Androgen insensitivity syndrome

Template:Infobox medical condition (new) Androgen insensitivity syndrome (AIS) is a condition involving the inability to respond to androgens, typically due to androgen receptor dysfunction.<ref>Template:Cite book</ref>

It affects 1 in 20,000 to 64,000 XY (karyotypically male) births. The condition results in the partial or complete inability of cells to respond to androgens.<ref name="lead:1" /> This unresponsiveness can impair or prevent the development of male genitals, as well as impairing or preventing the development of male 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, or more specifically, an SRY gene).<ref name="2006 hughes 20" /> Clinical phenotypes in these individuals range from a typical male habitus with mild spermatogenic defect or reduced secondary terminal hair, to a full 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 genital masculinization:

• Mild androgen insensitivity syndrome (MAIS) is indicated when the external genitalia are those of a typical male (a 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 undermasculinized genitalia.<ref name="1999 ahmed 80" />

Management of AIS is currently limited to 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 tumor risk, hormone replacement therapy, genetic counseling, and psychological counseling.

Genetics

File:Functional domains of the human androgen receptor.svg

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 proximal long arm of the X chromosome (locus Xq11-Xq12).<ref name="1989 brown 44" /> The 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 kb.<ref name="1995 quigley 16" /> Like other nuclear receptors, the AR protein consists of several functional domains: the transactivation domain (also called the transcription-regulation domain or the amino / NH2-terminal domain), the DNA-binding domain, the hinge region, and the steroid-binding domain (also called the carboxyl-terminal 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 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 polymorphic trinucleotide microsatellites in exon 1.<ref name="2008 galani 7" /> The first microsatellite (nearest the 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 transcriptional activity in the AR protein, and that longer polyglutamine tracts may be associated with male infertility<ref name="2003 casella 169" /><ref name="1999 dowsing 354" /><ref name="1997 tut 82" /> and 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" /> Inheritance is typically maternal and follows an X-linked recessive pattern;<ref name="2006 hughes 20" /><ref name="2001 gottlieb 17" /> individuals with a 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 mutations are the result of a germ cell mutation or germ cell mosaicism in the gonads of one of the parents, or a mutation in the 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 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 (SF-1) protein.<ref name="2007 coutant 92" /> In another patient, CAIS was the result of a deficit in the transmission of a transactivating signal from the N-terminal region of the androgen receptor to the 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).Template:Needs source 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 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>Template:Cite web</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.<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 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 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.Template:Citation needed

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 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.Template:Citation needed

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 and polyglycine tracts,<ref name="2006 werner 91" /> sensitivity to and variations in the intrauterine endocrine milieu,Template:Needs source the effect of 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 5RD2 gene in genital skin fibroblasts,<ref name="2001 boehmer 86" /> reduced AR transcription and translation from factors other than mutations in the AR coding region,<ref name="2005 holterhus 83" /> an unidentified 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 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

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

Template:Main The effects that androgens have on the human body (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" />

In this way, androgens bound to androgen receptors regulate the expression of target genes, thus produce androgenic effects.<ref>Template:Cite journal</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 unliganded conformation.<ref name="1995 quigley 16" />

File:Human sexual differentiation.gif

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 genital ridges at the back of the abdominal cavity, near the midline. By the fifth week, the genital ridges differentiate into an outer cortex and an inner medulla, and are called 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 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 internal genitalia (uterus, cervix, fallopian tubes, and 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 epididymides, 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

Masculinization of the male genitalia is dependent on both testosterone and dihydrotestosterone.<ref name="2000 gilbert" />

Masculinization of the male external genitalia (the 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 internal male genitalia, a functional androgen receptor is needed for dihydrotestosterone to regulate the 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 transcriptional ability of the 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 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 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 androgen binding affinity or retention, mutations in the hinge region have been known to affect 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 phenotypical consequences of a particular mutation (see Correlation of genotype and phenotype) is difficult.Template:Citation needed

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 downstream functional domains if a premature stop codon or 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 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 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 proteolyze and disperse properly.<ref name="1999 stenoien 8" /> These misfolded AR proteins form aggregates in the cell cytoplasm and nucleus.<ref name="1999 stenoien 8" /> Over the course of 30 to 50 years, these aggregates accumulate and have a cytotoxic effect, eventually resulting in the 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 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 gene sequencing reveals a mutation, although not all individuals with AIS (particularly PAIS) will have an AR mutation (see 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>Template:Cite journal</ref><ref>Template:Cite journal</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" /> Template:Columns-list

Classification

File:Women with androgen insensitivity syndrome.jpg

Individuals with AIS and related 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 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 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" />

Management

Management of AIS is currently limited to 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 tumor risk, hormone replacement therapy, genetic counseling, and psychological counseling.Template:Citation needed

Epidemiology

AIS represents about 15% to 20% of DSDs and affects 1 in 20,000 to 1 in 64,000 males.<ref>Template:Cite book</ref>

Estimates for the incidence of androgen insensitivity syndrome are based on a relatively small 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 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>Template:Cite web</ref>

In the UK, AIS appears on a list of serious genetic diseases that may be screened for via PGD.<ref>PGD conditions licensed by the HFEA Template:Webarchive, 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">Template:Cite journal</ref><ref name="pmid24024805">Template:Cite journal</ref><ref name="pmid24024809">Template:Cite journal</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 and nomenclature associated with androgen insensitivity went through a significant evolution that paralleled this understanding.Template:Citation needed

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 cloned and partially 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, however, was far from the first; taxonomies or descriptions for the classification of intersexuality were developed by Italian physician and physicist 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" 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

"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 intersexuality 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" 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 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 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">Template:Cite web</ref>

Recording artist Dalea is a Hispanic-American Activist who is public about her CAIS. She has given interviews about her condition<ref>Template:Cite web</ref><ref>Template:Cite web</ref> and founded Girl Comet, a non-profit diversity awareness and inspiration initiative.<ref>Template:Cite web</ref>

In 2017, fashion model Hanne Gaby Odiele disclosed that they were born with androgen insensitivity syndrome. As a child, they underwent medical procedures relating to the condition,<ref name="interAct">Template:Cite web</ref> which they said took place without their or their parents' informed consent.<ref name="dazed2017">Template:Cite news</ref> They were told about their intersex condition weeks before beginning their modelling career.<ref name="dazed2017" />

In the 1991 Japanese horror novel Ring and its sequels, by Koji Suzuki (later adapted into Japanese, Korean, and American films), the central antagonist Sadako has this syndrome, as revealed by Dr Nagao when confronted by Ryuji and Asakawa.<ref>Template:Cite book</ref> Sadako's condition is referred to by the earlier name "testicular feminisation syndrome".

In season 2, episode 13 ("Skin Deep") of the TV series House, the main patient's cancerous testicle is mistaken for an ovary due to the patient's undiscovered CAIS.<ref>Template:Cite web</ref> The episode has been criticized for its medical inaccuracy as well as its stigmatizing and offensive portrayal of CAIS.<ref>Template:Cite web</ref>

In season 2 of the MTV 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>Template:Cite web</ref><ref>Template:Cite web</ref>

In season 8, episode 11 ("Delko for the Defense") of the TV series CSI: Miami, the primary suspect has AIS which gets him off a rape charge.Template:Citation needed

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>Template:Cite web</ref>

People with AIS

• Kitty Anderson (activist)<ref name="interface">Template:Cite web</ref><ref name="amnesty">Template:Cite web</ref>
• Eden Atwood<ref>Template:Cite web</ref>
• Bonnie Hart<ref name="Hart"/>
• Phoebe Hart<ref name="Hart"/>
• Maria José Martínez-Patiño<ref name=Cole>Template:Cite book</ref>
• Hanne Gaby Odiele<ref name="miller2017">Template:Cite web</ref><ref name="BBC News">Template:Cite web</ref>
• Santhi Soundarajan<ref name="thappad">Template:Cite web</ref><ref name="huff2016">Template:Cite web</ref>
• Miriam van der Have<ref name="vice2014">Template:Cite web</ref>
• Kimberly Zieselman<ref name="goodh">Template:Cite web</ref>

People with Complete androgen insensitivity syndrome

• Georgiann Davis<ref>Template:Cite web</ref>
• Seven Graham<ref name="Independent Special Report">Template:Cite newsTemplate:Cbignore</ref>
• Alicia Roth Weigel

People with Partial androgen insensitivity syndrome

• Tony Briffa<ref name="Cr Tony Briffa">Template:Cite web</ref><ref name="transcript">Template:Citation</ref>
• Favorinus of Arelate has been described as having partial androgen insensitivity syndrome.<ref name="retief">Template:Cite journal</ref><ref>Mason, H.J., Favorinus’ Disorder: Reifenstein’s Syndrome in Antiquity?, in Janus 66 (1978) 1–13.</ref>
• Small Luk<ref name="time">Template:Cite news</ref>
• Eliana Rubashkyn<ref>Template:Cite news</ref><ref name="3news">Template:Cite web</ref><ref>Template:Cite web</ref>
• Sean Saifa Wall<ref name="wall2016">Template:Cite web</ref>
• Sogto Ochirov<ref>Template:Cite web</ref>

See also

• Estrogen insensitivity syndrome
• Spinal and bulbar muscular atrophy
• Congenital adrenal hyperplasia
• 5α-Reductase 2 deficiency

External links

Information

• Template:GeneTests
• Template:OMIM,Template:OMIM