HOME

TheInfoList



OR:

Androgen insensitivity syndrome (AIS) is a condition involving the inability to respond to
androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
s, typically due to
androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in th ...
dysfunction. 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
androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
s. 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 Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a female, the testicles i ...
. It does not significantly impair female genital or sexual development. 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). 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. 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 A penis (; : penises or penes) is a sex organ through which male and hermaphrodite animals expel semen during copulation (zoology), copulation, and through which male placental mammals and marsupials also Urination, urinate. The term ''pen ...
and a
scrotum In most terrestrial mammals, the scrotum (: scrotums or scrota; possibly from Latin ''scortum'', meaning "hide" or "skin") or scrotal sac is a part of the external male genitalia located at the base of the penis. It consists of a sac of skin ...
) * Partial androgen insensitivity syndrome (PAIS) is indicated when the external genitalia are partially, but not fully, masculinized * Complete androgen insensitivity syndrome (CAIS) is indicated when the external genitalia are those of a typical female (a
vulva In mammals, the vulva (: vulvas or vulvae) comprises mostly external, visible structures of the female sex organ, genitalia leading into the interior of the female reproductive tract. For humans, it includes the mons pubis, labia majora, lab ...
) Androgen insensitivity syndrome is the largest single entity that leads to 46,XY undermasculinized genitalia. 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 Sex assignment (also known as gender assignment) is the discernment of an infant's sex, typically made at birth based on an examination of the baby's external genitalia by a healthcare provider such as a midwife, nurse, or physician. In the v ...
, genitoplasty, gonadectomy to reduce
tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
risk, hormone replacement therapy, genetic counseling, and psychological counseling.


Genetics

The human
androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in th ...
(AR) is a protein encoded by a
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
located on the proximal long arm of the X chromosome ( locus Xq11-Xq12). The protein coding region consists of approximately 2,757
nucleotides Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...
(919 codons) spanning eight exons, designated 1-8 or A-H.
Introns An intron is any Nucleic acid sequence, nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of ...
vary in size between 0.7 and 26 kb. 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). The transactivation domain is encoded by exon 1, and makes up more than half of the AR protein. Exons 2 and 3 encode the DNA-binding domain, while the 5' portion of exon 4 encodes the hinge region. The remainder of exons 4 through 8 encodes the ligand binding domain.


Trinucleotide satellite lengths and AR transcriptional activity

The AR gene contains two polymorphic trinucleotide microsatellites in exon 1. The first microsatellite (nearest the 5' end) contains 8 to 60 repetitions of the glutamine codon "CAG" and is thus known as the polyglutamine tract. The second microsatellite contains 4 to 31 repetitions of the
glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid. Glycine is one of the proteinogenic amino acids. It is encoded by all the codons starting with GG (G ...
codon "GGC" and is known as the polyglycine tract. The average number of repetitions varies by ethnicity, with Caucasians exhibiting an average of 21 CAG repeats, and Blacks 18. In men, disease states are associated with extremes in polyglutamine tract length;
prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
, hepatocellular carcinoma, and
intellectual disability Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
are associated with too few repetitions, while spinal and bulbar muscular atrophy (SBMA) is associated with a CAG repetition length of 40 or more. 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 Male infertility refers to a sexually mature male's inability to impregnate a fertile female. Male infertility can wholly or partially account for 40% of infertility among couples who are trying to have children. "A problem with the male is the s ...
and undermasculinized genitalia in men. However, other studies have indicated no such correlation exists. A comprehensive
meta-analysis Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...
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. Some studies suggest longer polyglycine tract lengths are also associated with genital masculinization defects in men. Other studies find no such association.


AR mutations

As of 2010, over 400 ''AR''
mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...
have been reported in the ''AR'' mutation database, and the number continues to grow.
Inheritance Inheritance is the practice of receiving private property, titles, debts, entitlements, privileges, rights, and obligations upon the death of an individual. The rules of inheritance differ among societies and have changed over time. Offi ...
is typically maternal and follows an X-linked recessive pattern; 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. Such ''de novo'' mutations are the result of a
germ cell A germ cell is any cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate in the primitive streak and migrate via the gut of an embryo to the developing gonads. There, they unde ...
mutation or germ cell mosaicism in the
gonads A gonad, sex gland, or reproductive gland is a mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, ...
of one of the parents, or a mutation in the fertilized egg itself. In one study, 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. Not every mutation of the ''AR'' gene results in androgen insensitivity; one particular mutation occurs in 8 to 14% of genetic males, and is thought to adversely affect only a small number of individuals when other genetic factors are present.


Other causes

Some individuals with CAIS or PAIS do not have any ''AR'' mutations despite clinical, hormonal, and
histological Histology, also known as microscopic anatomy or microanatomy, is the branch of biology that studies the microscopic anatomy of biological tissue (biology), tissues. Histology is the microscopic counterpart to gross anatomy, which looks at large ...
features sufficient to warrant an AIS diagnosis; up to 5% of women with CAIS do not have an ''AR'' mutation, as well as between 27 and 72% of individuals with PAIS. In one patient, the underlying cause for presumptive PAIS was a mutant steroidogenic factor-1 (SF-1) protein. 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. A coactivator protein interacting with the activation function 1 (AF-1) transactivation domain of the androgen receptor may have been deficient in this patient. 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.


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, or may have genitalia that are only partially masculinized (PAIS). The gonads are testes regardless of phenotype due to the influence of the Y chromosome. A 46,XY female, thus, does not have ovaries, and can not contribute an egg towards conception. In some cases, 46, XY females do form a vestigial
uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...
and have been able to gestate children. Such examples are rare and have required the use of an egg donor, hormone therapy, and IVF. Several case studies of fertile 46,XY males with AIS have been published, although this group is thought to be a minority. In some cases, infertile males with MAIS have been able to conceive children after increasing their sperm count through the use of supplementary
testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...
. 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. 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. 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 In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
of such an individual is a matter of speculation; as of 2010, no such documented case has been published.


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. Unfortunately, little information regarding
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
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. Exactly what causes this variation is not entirely understood, although factors contributing to it could include the lengths of the polyglutamine and polyglycine tracts, sensitivity to and variations in the intrauterine
endocrine The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypotha ...
milieu, the effect of coregulatory proteins active in Sertoli cells, somatic mosaicism, expression of the ''5RD2''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
in genital skin fibroblasts, reduced ''AR'' transcription and
translation Translation is the communication of the semantics, meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The English la ...
from factors other than mutations in the AR coding region, an unidentified coactivator protein, enzyme deficiencies such as 21-hydroxylase deficiency, or other genetic variations such as a mutant steroidogenic factor-1 protein. The degree of variation, however, does not appear to be constant across all ''AR'' mutations, and is much more extreme in some. Missense mutations that result in a single amino acid substitution are known to produce the most phenotypic diversity.


Pathophysiology


Androgens and the androgen receptor

The effects that androgens have on the human body ( virilization, masculinization,
anabolism Anabolism () is the set of metabolic pathways that construct macromolecules like DNA or RNA from smaller units. These reactions require energy, known also as an Endergonic reaction, endergonic process. Anabolism is the building-up aspect of metabo ...
, 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. Likewise, the androgen receptor itself is generally inactive in the cell until androgen binding occurs. The following series of steps illustrates how androgens and the androgen receptor work together to produce androgenic effects: In this way, androgens bound to androgen receptors regulate the expression of target genes, thus produce androgenic effects. 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. Conversely, the steroid-binding domain may act to repress the AR transactivation domain, perhaps due to the AR's unliganded conformation.


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. The gonads begin as bulges of tissue called the genital ridges at the back of the
abdominal cavity The abdominal cavity is a large body cavity in humans and many other animals that contain Organ (anatomy), organs. It is a part of the abdominopelvic cavity. It is located below the thoracic cavity, and above the pelvic cavity. Its dome-shaped roo ...
, near the midline. By the fifth week, the genital ridges differentiate into an outer
cortex Cortex or cortical may refer to: Biology * Cortex (anatomy), the outermost layer of an organ ** Cerebral cortex, the outer layer of the vertebrate cerebrum, part of which is the ''forebrain'' *** Motor cortex, the regions of the cerebral cortex i ...
and an inner medulla, and are called indifferent gonads. 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 The Y chromosome is one of two sex chromosomes in therian mammals and other organisms. Along with the X chromosome, it is part of the XY sex-determination system, in which the Y is the sex-determining chromosome because the presence of the ...
's ''SRY'' gene. This process does not require the presence of androgen, nor a functional androgen receptor. 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. Sertoli cells within the testes secrete anti-Müllerian hormone around this time to suppress the development of the Müllerian ducts, and cause their degeneration. Without this anti-Müllerian hormone, the Müllerian ducts develop into the female internal genitalia (
uterus The uterus (from Latin ''uterus'', : uteri or uteruses) or womb () is the hollow organ, organ in the reproductive system of most female mammals, including humans, that accommodates the embryonic development, embryonic and prenatal development, f ...
,
cervix The cervix (: cervices) or cervix uteri is a dynamic fibromuscular sexual organ of the female reproductive system that connects the vagina with the uterine cavity. The human female cervix has been documented anatomically since at least the time ...
, fallopian tubes, and upper vaginal barrel). Unlike the Müllerian ducts, the Wolffian ducts will not continue to develop by default. In the presence of testosterone and functional androgen receptors, the Wolffian ducts develop into the
epididymides The epididymis (; : epididymides or ) is an elongated tubular genital organ attached to the posterior side of each one of the two male reproductive glands, the testicles. It is a single, narrow, tightly coiled tube in adult humans, in length; ...
, vasa deferentia, and seminal vesicles. If the testes fail to secrete testosterone, or the androgen receptors do not function properly, the Wolffian ducts degenerate. Masculinization of the male external genitalia (the
penis A penis (; : penises or penes) is a sex organ through which male and hermaphrodite animals expel semen during copulation (zoology), copulation, and through which male placental mammals and marsupials also Urination, urinate. The term ''pen ...
, penile
urethra The urethra (: urethras or urethrae) is the tube that connects the urinary bladder to the urinary meatus, through which Placentalia, placental mammals Urination, urinate and Ejaculation, ejaculate. The external urethral sphincter is a striated ...
, and
scrotum In most terrestrial mammals, the scrotum (: scrotums or scrota; possibly from Latin ''scortum'', meaning "hide" or "skin") or scrotal sac is a part of the external male genitalia located at the base of the penis. It consists of a sac of skin ...
), as well as the
prostate The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...
, are dependent on the androgen dihydrotestosterone. Testosterone is converted into dihydrotestosterone by the 5-alpha reductase enzyme. If this enzyme is absent or deficient, then dihydrotestosterone is not created, and the external male genitalia do not develop properly. 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.


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. 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. 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. 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. Unfortunately, even when the affected functional domain is known, predicting the
phenotypical In genetics, the phenotype () is the set of observable characteristics or phenotypic trait, traits of an organism. The term covers the organism's morphology (biology), morphology (physical form and structure), its Developmental biology, develo ...
consequences of a particular mutation (see Correlation of genotype and phenotype) is difficult. 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. 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. 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. 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 Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
, or in the case of spinal and bulbar muscular atrophy, disease of the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
. The form of breast cancer seen in some men with PAIS is caused by a mutation in the AR's DNA-binding domain. 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 Estrogen receptors (ERs) are proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...
protein, to cause cancerous growth. The pathogenesis of spinal and bulbar muscular atrophy (SBMA) demonstrates that even the mutant AR protein itself can result in
pathology Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...
. 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. These misfolded AR proteins form aggregates in the cell
cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
and nucleus. 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.


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. Clinical findings indicative of AIS include the presence of a short vagina or undermasculinized genitalia, partial or complete regression of Müllerian structures, bilateral nondysplastic testes, and impaired spermatogenesis and/or virilization. Laboratory findings include a 46,XY karyotype and typical or elevated postpubertal testosterone, luteinizing hormone, and estradiol levels. The androgen binding activity of genital skin fibroblasts is typically diminished, although exceptions have been reported. Conversion of testosterone to dihydrotestosterone may be impaired. 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). Each of the three types of AIS (complete, partial, and mild) has a different list of differential diagnoses to consider. However, cases have been reported of individuals with both AIS and certain diagnoses listed here, such as Klinefelter syndrome or Turner syndrome with mosaicism. Depending on the form of AIS suspected, the list of differentials can include:


Classification

AIS is broken down into three classes based on
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), and mild androgen insensitivity syndrome (MAIS). 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. 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. 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. 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.


Complete AIS


Partial AIS


Mild AIS


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 Sex assignment (also known as gender assignment) is the discernment of an infant's sex, typically made at birth based on an examination of the baby's external genitalia by a healthcare provider such as a midwife, nurse, or physician. In the v ...
, genitoplasty, gonadectomy in relation to
tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
risk, hormone replacement therapy, genetic counseling, and psychological counseling.


MAIS


PAIS


CAIS


Epidemiology

AIS represents about 15% to 20% of DSDs and affects 1 in 20,000 to 1 in 64,000 males. Estimates for the incidence of androgen insensitivity syndrome are based on a relatively small
population Population is a set of humans or other organisms in a given region or area. Governments conduct a census to quantify the resident population size within a given jurisdiction. The term is also applied to non-human animals, microorganisms, and pl ...
size, thus are known to be imprecise. CAIS is estimated to occur in one of every 20,400 46,XY births. 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. The incidence of PAIS is estimated to be one in 130,000. Due to its subtle presentation, MAIS is not typically investigated except in the case of
male infertility Male infertility refers to a sexually mature male's inability to impregnate a fertile female. Male infertility can wholly or partially account for 40% of infertility among couples who are trying to have children. "A problem with the male is the s ...
, thus its true prevalence is unknown.


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. In the UK, AIS appears on a list of serious genetic diseases that may be screened for via PGD. 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.


History

Recorded descriptions of the effects of AIS date back hundreds of years, although significant understanding of its underlying
histopathology Histopathology (compound of three Greek words: 'tissue', 'suffering', and '' -logia'' 'study of') is the microscopic examination of tissue in order to study the manifestations of disease. Specifically, in clinical medicine, histopatholog ...
did not occur until the 1950s. The
taxonomy image:Hierarchical clustering diagram.png, 280px, Generalized scheme of taxonomy Taxonomy is a practice and science concerned with classification or categorization. Typically, there are two parts to it: the development of an underlying scheme o ...
and
nomenclature Nomenclature (, ) is a system of names or terms, or the rules for forming these terms in a particular field of arts or sciences. (The theoretical field studying nomenclature is sometimes referred to as ''onymology'' or ''taxonymy'' ). The principl ...
associated with androgen insensitivity went through a significant evolution that paralleled this understanding.


Timeline of major milestones

* 1950: Lawson Wilkins administers daily
methyltestosterone Methyltestosterone, sold under the brand names Android, Metandren, and Testred among others, is an androgen and anabolic steroid (AAS) medication which is used in the treatment of low testosterone levels in men, delayed puberty in boys, at low ...
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. * 1970: Mary F. Lyon and Susan Hawkes reported that a gene on the X chromosome caused complete insensitivity to androgens in mice. * 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. * 1988: The human androgen receptor gene is first cloned and partially analyzed by multiple parties. Terry Brown ''et al.'' reported the first mutations proven to cause AIS. * 1989: Terry Brown ''et al.'' reported the exact locus of the AR gene (Xq11-Xq12), and Dennis Lubahn ''et al.'' published its
intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of the cistron .e., gen ...
-
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
boundaries. * 1994: The androgen receptor gene mutations database was created to provide a comprehensive listing of mutations published in medical journals and conference proceedings.


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 Intersex people are those born with any of several sex characteristics, including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical binar ...
physicalities. In 1839, Scottish obstetrician Sir James Young Simpson published one such description in an exhaustive study of intersexuality that has been credited with advancing the medical community's understanding of the subject. Simpson's system of
taxonomy image:Hierarchical clustering diagram.png, 280px, Generalized scheme of taxonomy Taxonomy is a practice and science concerned with classification or categorization. Typically, there are two parts to it: the development of an underlying scheme o ...
, 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, French surgeon Ambroise Paré in 1573, French physician and sexology pioneer Nicolas Venette in 1687 (under the pseudonym Vénitien Salocini), and French zoologist Isidore Geoffroy Saint-Hilaire in 1832. All five of these authors used the colloquial term "
hermaphrodite A hermaphrodite () is a sexually reproducing organism that produces both male and female gametes. Animal species in which individuals are either male or female are gonochoric, which is the opposite of hermaphroditic. The individuals of many ...
" as the foundation of their taxonomies, although Simpson himself questioned the propriety of the word in his publication. Use of the word "hermaphrodite" in the medical literature has persisted to this day, although its propriety is still in question. An alternative system of nomenclature has been recently suggested, but the subject of exactly which word or words should be used in its place still one of much debate.


Pseudohermaphroditism

"
Pseudohermaphroditism Pseudohermaphroditism is an outdated term for when an individual's gonads were mismatched with their internal reproductive system and/or external genitalia. The term was contrasted with "true hermaphroditism" (now known as ovotesticular syndrome), ...
" has, until very recently, 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". 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. German-Swiss pathologist Edwin Klebs is sometimes noted for using the word "pseudohermaphroditism" in his taxonomy of
intersex Intersex people are those born with any of several sex characteristics, including chromosome patterns, gonads, or genitals that, according to the Office of the United Nations High Commissioner for Human Rights, "do not fit typical binar ...
uality in 1876, 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 Anatomy () is the branch of morphology concerned with the study of the internal structure of organisms and their parts. Anatomy is a branch of natural science that deals with the structural organization of living things. It is an old scien ...
Frederik Ruysch used it in a publication describing a subject with testes and a mostly female phenotype. "Pseudohermaphrodite" also appeared in the ''
Acta Eruditorum (from Latin: ''Acts of the Erudite'') was the first scientific journal of the German-speaking lands of Europe, published from 1682 to 1782. History ''Acta Eruditorum'' was founded in 1682 in Leipzig by Otto Mencke, who became its first edit ...
'' later that same year, in a review of Ruysch's work. Also some evidence indicates the word was already being used by the German and French medical community long before Klebs used it; German
physiologist Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a subdiscipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out chemical and ...
Johannes Peter Müller Johannes Peter Müller (14 July 1801 – 28 April 1858) was a German physiologist, comparative anatomist, ichthyologist, and herpetologist, known not only for his discoveries but also for his ability to synthesize knowledge. The paramesonephri ...
equated "pseudohermaphroditism" with a subclass of hermaphroditism from Saint-Hilaire's taxonomy in a publication dated 1834, and by the 1840s "pseudohermaphroditism" was appearing in several French and German publications, including dictionaries.


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. 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. 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". 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".


Other names

A distinct name has been given to many of the various presentations of AIS, such as Reifenstein syndrome (1947), Goldberg-Maxwell syndrome (1948), Morris' syndrome (1953), Gilbert-Dreyfus syndrome (1957), Lub's syndrome (1959), "incomplete testicular feminization" (1963), Rosewater syndrome (1965), and Aiman's syndrome (1979). 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. 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. AIS is now the accepted terminology for the syndromes resulting from unresponsiveness of the target cell to the action of androgenic hormones. CAIS encompasses the phenotypes previously described by "testicular feminization", Morris' syndrome, and Goldberg-Maxwell syndrome; PAIS includes Reifenstein syndrome, Gilbert-Dreyfus syndrome, Lub's syndrome, "incomplete testicular feminization", and Rosewater syndrome; and MAIS includes Aiman's syndrome. 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. 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 A micropenis or microphallus is an unusually small Human penis, penis. A common criterion is a dorsal (measured on top) Human penis size, penile length of at least 2.5 standard deviations smaller than the mean human penis size for age. A micr ...
,
hypospadias Hypospadias is a common malformation in fetal development of the penis in which the urethra does not open from its usual location on the head of the penis. It is the second-most common birth defect of the male reproductive system, affecting about ...
, and undescended testes), while others are better described by MAIS (e.g. isolated male infertility or gynecomastia).


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. Recording artist Dalea is a Hispanic-American Activist who is public about her CAIS. She has given interviews about her condition and founded Girl Comet, a non-profit diversity awareness and inspiration initiative. 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, which they said took place without their or their parents' informed consent. They were told about their intersex condition weeks before beginning their modelling career. In the 1991 Japanese horror novel ''Ring'' and its sequels, by
Koji Suzuki is a Japanese writer, who was born in Hamamatsu and lives in Tokyo. Suzuki is the author of the Ring (novel series), ''Ring'' novels, which have been adapted into other formats, including films, manga, TV series and video games. He has written ...
(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. 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. The episode has been criticized for its medical inaccuracy as well as its stigmatizing and offensive portrayal of CAIS. 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. 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. In series 8, episode 5 of ''
Call the Midwife ''Call the Midwife'' is a British period drama television series about a group of nurse midwives working in the East End of London in the late 1950s, 1960s and 1970s. The principal cast of the show has included Jessica Raine, Miranda Hart, ...
'', 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.


People with AIS

* Kitty Anderson (activist) * Eden Atwood * Bonnie Hart * Phoebe Hart * Maria José Martínez-Patiño * Hanne Gaby Odiele * Santhi Soundarajan * Miriam van der Have * Kimberly Zieselman


People with Complete androgen insensitivity syndrome

* Georgiann Davis * Seven Graham * Alicia Roth Weigel


People with Partial androgen insensitivity syndrome

* Tony Briffa * Favorinus of Arelate has been described as having partial androgen insensitivity syndrome. * Small Luk * Eliana Rubashkyn * Sean Saifa Wall * Sogto Ochirov


See also

* Estrogen insensitivity syndrome * Spinal and bulbar muscular atrophy *
Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of Genetic disorder#Autosomal recessive, autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the Biosy ...
* 5α-Reductase 2 deficiency


References


External links


Information

* * , {{DEFAULTSORT:Androgen Insensitivity Syndrome Transcription factor deficiencies Syndromes affecting the endocrine system Endocrine gonad disorders Syndromes with tumors Intersex variations