stenoien 8" />  Over the course of 30 to 50 years, these aggregates accumulate and have a [[cytotoxicity|cytotoxic]] effect, eventually resulting in the [[neurodegeneration|neurodegenerative]] symptoms associated with SBMA.<ref name="1999 stenoien 8" />

==Diagnosis==
The phenotypes that result from the insensitivity to androgens are not unique to AIS, thus the diagnosis of AIS requires thorough exclusion of other causes.<ref name="1999 ahmed 80" /><ref name="1987 perez-palacios 27" />  Clinical findings indicative of AIS include the presence of a short vagina <ref name="2007 ismail-pratt 22" /> or undermasculinized genitalia,<ref name="2006 hughes 20" /><ref name="1997 evans 76" /><ref name="2008 oakes 21" /> partial or complete regression of Müllerian structures,<ref name="2009 nichols 91" /> bilateral [[Dysplastic|nondysplastic]] testes,<ref name="2006 hannema 208" /> and impaired [[spermatogenesis]] and/or virilization.<ref name="2006 hughes 20" /><ref name="2008 zuccarello 68" /><ref name="2006 ferlin 65" /><ref name="2003 lund 79" />  Laboratory findings include a 46,XY karyotype<ref name="2008 galani 7" /> and typical or elevated postpubertal testosterone, [[luteinizing hormone]], and [[estradiol]] levels.<ref name="2008 galani 7" /><ref name="1999 ahmed 80" />  The androgen binding activity of genital skin [[fibroblasts]] is typically diminished,<ref name="1995 quigley 16" /><ref name="1996 weidemann 45" /> although exceptions have been reported.<ref name="2008 deeb 93" />  Conversion of testosterone to dihydrotestosterone may be impaired.<ref name="1995 quigley 16" />  The diagnosis of AIS is confirmed if androgen receptor [[DNA sequencing|gene sequencing]] reveals a mutation, although not all individuals with AIS (particularly PAIS) will have an ''AR'' mutation (see [[#Other causes|Other Causes]]).<ref name="2008 galani 7" /><ref name="2006 ferlin 65" /><ref name="2003 melo 88" /><ref name="2000 ahmed 85" />

Each of the three types of AIS (complete, partial, and mild) has a different list of [[differential diagnoses]] to consider.<ref name="2006 hughes 20" />  However, cases have been reported of individuals with both AIS and certain diagnoses listed here, such as Klinefelter syndrome or Turner syndrome with mosaicism.<ref>{{Cite journal |last1=Skalska |first1=Karolina |last2=Ziółkowski |first2=Maciej |last3=Skoczylas |first3=Adrian |last4=Teleon |first4=Marta |last5=Grymowicz |first5=Monika |last6=Pollak |first6=Agnieszka |last7=Smolarczyk |first7=Roman |last8=Płoski |first8=Rafał |last9=Męczekalski |first9=Błażej |date=June 2021 |title=18-Year-old patient with Klinefelter syndrome (47, XXY) and complete androgen insensitivity syndrome (CAIS) - case report |url=https://pubmed.ncbi.nlm.nih.gov/33960260/ |journal=Gynecological Endocrinology|volume=37 |issue=6 |pages=572–575 |doi=10.1080/09513590.2021.1921139 |issn=1473-0766 |pmid=33960260}}</ref><ref>{{Cite journal |last1=Wong |first1=Wai Yu |last2=Wong |first2=Lap Ming |last3=Tam |first3=Yuk Him |last4=Luk |first4=Ho Ming |date=August 2023 |title=A Baby With Complete Androgen Insensitivity Syndrome and the Fortuitous Discovery of 45,X/46,XY Mosaicism |journal=Cureus |volume=15 |issue=8 |pages=e43352 |doi=10.7759/cureus.43352 |doi-access=free |issn=2168-8184 |pmid=37700992|pmc=10493458 }}</ref> Depending on the form of AIS suspected, the list of differentials can include:<ref name="2006 achermann" /><ref name="1995 simpson" /><ref name="2010 quint 53" /><ref name="2008 hughes 22" /><ref name="2002 kim 15" />
{{columns-list|colwidth=30em|
* [[Chromosome abnormality|Chromosomal anomalies]]:
** [[Klinefelter syndrome]] (47,XXY karyotype)
** [[Turner syndrome]] (45,XO karyotype)
** [[Mixed gonadal dysgenesis]] (45,XO/46,XY karyotype)
** [[Chimera (genetics)#Tetragametic chimerism|Tetragametic chimerism]] (46,XX/46,XY karyotype)
* [[Androgen]] [[Biosynthesis|biosynthetic]] dysfunction in [[karyotype|46,XY individuals]]:
** [[Luteinizing hormone/choriogonadotropin receptor#LHCGR abnormalities|Luteinizing hormone (LH) receptor mutations]]
** [[Smith–Lemli–Opitz syndrome]] (associated with intellectual disability)
** [[Lipoid congenital adrenal hyperplasia]]
** [[Congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency|3β-hydroxysteroid dehydrogenase 2 deficiency]]
** [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency|17α-hydroxylase deficiency]]
** [[Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency#17,20-Lyase deficiency|17,20 lyase deficiency]]
** [[17-beta-hydroxysteroid dehydrogenase deficiency|17β-hydroxysteroid dehydrogenase deficiency]]
** [[5-alpha-reductase deficiency|5α-reductase deficiency]]
* Androgen excess in 46,XX individuals:
** [[Congenital adrenal hyperplasia due to 21-hydroxylase deficiency|21-hydroxylase deficiency]]
** [[Congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency|3β-hydroxysteroid dehydrogenase 2 deficiency]]
** [[Cytochrome P450 reductase#POR Deficiency – Mixed Oxidase Disease|Cytochrome P450 oxidoreductase deficiency (disorder in mother causes 46,XX fetal virilization)]]
** [[Congenital adrenal hyperplasia due to 11β-hydroxylase deficiency|11β-hydroxylase deficiency]]
** [[Aromatase deficiency]]
** Glucocorticoid receptor mutations
** Maternal virilizing tumor (e.g. [[luteoma]])
** Increased androgen exposure in utero, not otherwise specified (e.g. [[Anabolic steroid|androgenic drugs]])
* Developmental
** [[Mayer–Rokitansky–Küster–Hauser syndrome]] (46,XX karyotype)
** [[Swyer syndrome]] (46,XY karyotype)
** [[XX gonadal dysgenesis]] (46,XX karyotype)
** [[Leydig cell]] [[agenesis]] or [[hypoplasia]], not otherwise specified (46,XY karyotype)
** [[anorchia|Absent (vanishing) testes syndrome]]
** [[True hermaphroditism|Ovotesticular DSD]]
** [[Testicular DSD]] (i.e. [[Intersex|46,XX sex reversal]])
* [[Teratology#Teratogenic agents|Teratogenic]] causes (e.g. [[estrogens]], [[antiestrogen]]s)
* Other causes:
** [[Frasier syndrome]] (associated with progressive glomerulopathy)
** [[Denys–Drash syndrome]] (associated with nephropathy and Wilms tumor)
** [[WAGR syndrome]] (associated with Wilms tumor and aniridia)
** [[McKusick–Kaufman syndrome]] (associated with postaxial polydactyly)
** [[Robinow syndrome]] (associated with dwarfism)
** [[Aarskog–Scott syndrome]] (associated with facial anomalies)
** [[Hand-foot-genital syndrome]] (associated with limb malformations)
** [[Popliteal pterygium syndrome]] (associated with extensive webbing behind knees)
** [[Kallmann syndrome]] (often associated with anosmia)
** [[Hypospadias]] not otherwise specified
** [[Cryptorchidism]] not otherwise specified
** [[vaginal atresia]] not otherwise specified
}}

===Classification===
[[File:Women with androgen insensitivity syndrome.jpg|thumb|238px|Individuals with AIS and related [[Disorders of sex development|DSD]]/[[intersex]] conditions]]

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).<ref name="2006 hughes 20" /><ref name="2008 galani 7" /><ref name="2008 zuccarello 68" /><ref name="2006 ferlin 65" /><ref name="2009 stouffs 15" /><ref name="2010 ozulker 24" /><ref name="2007 davis-dao 92" /><ref name="2005 kawate 90" /><ref name="2005 gottlieb 10" />  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.<ref name="1995 quigley 16" />  The first six grades of the scale, grades 1 through 6, are differentiated by the degree of [[Development of the reproductive system#External genitalia|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.<ref name="1995 quigley 16" />  Grade 7 is indistinguishable from grade 6 until puberty, and is thereafter differentiated by the presence of [[Secondary sex characteristic|secondary]] [[terminal hair]]; grade 6 is indicated when secondary terminal hair is present, whereas grade 7 is indicated when it is absent.<ref name="1995 quigley 16" />  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.<ref name="2008 galani 7" /><ref name="2001 sultan 7" />

====Complete AIS====
{{Main|Complete androgen insensitivity syndrome}}

====Partial AIS====
{{Main|Partial androgen insensitivity syndrome}}

====Mild AIS====
{{Main|Mild androgen insensitivity syndrome}}

==Management==
Management of AIS is currently limited to [[symptomatic treatment|symptomatic management]]; no method is currently available to correct the malfunctioning androgen receptor proteins produced by ''AR'' gene mutations.  Areas of management include [[sex assignment]], [[genitoplasty]], [[gonadectomy]] in relation to [[germ cell tumor|tumor]] risk, [[Hormone replacement therapy (menopause)|hormone replacement therapy]], [[genetic counseling]], and [[psychotherapy|psychological counseling]].{{citation needed|date=September 2021}}

===MAIS===
{{Main|Mild androgen insensitivity syndrome#Management|l1=Management of Mild Androgen Insensitivity Syndrome}}

===PAIS===
{{Main|Partial androgen insensitivity syndrome#Management|l1=Management of Partial Androgen Insensitivity Syndrome}}

===CAIS===
{{Main|Complete androgen insensitivity syndrome#Management|l1=Management of Complete Androgen Insensitivity Syndrome}}

==Epidemiology==
AIS represents about 15% to 20% of [[Disorders of sex development|DSDs]] and affects 1 in 20,000 to 1 in 64,000 males.<ref>{{Cite book|last1=Nistal|first1=Manuel|url=https://books.google.com/books?id=Xi9IDgAAQBAJ&q=androgen+insensitivity+syndrome|title=Clues in the Diagnosis of Non-tumoral Testicular Pathology|last2=González-Peramato|first2=Pilar|last3=Serrano|first3=Álvaro|date=2017-03-07|publisher=Springer|isbn=978-3-319-49364-0|pages=41|language=en}}</ref>

Estimates for the [[Incidence (epidemiology)|incidence]] of androgen insensitivity syndrome are based on a relatively small [[Statistical population|population]] size, thus are known to be imprecise.<ref name="2006 hughes 20" />  CAIS is estimated to occur in one of every 20,400 46,XY births.<ref name="2006 banksboll 71" />  A nationwide survey in the Netherlands based on patients with [[Genetic testing|genetic confirmation]] of the diagnosis estimates that the minimal incidence of CAIS is one in 99,000.<ref name="2001 boehmer 86" />  The incidence of PAIS is estimated to be one in 130,000.<ref name="2010 mazen 73" />  Due to its subtle presentation, MAIS is not typically investigated except in the case of [[male infertility]],<ref name="2008 oakes 21" /> thus its true prevalence is unknown.<ref name="2008 galani 7" />

==Controversy==

===Preimplantation genetic diagnosis===
[[Preimplantation genetic diagnosis]] (PGD or PIGD) refers to genetic profiling of embryos prior to implantation (as a form of embryo profiling), and sometimes even of oocytes prior to fertilization. When used to screen for a specific genetic sequence, its main advantage is that it avoids selective pregnancy termination, as the method makes it highly likely that a selected embryo will be free of the condition under consideration.<ref>{{Cite web|url=https://americanpregnancy.org/getting-pregnant/infertility/preimplantation-genetic-diagnosis-70971|title = Diagnóstico Genético Preimplantacional: DGP|date = 25 April 2017}}</ref>

In the UK, AIS appears on a list of serious genetic diseases that may be screened for via PGD.<ref>[http://guide.hfea.gov.uk/pgd/ PGD conditions licensed by the HFEA] {{webarchive |url=https://web.archive.org/web/20141006102127/http://guide.hfea.gov.uk/pgd/ |date=October 6, 2014 }}, Human Fertilization and Embryology Authority, 1 October 2014. Retrieved on October 1, 2014.</ref>  Some ethicists, clinicians, and intersex advocates have argued that screening embryos to specifically exclude intersex traits is based on social and cultural norms as opposed to medical necessity.<ref name="pmid24024804">{{cite journal | vauthors = Sparrow R | s2cid = 41857961 | title = Gender eugenics? The ethics of PGD for intersex conditions | journal = Am J Bioeth | volume = 13 | issue = 10 | pages = 29–38 | year = 2013 | pmid = 24024804 | doi = 10.1080/15265161.2013.828115 | url = https://research.monash.edu/en/publications/083bdf94-36bc-41fe-8995-fcc8164ff350 }}</ref><ref name="pmid24024805">{{cite journal | vauthors = Behrmann J, Ravitsky V | s2cid = 27065247 | title = Queer liberation, not elimination: why selecting against intersex is not "straight" forward | journal = Am J Bioeth | volume = 13 | issue = 10 | pages = 39–41 | year = 2013 | pmid = 24024805 | doi = 10.1080/15265161.2013.828131 }}</ref><ref name="pmid24024809">{{cite journal | vauthors = Nisker J | s2cid = 6085229 | title = Informed choice and PGD to prevent "intersex conditions" | journal = Am J Bioeth | volume = 13 | issue = 10 | pages = 47–9 | year = 2013 | pmid = 24024809 | doi = 10.1080/15265161.2013.828125 }}</ref>

==History==
Recorded descriptions of the effects of AIS date back hundreds of years, although significant understanding of its underlying [[histopathology]] did not occur until the 1950s.<ref name="2006 hughes 20" />  The [[Taxonomy (biology)|taxonomy]] and [[nomenclature]] associated with androgen insensitivity went through a significant evolution that paralleled this understanding.{{citation needed|date=October 2021}}

===Timeline of major milestones===
* 1950: [[Lawson Wilkins]] administers daily [[methyltestosterone]] to a karyotype 46,XY female patient, who shows no signs of virilization. His experiment is the first documented demonstration of the pathophysiology of AIS.<ref name="1987 perez-palacios 27" /><ref name="1950 wilkins" />
* 1970: [[Mary F. Lyon]] and [[Susan Hawkes]] reported that a gene on the X chromosome caused complete insensitivity to androgens in mice.<ref name="1970 lyon 227" /><ref name="1971 ohno 1" />
* 1981: [[Barbara Migeon]] ''et al.'' narrowed down the locus of the human androgen receptor gene (or a factor controlling the androgen receptor gene) to somewhere between Xq11 and Xq13.<ref name="1981 migeon 78" /><ref name="1988 brown 85" />
* 1988: The human androgen receptor gene is first [[molecular cloning|cloned]] and partially [[genetic analysis|analyzed]] by multiple parties.<ref name="1988 lubahn 240" /><ref name="1988 chang 240" />  Terry Brown ''et al.'' reported the first mutations proven to cause AIS.<ref name="2008 galani 7" /><ref name="1988 brown 85" />
* 1989: Terry Brown ''et al.'' reported the exact locus of the AR gene (Xq11-Xq12),<ref name="1989 brown 44" /> and Dennis Lubahn ''et al.'' published its [[intron]]-[[exon]] boundaries.<ref name="1989 lubahn 86" />
* 1994: The androgen receptor gene mutations database was created to provide a comprehensive listing of mutations published in medical journals and conference proceedings.<ref name="1994 patterson 22" />

===Early terminology===
The first descriptions of the effects of AIS appeared in the medical literature as individual [[case reports]] or as part of a comprehensive description of [[intersex]] physicalities.  In 1839, Scottish obstetrician Sir [[James Young Simpson]] published one such description<ref name="1839 simpson" /> in an exhaustive study of intersexuality that has been credited with advancing the medical community's understanding of the subject.<ref name="2007 king" />  Simpson's system of [[Taxonomy (biology)|taxonomy]], however, was far from the first; taxonomies or descriptions for the classification of intersexuality were developed by Italian physician and physicist [[Fortunio Affaitati|Fortuné Affaitati]] in 1549,<ref name="1549 affaitati" /><ref name="1820 panckoucke 1" /> French surgeon [[Ambroise Paré]] in 1573,<ref name="2007 king" /><ref name="1573 pare" /> French physician and sexology pioneer [[Nicolas Venette]] in 1687 (under the pseudonym Vénitien Salocini),<ref name="1687 venette" /><ref name="1718 jacob" /> and French zoologist [[Isidore Geoffroy Saint-Hilaire]] in 1832.<ref name="1832 st. hilaire" />  All five of these authors used the colloquial term "[[Hermaphrodite#Other uses of the term|hermaphrodite]]" as the foundation of their taxonomies, although Simpson himself questioned the propriety of the word in his publication.<ref name="1839 simpson" />  Use of the word "hermaphrodite" in the medical literature has persisted to this day,<ref name="2009 dorsey 73" /><ref name="2007 verkauskas 177" /> although its propriety is still in question.  An alternative system of nomenclature has been recently suggested,<ref name="2006 hughes 91" /> but the subject of exactly which word or words should be used in its place still one of much debate.<ref name="2008 hughes 22" /><ref name="2007 simmonds 92" /><ref name="2010 zannoni 29" /><ref name="2008 federer 38" /><ref name="2007 reis 50" />

[[File:Pudenda pseudohermaphroditi.jpg|thumb|"Pudenda pseudo-hermaphroditi ovini." Illustration of ambiguous genitalia from Frederik Ruysch's ''Thesaurus Anitomicus Octavius'', 1709.<ref name="1709 ruysch 8" />]]

===Pseudohermaphroditism===
"[[Pseudohermaphroditism]]" has, until very recently,<ref name="2006 hughes 91" /> been the term used in the medical literature to describe the condition of an individual whose gonads do not match the expected external genitalia in of their sex.  For example, 46,XY individuals who have a female phenotype, but also have testes instead of ovaries—a group that includes all individuals with CAIS, as well as some individuals with PAIS—are classified as having "male pseudohermaphroditism", while individuals with both an ovary and a testis (or at least one ovotestis) are classified as having "[[true hermaphroditism]]".<ref name="2007 verkauskas 177" /><ref name="2006 hughes 91" />  Use of the word in the medical literature antedates the discovery of the chromosome,  thus its definition has not always taken karyotype into account when determining an individual's sex.  Previous definitions of "pseudohermaphroditism" relied on perceived inconsistencies between the internal and external organs; the "true" sex of an individual was determined by the internal organs, and the external organs determined the "perceived" sex of an individual.<ref name="1839 simpson" /><ref name="1832 st. hilaire" />

German-Swiss pathologist [[Edwin Klebs]] is sometimes noted for using the word "pseudohermaphroditism" in his taxonomy of [[intersex]]uality in 1876,<ref name="1876 klebs" /> although the word is clearly not his invention as is sometimes reported; the history of the word "[[pseudohermaphrodite]]" and the corresponding desire to separate [[true hermaphrodite|"true" hermaphrodites]] from "false", "spurious", or "pseudo" hermaphrodites, dates back to at least 1709, when Dutch [[anatomist]] [[Frederik Ruysch]] used it in a publication describing a subject with testes and a mostly female phenotype.<ref name="1709 ruysch 8" />  "Pseudohermaphrodite" also appeared in the ''[[Acta Eruditorum]]'' later that same year, in a review of Ruysch's work.<ref name="1709 mencke 28" />  Also some evidence indicates the word was already being used by the German and French medical community long before Klebs used it; German [[physiologist]] [[Johannes Peter Müller]] equated "pseudohermaphroditism" with a subclass of hermaphroditism from Saint-Hilaire's taxonomy in a publication dated 1834,<ref name="1834 muller" /> and by the 1840s "pseudohermaphroditism" was appearing in several French and German publications, including dictionaries.<ref name="1843 academie francaise" /><ref name="1840 ritter von raimann 22" /><ref name="1815 bertuch" /><ref name="1859 peschier" />

===Testicular feminization===
In 1953, American [[gynecologist]] [[John McLean Morris|John Morris]] provided the first full description of what he called "testicular feminization syndrome" based on 82 cases compiled from the medical literature, including two of his own patients.<ref name="2006 hughes 20" /><ref name="1995 quigley 16" /><ref name="1953 morris 65" />  The term "testicular feminization" was coined to reflect Morris' observation that the testicles in these patients produced a hormone that had a feminizing effect on the body, a phenomenon now understood to be due to the inaction of androgens, and subsequent [[aromatization]] of testosterone into estrogen.<ref name="2006 hughes 20" />   A few years before Morris published his landmark paper, [[Lawson Wilkins]] had shown through experiment that unresponsiveness of the target cell to the action of androgenic hormones was a cause of "male pseudohermaphroditism".<ref name="1987 perez-palacios 27" /><ref name="1950 wilkins" />   Wilkins' work, which clearly demonstrated the lack of a therapeutic effect when [[46,XY]] patients were treated with androgens, caused a gradual shift in nomenclature from "testicular feminization" to "androgen resistance".<ref name="2008 oakes 21" />

===Other names===
A distinct name has been given to many of the various presentations of AIS, such as Reifenstein syndrome (1947),<ref name="1947 reifenstein 3" /> Goldberg-Maxwell syndrome (1948),<ref name="1948 goldberg 8" /> Morris' syndrome (1953),<ref name="1953 morris 65" /> Gilbert-Dreyfus syndrome (1957),<ref name="1957 gilbert-dreyfus 18" /> Lub's syndrome (1959),<ref name="1959 lubs 19" /> "incomplete testicular feminization" (1963),<ref name="1963 morris 87" /> Rosewater syndrome (1965),<ref name="1965 rosewater 63" /> and Aiman's syndrome (1979).<ref name="1979 aiman 300" />  Since it was not understood that these different presentations were all caused by the same set of mutations in the androgen receptor gene, a unique name was given to each new combination of symptoms, resulting in a complicated stratification of seemingly disparate disorders.<ref name="1987 perez-palacios 27" /><ref name="2008 simpson" />

Over the last 60 years, as reports of strikingly different phenotypes were reported to occur even among members of the same family, and as steady progress was made towards the understanding of the underlying molecular [[pathogenesis]] of AIS, these disorders were found to be different phenotypic expressions of one syndrome caused by molecular defects in the androgen receptor gene.<ref name="2006 hughes 20" /><ref name="2005 gottlieb 10" /><ref name="1987 perez-palacios 27" /><ref name="2008 simpson" />

AIS is now the accepted terminology for the syndromes resulting from unresponsiveness of the target cell to the action of androgenic hormones.<ref name="2006 hughes 20" />  CAIS encompasses the phenotypes previously described by "testicular feminization", Morris' syndrome, and Goldberg-Maxwell syndrome;<ref name="2006 hughes 20" /><ref name="2004 hester 16" /> PAIS includes Reifenstein syndrome, Gilbert-Dreyfus syndrome, Lub's syndrome, "incomplete testicular feminization", and Rosewater syndrome;<ref name="2008 simpson" /><ref name="1999 mcphaul 69" /><ref name="2000 miller" /> and MAIS includes Aiman's syndrome.<ref name="2002 sultan 20" />

The more virilized phenotypes of AIS have sometimes been described as "undervirilized male syndrome", "infertile male syndrome", "undervirilized fertile male syndrome", etc., before evidence was reported that these conditions were caused by mutations in the ''AR'' gene.<ref name="1994 tsukada 79" />  These diagnoses were used to describe a variety of mild defects in virilization; as a result, the phenotypes of some men who have been diagnosed as such are better described by PAIS (e.g. [[micropenis]], [[hypospadias]], and [[cryptorchidism|undescended testes]]), while others are better described by MAIS (e.g. isolated male infertility or gynecomastia).<ref name="2006 hughes 20" /><ref name="1994 tsukada 79" /><ref name="2000 giwercman 85" /><ref name="2000 miller" /><ref name="2002 chu 87" /><ref name="1997 mesched 3" />

== Society and culture ==

In the film ''[[Orchids, My Intersex Adventure]]'', [[Phoebe Hart]] and her sister [[Bonnie Hart]], both women with CAIS, documented their exploration of AIS and other intersex issues.<ref name="Hart">{{Cite web|url=http://www.orchids-themovie.com/index.html|title=Orchids: My Intersex Adventure |last=Hart |first=Phoebe | name-list-style = vanc |publisher=hartflicker Moving Pictures|archive-url=https://web.archive.org/web/20171211183007/http://www.orchids-themovie.com/index.html|archive-date=2017-12-11|url-status=dead}}</ref>

Recording artist Dalea is a Hispanic-American Activist who is public about her CAIS. She has given interviews about her condition<ref>{{Cite web|url=http://vadamagazine.com/entertainment/arts/challenging-perspectives-interview-dalea|title=Challenging Perspectives: Interview Dalea|last=Carter|first=Sophia | name-list-style = vanc |date=31 May 2014|publisher=Vada Magazine|access-date=23 January 2017}}</ref><ref>{{Cite web|url=http://www.cosmopolitan.com/sex-love/q-and-a/a30357/what-its-really-like-to-be-intersex/|title=What It's Really Like to be Intersex|last=Peikoff|first=Kira | name-list-style = vanc |date=22 August 2014|website=Cosmopolitan|access-date=23 January 2017}}</ref> and founded Girl Comet, a non-profit diversity awareness and inspiration initiative.<ref>{{Cite web|url=http://www.daleamusic.com/girl-comet.html|title=All about 'Girl Comet'|website=Dalea Music |language=en|access-date=2017-01-24|archive-url=https://web.archive.org/web/20161225151547/http://www.daleamusic.com/girl-comet.html|archive-date=2016-12-25|url-status=dead}}</ref>

In 2017, fashion model [[Hanne Gaby Odiele]] disclosed that they were born with androgen insensitivity syndrome. As a child, they underwent [[intersex medical interventions|medical procedures relating to the condition]],<ref name="interAct">{{cite web | url = http://interactadvocates.org/wp-content/uploads/2017/01/PRESSRELEASE-HannesAnnouncement.pdf | title = International Fashion Model Hanne Gaby Odiele Reveals She is Intersex; Announces Partnership with interACT Advocates for Intersex Youth to Raise Awareness About the Importance of Human Rights Protections for Intersex People Worldwide | work = [[Interact Advocates for Intersex Youth|interACT]] | date = January 23, 2017}}</ref> which they said took place without their or their parents' informed consent.<ref name="dazed2017">{{Cite news| issue = 250| last1 = Faye| first1 = Shon| last2 = Balzary| first2 = Clare| last3 = Wyman| first3 = Emma| last4 = Jawara| last5 = Sobol| first5 = Susie| last6 = Shelley| first6 = Noah | name-list-style = vanc | title = Hanne Gaby Odiele| work = [[Dazed]]| date = 2017| url = http://www.womenmanagement.com/hanne-gaby-odiele-dazed-confused-spring-2017/| access-date = 2017-05-30| archive-url = https://web.archive.org/web/20180907110245/http://www.womenmanagement.com/hanne-gaby-odiele-dazed-confused-spring-2017/| archive-date = 2018-09-07| url-status = dead}}</ref> They were told about their intersex condition weeks before beginning their modelling career.<ref name="dazed2017" />

In the 1991 Japanese horror novel [[Ring (Suzuki novel)|''Ring'']] and its sequels, by [[Koji Suzuki (writer)|Koji Suzuki]] (later adapted into Japanese, Korean, and American films), the central antagonist [[Sadako Yamamura|Sadako]] has this syndrome, as revealed by Dr Nagao when confronted by Ryuji and Asakawa.<ref>{{cite book | chapter = Chapter 11-12 | isbn = 9780007331574 | date = 2015-10-06 | publisher = HarperCollins | first1 = Koji | last1 = Suzuki | title = Ring | translator-first1 = Robert B. | translator-last1 = Rohmer | translator-first2 = Glynne | translator-last2 = Walley}}</ref> Sadako's condition is referred to by the earlier name "testicular feminisation syndrome".

In [[House (season 2)|season 2]], episode 13 ("Skin Deep") of the [[House (TV series)|TV series ''House'']], the main patient's [[testicular cancer|cancerous testicle]] is mistaken for an ovary due to the patient's undiscovered CAIS.<ref>{{Cite web|url=https://www.youtube.com/watch?v=2ry6hn9twow|title=I AM A GIRL! House M.D.|website=[[YouTube]]|date=2020-01-15|access-date=2022-07-01}}</ref> The episode has been criticized for its medical inaccuracy as well as its stigmatizing and offensive portrayal of CAIS.<ref>{{Cite web |title=House Gets It Wrong {{!}} Intersex Society of North America |url=https://isna.org/node/1008/ |access-date=2024-06-14 |website=isna.org}}</ref>

In season 2 of the [[MTV]] series [[Faking It (2014 TV series)|''Faking It'']], a character has CAIS. The character, Lauren Cooper, played by [[Bailey De Young]], was the first intersex series regular on American television.<ref>{{Cite web|url=http://www.hollywoodreporter.com/live-feed/faking-canceled-carter-covington-interview-892656|title='Faking It' canceled; Carter Covington interview – Hollywood Reporter|website=[[The Hollywood Reporter]]|date=2016-05-16|archive-url=https://web.archive.org/web/20160516011652/http://www.hollywoodreporter.com/live-feed/faking-canceled-carter-covington-interview-892656|archive-date=2016-05-16|access-date=2019-02-11|quote=What the show will really be known for is Lauren's coming out as intersex and being the first series regular who is intersex on television}}</ref><ref>{{Cite web|url=https://www.bustle.com/articles/40063-faking-it-season-2-spoilers-reveal-that-lauren-is-intersex-thats-a-huge-step-forward|title='Faking It' Will Make LGBT History in Season 2|last=Kay|first=Ariel | name-list-style = vanc |website=Bustle|date=16 September 2014 |language=en|access-date=2019-02-11}}</ref>

In [[CSI: Miami (season 8)|season 8]], episode 11 ("Delko for the Defense") of the [[CSI: Miami|TV series ''CSI: Miami'']], the primary suspect has AIS which gets him off a rape charge.{{citation needed|date=August 2020}}

In series 8, episode 5 of ''[[Call the Midwife]]'', a woman discovers that she has AIS. She attends a [[cervical smear]] and brings up that she has never had a period, and is concerned about having children as she is about to be married. She is then diagnosed with "testicular feminisation syndrome", the old term for AIS.<ref>{{Cite web|url=https://www.radiotimes.com/news/tv/2019-02-10/call-the-midwife-what-is-testicular-feminisation-syndrome/|title=Call the Midwife: What is Testicular Feminisation Syndrome?|website=Radio Times|language=en|access-date=2019-02-11}}</ref>

===People with AIS===
* [[Kitty Anderson (activist)]]<ref name="interface">{{Cite web |url=https://www.interfaceproject.org/kitty-anderson/ |title=Kitty Anderson – Reykjavík, Iceland |website=[[Interact Advocates for Intersex Youth#Interface Project|Interface Project]] |date=October 2017| access-date = 2018-11-22}}</ref><ref name="amnesty">{{Cite web |author=Amnesty International |title=Understanding the 'i' in LGBTI |access-date=2018-11-22 |date=October 25, 2016 |url=https://www.amnesty.org/en/latest/news/2016/10/intersex-awareness-day/}}</ref>
* [[Eden Atwood]]<ref>{{Cite web|title=Eden Atwood|url=https://montanakids.com/cool_stories/famous_montanans/atwood.htm|access-date=2021-10-23|website=Montana Kids|publisher=Montana Office of Tourism}}</ref>
* [[Bonnie Hart]]<ref name="Hart"/>
* [[Phoebe Hart]]<ref name="Hart"/>
* [[Maria José Martínez-Patiño]]<ref name=Cole>{{cite book|last=Cole|first=Cheryl L.|editor=Kay Schaffer|others=Sidonie Smith|editor-link2=Sidonie Smith|title=The Olympics at the Millennium: Power, Politics, and the Games|chapter-url=https://books.google.com/books?id=nMzYdZpk8qMC&pg=PA138|access-date=2 March 2015|year=2000|publisher=Rutgers UP|isbn=9780813528205|pages=128–146|chapter=One Chromosome Too Many?}}</ref>
* [[Hanne Gaby Odiele]]<ref name="miller2017">{{cite web | url = https://www.usatoday.com/story/news/nation/2017/01/23/model-hanne-gaby-odiele-reveals-she-intersex/96622908/ | title = Model Hanne Gaby Odiele Reveals She Is Intersex  | last = Miller | first = Susan | work = [[USA Today]] | date = 23 January 2017}}</ref><ref name="BBC News">{{cite web | url = https://www.bbc.co.uk/news/world-europe-38730291 | title = Model Hanne Gaby Odiele reveals she is intersex to 'break taboo'  | work = [[BBC News]] | date = 24 January 2017}}</ref>
* [[Santhi Soundarajan]]<ref name="thappad">{{cite web| url = http://thappad.in/petition/shanti/ | title = #FairTreatment for Shanthi Soundarajan | work = Thappad |year = 2016}}</ref><ref name="huff2016">{{cite web|first=Sonam |last=Joshi |url=http://www.huffingtonpost.in/2016/08/09/why-we-should-join-the-campaign-seeking-justice-for-runner-shant/ |title=Why We Should Join The Campaign Seeking Justice For Runner Shanthi Soundarajan |website=Huffingtonpost.in |access-date=2017-03-02 |archive-url=https://web.archive.org/web/20170317113808/http://www.huffingtonpost.in/2016/08/09/why-we-should-join-the-campaign-seeking-justice-for-runner-shant/ |archive-date=2017-03-17}}</ref>
* [[Miriam van der Have]]<ref name="vice2014">{{cite web | url = https://www.vice.com/nl/article/duizenden-nederlanders-passen-niet-in-het-biologische-hokje-man-of-vrouw-312/ | title =Duizenden Nederlanders passen niet in het biologische hokje man of vrouw | last = Punt | first = Anne | work = [[Vice (magazine)|Vice]] | access-date = 2017-01-12 | date = August 28, 2014}}</ref>
* [[Kimberly Zieselman]]<ref name="goodh">{{Cite web| last = Fogle| first = Asher| title = Falling In Between: Inside the lives of intersex women| work = [[Good Housekeeping]]| access-date = 2017-08-05| date = October 21, 2016| url = http://www.goodhousekeeping.com/life/a40787/intersex-stories/}}</ref>

====People with Complete androgen insensitivity syndrome====
* [[Georgiann Davis]]<ref>{{cite web | url = http://www.interfaceproject.org/georgiann-davis/ | title = Georgiann Davis | work = [[Advocates for Informed Choice#The Interface Project|The Interface Project]] | date = November 7, 2012}}</ref>
* [[Seven Graham]]<ref name="Independent Special Report">{{cite news|url=https://www.independent.co.uk/news/uk/home-news/special-report-intersex-women-speak-out-to-protect-the-next-generation-8974892.html |archive-url=https://ghostarchive.org/archive/20220507/https://www.independent.co.uk/news/uk/home-news/special-report-intersex-women-speak-out-to-protect-the-next-generation-8974892.html |archive-date=2022-05-07 |url-access=subscription |url-status=live|newspaper=[[The Independent]]|title=Special report: Intersex women speak out to protect the next generation|first=Sarah|last=Morrison|date=30 November 2013|access-date=19 November 2015}}{{cbignore}}</ref>
* [[Alicia Roth Weigel]]

====People with Partial androgen insensitivity syndrome====
* [[Tony Briffa (politician)|Tony Briffa]]<ref name="Cr Tony Briffa">{{cite web | url = http://briffa.org/about | title = About Tony | work = Briffa.org | date = 2012 | access-date = 2020-12-28 | archive-date = 2014-04-06 | archive-url = https://web.archive.org/web/20140406012528/http://briffa.org/about | url-status = dead }}</ref><ref name="transcript">{{Citation
| title = Involuntary or coerced sterilisation of people with disabilities in Australia: Thursday 28 March 2013
| location = Canberra
| date = 28 March 2013
| last1 = Senate of Australia
| last2 = Community Affairs References Committee
| url = http://www.aph.gov.au/hansard
| author1-link = Senate of Australia
}}</ref>
* [[Favorinus|Favorinus of Arelate]] has been described as having partial androgen insensitivity syndrome.<ref name="retief">{{Cite journal| volume = 93| issue = 1| pages = 73–76| last1 = Retief| first1 = F P| last2 = Cilliers| first2 = J F G| title = Congenital eunuchism and Favorinus| journal = South African Medical Journal| date = 2003| pmid = 12564336| url = http://www.samj.org.za/index.php/samj/article/viewFile/2019/1278}}</ref><ref>Mason, H.J., Favorinus’ Disorder: Reifenstein’s Syndrome in Antiquity?, in Janus 66 (1978) 1–13.</ref>
* [[Small Luk]]<ref name="time">{{cite news | url = http://www.timeout.com.hk/gay-lesbian/features/72091/interview-we-talk-to-intersex-individual-dr-small-luk-about-her-gender-struggles.html | title = We talk to intersex individual Dr Small Luk about her gender struggles | publisher = Time Out Hong Kong | access-date = 2020-12-28 | archive-date = 2016-05-29 | archive-url = https://web.archive.org/web/20160529011535/http://www.timeout.com.hk/gay-lesbian/features/72091/interview-we-talk-to-intersex-individual-dr-small-luk-about-her-gender-struggles.html | url-status = dead }}</ref>
* [[Eliana Rubashkyn]]<ref>{{cite news|url=http://www.inmediahk.net/node/eliana|title=專訪：前跨性別難民Eliana（國際特赦組織香港分會人權雜誌春季號）Interview: Former Transgender Refugee Eliana (Amnesty International Hong Kong) Human Rights Magazine Spring Issue)|date=28 April 2016}}</ref><ref name="3news">{{cite web| title = Gender refugee hopes for NZ citizenship| url = http://www.3news.co.nz/tvshows/3d/gender-refugee-hopes-for-nz-citizenship-2015072616| publisher = 3 Degrees - TV3 New Zealand| date = 26 July 2015| access-date = 23 December 2015| archive-url = https://web.archive.org/web/20151225151833/http://www.3news.co.nz/tvshows/3d/gender-refugee-hopes-for-nz-citizenship-2015072616| archive-date = 25 December 2015| url-status = dead}}</ref><ref>{{cite web | url = http://www.kienyke.com/historias/el-purgatorio-de-una-transgenero-victima-de-un-pasaporte-con-sexo-masculino/ | title = El purgatorio de una transgénero víctima de un pasaporte con sexo masculino | first = Alejandro | last = Vesga | date = 11 July 2015}}</ref>
* [[Sean Saifa Wall]]<ref name="wall2016">{{Cite web| last = Wall| first = Sean Saifa| title = Love, complexity and inter-sectionality| work = [[Intersex Day]]| access-date = 2017-01-19| date = November 8, 2016 | url = http://intersexday.org/en/love-complexity-intersectionality/}}</ref>
* [[Sogto Ochirov]]<ref>{{Cite web |last=один |first=Номер |title=Бурятский лучник полжизни провел в чужом теле |url=https://gazeta-n1.ru/news/society/111724/ |access-date=2022-05-30 |website=gazeta-n1.ru |language=ru}}</ref>

==See also==
* [[Estrogen insensitivity syndrome]]
* [[Spinal and bulbar muscular atrophy]]
* [[Congenital adrenal hyperplasia]]
* [[5α-Reductase 2 deficiency]]

==References==
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<ref name="lead:1">
{{cite journal |vauthors=Hughes IA, Deeb A | title = Androgen resistance | journal = Best Pract. Res. Clin. Endocrinol. Metab. | volume = 20 | issue = 4 | pages = 577–98 |date=December 2006 | pmid = 17161333 | doi = 10.1016/j.beem.2006.11.003 }}
{{cite journal |vauthors=Galani A, Kitsiou-Tzeli S, Sofokleous C, Kanavakis E, Kalpini-Mavrou A | title = Androgen insensitivity syndrome: clinical features and molecular defects | journal = Hormones (Athens) | volume = 7 | issue = 3 | pages = 217–29 | year = 2008 | pmid = 18694860 | doi = 10.14310/horm.2002.1201| doi-access = free }}
{{cite journal |vauthors=Quigley CA, De Bellis A, Marschke KB, el-Awady MK, Wilson EM, French FS | title = Androgen receptor defects: historical, clinical, and molecular perspectives | journal = Endocr. Rev. | volume = 16 | issue = 3 | pages = 271–321 |date=June 1995 | pmid = 7671849 | doi = 10.1210/edrv-16-3-271}}</ref>

<ref name="lead:2">
* {{cite journal |vauthors=Hughes IA, Deeb A | title = Androgen resistance | journal = Best Pract. Res. Clin. Endocrinol. Metab. | volume = 20 | issue = 4 | pages = 577–98 |date=December 2006 | pmid = 17161333 | doi = 10.1016/j.beem.2006.11.003 }}
* {{cite journal |vauthors=Zuccarello D, Ferlin A, Vinanzi C, Prana E, Garolla A, Callewaert L, Claessens F, Brinkmann AO, Foresta C | title = Detailed functional studies on androgen receptor mild mutations demonstrate their association with male infertility | journal = Clin. Endocrinol. | volume = 68 | issue = 4 | pages = 580–8 |date=April 2008 | pmid = 17970778 | doi = 10.1111/j.1365-2265.2007.03069.x | s2cid = 2783902 }}
* {{cite journal |vauthors=Ferlin A, Vinanzi C, Garolla A, Selice R, Zuccarello D, Cazzadore C, Foresta C | title = Male infertility and androgen receptor gene mutations: clinical features and identification of seven novel mutations | journal = Clin. Endocrinol. | volume = 65 | issue = 5 | pages = 606–10 |date=November 2006 | pmid = 17054461 | doi = 10.1111/j.1365-2265.2006.02635.x | s2cid = 33713391 }}
* {{cite journal |vauthors=Stouffs K, Tournaye H, Liebaers I, Lissens W | title = Male infertility and the involvement of the X chromosome | journal = Hum. Reprod. Update | volume = 15 | issue = 6 | pages = 623–37 | year = 2009 | pmid = 19515807 | doi = 10.1093/humupd/dmp023 | doi-access = free }}
* {{cite journal |vauthors=Giwercman YL, Nikoshkov A, Byström B, Pousette A, Arver S, Wedell A | title = A novel mutation (N233K) in the transactivating domain and the N756S mutation in the ligand binding domain of the androgen receptor gene are associated with male infertility | journal = Clin. Endocrinol. | volume = 54 | issue = 6 | pages = 827–34 |date=June 2001 | pmid = 11422119 | doi =10.1046/j.1365-2265.2001.01308.x | s2cid = 23554058 }}
* {{cite journal |vauthors=Lund A, Juvonen V, Lähdetie J, Aittomäki K, Tapanainen JS, Savontaus ML | title = A novel sequence variation in the transactivation regulating domain of the androgen receptor in two infertile Finnish men | series = 79 | journal = Fertil. Steril. | volume = Suppl 3 | pages = 1647–8 |date=June 2003 | pmid = 12801573 | doi = 10.1016/s0015-0282(03)00256-5| doi-access = free }}</ref>

<ref name="lead:3">
* {{cite journal |vauthors=Hughes IA, Deeb A | title = Androgen resistance | journal = Best Pract. Res. Clin. Endocrinol. Metab. | volume = 20 | issue = 4 | pages = 577–98 |date=December 2006 | pmid = 17161333 | doi = 10.1016/j.beem.2006.11.003 }}
* {{cite journal |vauthors=Galani A, Kitsiou-Tzeli S, Sofokleous C, Kanavakis E, Kalpini-Mavrou A | title = Androgen insensitivity syndrome: clinical features and molecular defects | journal = Hormones (Athens) | volume = 7 | issue = 3 | pages = 217–29 | year = 2008 | pmid = 18694860 | doi = 10.14310/horm.2002.1201| doi-access = free }}
* {{cite journal |vauthors=Zuccarello D, Ferlin A, Vinanzi C, Prana E, Garolla A, Callewaert L, Claessens F, Brinkmann AO, Foresta C | title = Detailed functional studies on androgen receptor mild mutations demonstrate their association with male infertility | journal = Clin. Endocrinol. | volume = 68 | issue = 4 | pages = 580–8 |date=April 2008 | pmid = 17970778 | doi = 10.1111/j.1365-2265.2007.03069.x | s2cid = 2783902 }}
* {{cite journal |vauthors=Ferlin A, Vinanzi C, Garolla A, Selice R, Zuccarello D, Cazzadore C, Foresta C | title = Male infertility and androgen receptor gene mutations: clinical features and identification of seven novel mutations | journal = Clin. Endocrinol. | volume = 65 | issue = 5 | pages = 606–10 |date=November 2006 | pmid = 17054461 | doi = 10.1111/j.1365-2265.2006.02635.x | s2cid = 33713391 }}
</ref>

<ref name="lead:4">
* {{cite journal |vauthors=Stouffs K, Tournaye H, Liebaers I, Lissens W | title = Male infertility and the involvement of the X chromosome | journal = Hum. Reprod. Update | volume = 15 | issue = 6 | pages = 623–37 | year = 2009 | pmid = 19515807 | doi = 10.1093/humupd/dmp023 | doi-access = free }}
* {{cite journal |vauthors=Ozülker T, Ozpaçaci T, Ozülker F, Ozekici U, Bilgiç R, Mert M | title = Incidental detection of Sertoli-Leydig cell tumor by FDG PET/CT imaging in a patient with androgen insensitivity syndrome | journal = Ann Nucl Med | volume = 24 | issue = 1 | pages = 35–9 |date=January 2010 | pmid = 19957213 | doi = 10.1007/s12149-009-0321-x | s2cid = 10450803 }}
* {{cite journal |vauthors=Davis-Dao CA, Tuazon ED, Sokol RZ, Cortessis VK | title = Male infertility and variation in CAG repeat length in the androgen receptor gene: a meta-analysis | journal = J. Clin. Endocrinol. Metab. | volume = 92 | issue = 11 | pages = 4319–26 |date=November 2007 | pmid = 17684052 | doi = 10.1210/jc.2007-1110 | doi-access = free }}
* {{cite journal |vauthors=Kawate H, Wu Y, Ohnaka K, Tao RH, Nakamura K, Okabe T, Yanase T, Nawata H, Takayanagi R | title = Impaired nuclear translocation, nuclear matrix targeting, and intranuclear mobility of mutant androgen receptors carrying amino acid substitutions in the deoxyribonucleic acid-binding domain derived from androgen insensitivity syndrome patients | journal = J. Clin. Endocrinol. Metab. | volume = 90 | issue = 11 | pages = 6162–9 |date=November 2005 | pmid = 16118342 | doi = 10.1210/jc.2005-0179 | doi-access = free }}
* {{cite journal |vauthors=Gottlieb B, Lombroso R, Beitel LK, Trifiro MA | title = Molecular pathology of the androgen receptor in male (in)fertility | journal = Reprod. Biomed. Online | volume = 10 | issue = 1 | pages = 42–8 |date=January 2005 | pmid = 15705293 | doi = 10.1016/S1472-6483(10)60802-4 }}
</ref>

}}

== External links ==
{{Medical resources
|   DiseasesDB     = 29662
|   ICD11          = {{ICD11| 5A81}}
|   ICD10          = {{ICD10|E|34|5|e|20}}
|   ICD9           = {{ICD9|259.5}}
|   ICDO           =
|   OMIM           = 312300
|   OMIM_mult      = {{OMIM|300068||none}}
|   MedlinePlus    = 001180
|   eMedicineSubj  = ped
|   eMedicineTopic = 2222
|   MeshID         = D013734
|   GeneReviewsNBK  = NBK1429
|   GeneReviewsName = Androgen insensitivity syndrome
}}

===Information===
* {{GeneTests|androgen|Androgen Insensitivity Syndrome}}
* {{OMIM|300068|Androgen Insensitivity Syndrome}},{{OMIM|313700||none}}

{{Gonadal disorder}}
{{X-linked disorders}}
{{Intracellular receptor deficiencies}}

{{DEFAULTSORT:Androgen Insensitivity Syndrome}}
[[Category:Transcription factor deficiencies]]
[[Category:Syndromes affecting the endocrine system]]
[[Category:Endocrine gonad disorders]]
[[Category:Syndromes with tumors]]
[[Category:Intersex variations]]