Androgen insensitivity syndrome
Encyclopedia
Androgen insensitivity syndrome (AIS) is a condition that results in the partial or complete inability of the cell to respond to androgen
s. The unresponsiveness of the cell to the presence of androgenic hormones can impair or prevent the masculinization of male genitalia in the developing fetus, as well as the development of male secondary sexual characteristics at puberty
, but does not significantly impair female genital or sexual development. As such, the insensitivity to androgens is only clinically significant when it occurs in genetic males (i.e. individuals with a Y-chromosome
, or more specifically, an SRY gene
). Clinical phenotypes in these individuals ranges from a normal 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: complete androgen insensitivity syndrome (CAIS
) is indicated when the external genitalia is that of a normal female, mild androgen insensitivity syndrome (MAIS
) is indicated when the external genitalia is that of a normal male, and partial androgen insensitivity syndrome (PAIS
) is indicated when the external genitalia is partially, but not fully masculinized.
Androgen insensitivity syndrome is the largest single entity that leads to 46,XY undermasculinized genitalia.
: 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.
(AR) is a protein
encoded by a gene
located on the proximal long arm
of the X chromosome
(locus
Xq11-Xq12). The protein coding region consists of approximately 2,757 nucleotides (919 codons) spanning eight exons, designated 1-8 or A-H. Introns vary in size between 0.7 and 26 kb. Like other nuclear receptors, the androgen receptor 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 exon 4 through exon 8 encodes the ligand binding domain.
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
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
, hepatocellular carcinoma
, and mental retardation
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
and undermasculinized genitalia in men. However, other studies have indicated that no such correlation exists. A comprehensive meta-analysis
of the subject published in 2007 supports the existence of the correlation, and concluded that these discrepancies could be resolved when sample size
and study design are taken into account. Some studies suggest that longer polyglycine tract lengths are also associated with genital masculinization defects in men. Other studies find no such association.
mutations have been reported in the AR mutation database, and the number continues to grow. Inheritance
is typically maternal and follows an X-linked recessive
pattern; individuals with a 46,XY karyotype
will always express the mutant gene since they only have one X chromosome
, whereas 46,XX carriers will be minimally affected. 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
mutation or germ cell mosaicism
in the gonads of one of the parents, or a mutation in the fertilized egg
itself. In one study, it was found that 3 out of 8 de novo mutations occurred in the post-zygotic stage, leading to the estimate that up to one third of de novo mutations result in somatic mosaicism
. It is worthwhile to note that not every mutation of the AR gene results in androgen insensitivity; one particular mutation occurs in 8 to 14 percent of genetic males
, and is thought to adversely affect only a small number of individuals when other genetic factors are present.
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, as well as between 27% and 72% of individuals with PAIS.
In one patient, it was shown that the underlying cause for presumptive PAIS was a mutant steroidogenic factor-1 (SF-1)
protein. In another patient, it was shown that CAIS was the result of a deficit in the transmission of a transactivating
signal from the N-terminal region of the normal androgen receptor to the basal transcription machinery of the cell. It was suggested that a coactivator protein interacting with the activation function 1 (AF-1) transactivation
domain of the androgen receptor was 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 normal AR gene.
, a person with a (46,XY karyotype
) and AIS can have either a male (MAIS) or female (CAIS) phenotype
, or may have genitalia that is 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 or a uterus
, and can neither contribute an egg
towards conception nor gestate a child.
Several case studies of fertile
46,XY males with androgen insensitivity have been published, although this group is thought to be a minority. Additionally, some infertile
males with MAIS have been able to conceive children after increasing their sperm count through the use of supplementary testosterone
. A genetic male conceived by a man with androgen insensitivity would not receive his father's X chromosome
, and 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, and would thus become a carrier.
) have two X chromosomes, and thus have two AR
genes
. A mutation
in one (but not both) of the AR genes 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 androgen insensitivity syndrome.
A genetic female with mutations in both AR genes could theoretically result from the union of a fertile man with androgen insensitivity and a female carrier of the gene
, or from de novo
mutation. However, given the scarcity of fertile androgen insensitive men and low incidence
of AR mutation, the chances of this occurrence is small. The phenotype
of such an individual is a matter of speculation; as of 2010, no such documented case has been published.
can be gleaned from precise knowledge of the AR
mutation
itself; it is well established that 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 milieu, the effect of coregulatory
proteins that are active in Sertoli cells, somatic mosaicism
, expression of the 5RD2
gene
in genital skin fibroblasts, reduced AR transcription
and translation
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
(SF-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.
, etc. --- are not brought about by androgens themselves, but rather are the result of androgens bound to androgen receptor
s; the androgen receptor mediates the effects of androgens in the human body. Likewise, under normal circumstances, the androgen receptor itself is 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
, and thus produce androgenic effects.
It is theoretically possible for certain mutant
androgen receptors to 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.
); 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
, near the midline. By the fifth week, the genital ridges differentiate
into an outer cortex
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
’s SRY gene. This process does not require the presence of androgen
, nor a functional androgen receptor
.
Until approximately 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. 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
, cervix
, 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
, 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 external genitalia
(the penis
, penile urethra
, and scrotum
), as well as the prostate
, 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 will not be created, and the external male genitalia will not develop properly. As is the case with the internal male genitalia
, a functional androgen receptor is needed in order for dihydrotestosterone to regulate the transcription of target genes involved in development.
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 in order for androgens to successfully activate the AR 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, it is difficult to predict the phenotypical
consequences of a particular mutation (see Correlation of genotype and phenotype).
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
, or in the case of spinal and bulbar muscular atrophy, disease of the central nervous system
. The form of breast cancer that is seen in some men with partial androgen insensitivity syndrome is caused by a mutation in the AR's DNA-binding domain. It has been hypothesized that this mutation causes 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. The etiology
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 properly proteolyze
and disperse. These misfolded AR proteins form aggregates in the cell cytoplasm
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.
and / or virilization. Laboratory findings include a 46,XY karyotype
and normal 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. Depending on the form of AIS that is suspected, the list of differentials can include:
; methods to correct a malfunctioning androgen receptor
protein that result from an AR gene mutation
are not currently available. Areas of management include sex assignment
, genitoplasty, gonadectomy in relation to tumor
risk, hormone replacement therapy
, and genetic
and psychological counseling
.
of androgen insensitivity syndrome are based on a relatively small population
size, and thus are known to be imprecise. CAIS is estimated to occur in 1 out 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 1 in 99,000. The incidence of PAIS is estimated to be 1 in 130,000. Due to its subtle presentation, MAIS is not typically investigated except in the case of male infertility
, and thus its true prevalence is unknown.
would not occur until the 1950s. The taxonomy
and nomenclature
associated with androgen insensitivity went through a significant evolution that paralleled this understanding.
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 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
, however, was far from the first; taxonomies / 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 St. Hilaire
in 1832. All five of the aforementioned authors used the colloquial term "hermaphrodite" 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.
" has, until very recently, been the term used in the medical literature
to describe the condition of an individual whose gonads and karyotype
do not match the external genitalia in the gender binary
sense. For example, 46,XY
individuals that have a female phenotype
, but also have testes instead of ovaries --- a group that includes all individuals with complete androgen insensitivity (CAIS), as well as some individuals with partial androgen insensitivity (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
.". Usage of the word in the medical literature predates the discovery of the chromosome
, and 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
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 Frederik Ruysch
used it in a publication describing a subject with testes and a mostly female phenotype. "Pseudohermaphrodite" also appeared in the Acta Eruditorum
later that same year, in a review of Ruysch's work. There is also evidence that 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 sub-class of hermaphroditism from St. Hilaire's
taxonomy in a publication dated 1834, and by the 1840s "pseudo-hermaphroditism" was appearing in several French and German publications, including dictionaries.
, including 2 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 that is 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 his own experiments 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
women were treated with androgens, caused a gradual shift in nomenclature from "testicular feminization" to "androgen resistance".
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, it has been demonstrated that these disorders are different phenotypic expressions of one syndrome caused by molecular defects in the androgen receptor gene.
Androgen insensitivity syndrome (AIS) is now the accepted terminology
for the syndromes resulting from unresponsiveness of the target cell to the action of androgenic hormones. 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). 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 androgen receptor gene. These diagnoses were used to describe a variety of mild defects in virilization; as a result, the phenotypes of some men that 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 infertility
or gynecomastia
).
(later adopted into English "The Ring" series) describes that the central antagonist Sadako) has this syndrome.
In Season 2 Episode 13 "Skin Deep" of House
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
s. The unresponsiveness of the cell to the presence of androgenic hormones can impair or prevent the masculinization of male genitalia in the developing fetus, as well as the development of male secondary sexual characteristics at puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
, but does not significantly impair female genital or sexual development. As such, the insensitivity to androgens is only clinically significant when it occurs in genetic males (i.e. individuals with a Y-chromosome
Y chromosome
The Y chromosome is one of the two sex-determining chromosomes in most mammals, including humans. In mammals, it contains the gene SRY, which triggers testis development if present. The human Y chromosome is composed of about 60 million base pairs...
, or more specifically, an SRY gene
SRY
SRY is a sex-determining gene on the Y chromosome in the therians .This intronless gene encodes a transcription factor that is a member of the SOX gene family of DNA-binding proteins...
). Clinical phenotypes in these individuals ranges from a normal male habitus
Body shape
Human body shape is a complex phenomenon with sophisticated detail and function. The general shape or figure of a person is defined mainly by skeletal structure, muscles and fat...
with mild spermatogenic
Spermatogenesis
Spermatogenesis is the process by which male primary germ cells undergo division, and produce a number of cells termed spermatogonia, from which the primary spermatocytes are derived. Each primary spermatocyte divides into two secondary spermatocytes, and each secondary spermatocyte into two...
defect or reduced secondary terminal hair
Terminal hair
Terminal hairs are thick, long, and dark, as compared with vellus hair. During puberty, the increase in androgenic hormone levels causes vellus hair to be replaced with terminal hair in certain parts of the human body...
, to a full female habitus
Female body shape
Female body shape or figure is the cumulative product of a woman's skeletal structure and the quantity and distribution of muscle and fat on the body. There are, and have been, wide differences on what should be considered an ideal or preferred body shape, both for attractiveness and for health...
, despite the presence of a Y-chromosome.
AIS is divided into three categories that are differentiated by the degree of genital masculinization: complete androgen insensitivity syndrome (CAIS
Complete androgen insensitivity syndrome
Complete androgen insensitivity syndrome is a condition that results in the complete inability of the cell to respond to androgens. The unresponsiveness of the cell to the presence of androgenic hormones prevents the masculinization of male genitalia in the developing fetus, as well as the...
) is indicated when the external genitalia is that of a normal female, mild androgen insensitivity syndrome (MAIS
Mild androgen insensitivity syndrome
Mild androgen insensitivity syndrome is a condition that results in a mild impairment of the cell's ability to respond to androgens. The degree of impairment is sufficient to impair spermatogenesis and / or the development of secondary sexual characteristics at puberty in males, but does not...
) is indicated when the external genitalia is that of a normal male, and partial androgen insensitivity syndrome (PAIS
Partial androgen insensitivity syndrome
Partial androgen insensitivity syndrome is a condition that results in the partial inability of the cell to respond to androgens. The partial unresponsiveness of the cell to the presence of androgenic hormones impairs the masculinization of male genitalia in the developing fetus, as well as the...
) is indicated when the external genitalia is partially, but not fully masculinized.
Androgen insensitivity syndrome is the largest single entity that leads to 46,XY undermasculinized genitalia.
Signs and symptoms
AIS is broken down into three classes based on phenotypePhenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
: 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
Secondary sex characteristic
Secondary sex characteristics are features that distinguish the two sexes of a species, but that are not directly part of the reproductive system. They are believed to be the product of sexual selection for traits which give an individual an advantage over its rivals in courtship and aggressive...
terminal hair
Terminal hair
Terminal hairs are thick, long, and dark, as compared with vellus hair. During puberty, the increase in androgenic hormone levels causes vellus hair to be replaced with terminal hair in certain parts of the human body...
; 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.
Genetics
The human androgen receptorAndrogen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
(AR) is a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
encoded by a gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
located on the proximal long arm
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
of the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
(locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
Xq11-Xq12). The protein coding region consists of approximately 2,757 nucleotides (919 codons) spanning eight exons, designated 1-8 or A-H. Introns vary in size between 0.7 and 26 kb. Like other nuclear receptors, the androgen receptor protein consists of several functional domains
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
: the transactivation
Transactivation
In molecular biology and genetics, transactivation is an increased rate of gene expression triggered either by biological processes or by artificial means.- Natural transactivation :...
domain (also called the transcription-regulation domain or the amino / NH2-terminal domain), the DNA-binding domain
DNA-binding domain
A DNA-binding domain is an independently folded protein domain that contains at least one motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence or have a general affinity to DNA...
, the hinge region, and the steroid-binding domain (also called the carboxyl-terminal ligand-binding
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
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 exon 4 through exon 8 encodes the ligand binding domain.
Trinucleotide satellite lengths and AR transcriptional activity
The androgen receptorAndrogen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
gene contains two polymorphic trinucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
microsatellites in exon 1. The first microsatellite (nearest the 5' end) contains 8 to 60 repetitions of the glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
codon "CAG" and is thus known as the polyglutamine tract
Polyglutamine tract
A polyglutamine tract or polyQ tract is a portion of a protein consisting of a sequence of several glutamine units. A tract typically consists of about 10 to a few hundred such units....
. The second microsatellite contains 4 to 31 repetitions of the glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
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
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
, hepatocellular carcinoma
Hepatocellular carcinoma
Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
, and mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
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
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
in the AR protein, and that longer polyglutamine tracts may be associated with male infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
and undermasculinized genitalia in men. However, other studies have indicated that no such correlation exists. A comprehensive meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
of the subject published in 2007 supports the existence of the correlation, and concluded that these discrepancies could be resolved when sample size
Sample size
Sample size determination is the act of choosing the number of observations to include in a statistical sample. The sample size is an important feature of any empirical study in which the goal is to make inferences about a population from a sample...
and study design are taken into account. Some studies suggest that 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 ARAndrogen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
mutations have been reported in the AR mutation database, and the number continues to grow. Inheritance
Heredity
Heredity is the passing of traits to offspring . This is the process by which an offspring cell or organism acquires or becomes predisposed to the characteristics of its parent cell or organism. Through heredity, variations exhibited by individuals can accumulate and cause some species to evolve...
is typically maternal and follows an X-linked recessive
X-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males and in females who are homozygous for the gene mutation X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on...
pattern; individuals with a 46,XY karyotype
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
will always express the mutant gene since they only have one X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
, whereas 46,XX carriers will be minimally affected. 30% of the time, the AR mutation is a spontaneous result, and is not inherited. Such de novo
De novo
In general usage, de novo is a Latin expression meaning "from the beginning," "afresh," "anew," "beginning again." It is used in:* De novo transcriptome assembly, the method of creating a transcriptome without a reference genome...
mutations are the result of a germ cell
Germ cell
A germ cell is any biological cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate near the gut of an embryo and migrate to the developing gonads. There, they undergo cell division of two types, mitosis and meiosis, followed by...
mutation or germ cell mosaicism
Mosaic (genetics)
In genetic medicine, a mosaic or mosaicism denotes the presence of two populations of cells with different genotypes in one individual who has developed from a single fertilized egg...
in the gonads of one of the parents, or a mutation in the fertilized egg
Zygote
A zygote , or zygocyte, is the initial cell formed when two gamete cells are joined by means of sexual reproduction. In multicellular organisms, it is the earliest developmental stage of the embryo...
itself. In one study, it was found that 3 out of 8 de novo mutations occurred in the post-zygotic stage, leading to the estimate that up to one third of de novo mutations result in somatic mosaicism
Mosaic (genetics)
In genetic medicine, a mosaic or mosaicism denotes the presence of two populations of cells with different genotypes in one individual who has developed from a single fertilized egg...
. It is worthwhile to note that not every mutation of the AR gene results in androgen insensitivity; one particular mutation occurs in 8 to 14 percent of genetic males
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
, 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 ARAndrogen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
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, as well as between 27% and 72% of individuals with PAIS.
In one patient, it was shown that the underlying cause for presumptive PAIS was a mutant steroidogenic factor-1 (SF-1)
Steroidogenic factor 1
The steroidogenic factor 1 protein controls sexual development in the embryo and at puberty.SF1 is a member of the nuclear receptor family of intracellular transcription factors and is encoded by the NR5A1 gene .- Function :SF-1 is a critical regulator of reproduction, regulating the transcription...
protein. In another patient, it was shown that CAIS was the result of a deficit in the transmission of a transactivating
Transactivation
In molecular biology and genetics, transactivation is an increased rate of gene expression triggered either by biological processes or by artificial means.- Natural transactivation :...
signal from the N-terminal region of the normal androgen receptor to the basal transcription machinery of the cell. It was suggested that a coactivator protein interacting with the activation function 1 (AF-1) transactivation
Transactivation
In molecular biology and genetics, transactivation is an increased rate of gene expression triggered either by biological processes or by artificial means.- Natural transactivation :...
domain of the androgen receptor was 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 normal AR gene.
XY karyotype
Depending on the mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
, a person with a (46,XY karyotype
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
) and AIS can have either a male (MAIS) or female (CAIS) phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
, or may have genitalia that is 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 or a uterus
Uterus
The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
, and can neither contribute an egg
Ovum
An ovum is a haploid female reproductive cell or gamete. Both animals and embryophytes have ova. The term ovule is used for the young ovum of an animal, as well as the plant structure that carries the female gametophyte and egg cell and develops into a seed after fertilization...
towards conception nor gestate a child.
Several case studies of fertile
Fertile
The term fertile describes a condition whereby organisms are able to produce physically healthy offspring.Fertile may also refer to:...
46,XY males with androgen insensitivity have been published, although this group is thought to be a minority. Additionally, some infertile
Male infertility
Male infertility refers to the inability of a male to achieve a pregnancy in a fertile female. In humans it accounts for 40-50% of infertility. Male infertility is commonly due to deficiencies in the semen, and semen quality is used as a surrogate measure of male fecundity.-Pre-testicular...
males with MAIS have been able to conceive children after increasing their sperm count through the use of supplementary testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
. A genetic male conceived by a man with androgen insensitivity would not receive his father's X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
, and thus would neither inherit
Heredity
Heredity is the passing of traits to offspring . This is the process by which an offspring cell or organism acquires or becomes predisposed to the characteristics of its parent cell or organism. Through heredity, variations exhibited by individuals can accumulate and cause some species to evolve...
nor carry the gene for the syndrome. A genetic female conceived in such a way would receive her father's X chromosome, and would thus become a carrier.
XX karyotype
Genetic females (46,XX karyotypeKaryotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
) have two X chromosomes, and thus have two AR
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
. A mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in one (but not both) of the AR genes results in a minimally affected, fertile
Fertile
The term fertile describes a condition whereby organisms are able to produce physically healthy offspring.Fertile may also refer to:...
, 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
X-inactivation
X-inactivation is a process by which one of the two copies of the X chromosome present in female mammals is inactivated. The inactive X chromosome is silenced by packaging into transcriptionally inactive heterochromatin...
. 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 androgen insensitivity syndrome.
A genetic female with mutations in both AR genes could theoretically result from the union of a fertile man with androgen insensitivity and a female carrier of the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, or from de novo
De novo
In general usage, de novo is a Latin expression meaning "from the beginning," "afresh," "anew," "beginning again." It is used in:* De novo transcriptome assembly, the method of creating a transcriptome without a reference genome...
mutation. However, given the scarcity of fertile androgen insensitive men and low incidence
Incidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
of AR mutation, the chances of this occurrence is small. The phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
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 androgen insensitivity, 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, it is often the case that little information regarding phenotypePhenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
can be gleaned from precise knowledge of the AR
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
itself; it is well established that 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
Polyglutamine tract
A polyglutamine tract or polyQ tract is a portion of a protein consisting of a sequence of several glutamine units. A tract typically consists of about 10 to a few hundred such units....
and polyglycine tracts, sensitivity to and variations in the intrauterine endocrine milieu, the effect of coregulatory
Transcription coregulator
In molecular biology and genetics, transcription coregulators are proteins that interact with transcription factors to either activate or repress the transcription of specific genes. Transcription coregulators that activate gene transcription are referred to as coactivators while those that...
proteins that are active in Sertoli cells, somatic mosaicism
Mosaic (genetics)
In genetic medicine, a mosaic or mosaicism denotes the presence of two populations of cells with different genotypes in one individual who has developed from a single fertilized egg...
, expression of the 5RD2
5-alpha reductase
5α-reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in 3 metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism, and prostate cancer....
gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
in genital skin fibroblasts, reduced AR transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
and translation
Translation (genetics)
In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...
from factors other than mutations in the AR coding region, an unidentified coactivator
Coactivator (genetics)
A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....
protein, enzyme deficiencies such as 21-hydroxylase deficiency, or other genetic variations such as a mutant steroidogenic factor-1
Steroidogenic factor 1
The steroidogenic factor 1 protein controls sexual development in the embryo and at puberty.SF1 is a member of the nuclear receptor family of intracellular transcription factors and is encoded by the NR5A1 gene .- Function :SF-1 is a critical regulator of reproduction, regulating the transcription...
(SF-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
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
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, anabolismAnabolism
Anabolism is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy. One way of categorizing metabolic processes, whether at the cellular, organ or organism level is as 'anabolic' or as 'catabolic', which is the opposite...
, etc. --- are not brought about by androgens themselves, but rather are the result of androgens bound to androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
s; the androgen receptor mediates the effects of androgens in the human body. Likewise, under normal circumstances, the androgen receptor itself is 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:
- Androgen enters the cell.
- Only certain organs in the body, such as the gonads and the adrenal glands, produce the androgen testosteroneTestosteroneTestosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
. - Testosterone is converted into dihydrotestosteroneDihydrotestosteroneDihydrotestosterone is an androgen or male sex hormone. The enzyme 5α-reductase synthesises DHT in the prostate, testes, hair follicles, and adrenal glands...
, a chemically similar androgen, in cells containing the 5 alpha reductase enzymeEnzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
. - Both androgens exert their influence through binding with the androgen receptor.
- Androgen binds with the androgen receptor.
- The androgen receptor is expressed ubiquitously throughout the tissues of the human body.
- Before it binds with an androgen, the androgen receptor is bound to heat shock proteins.
- These heat shock proteins are released upon androgen binding.
- Androgen binding induces a stabilizing, conformationalChemical structureA chemical structure includes molecular geometry, electronic structure and crystal structure of molecules. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together. Molecular geometry can range from the very simple, such as...
change in the androgen receptor.
- The two zinc fingers of the DNA-binding domainDNA-binding domainA DNA-binding domain is an independently folded protein domain that contains at least one motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence or have a general affinity to DNA...
are exposed as a result of this new conformation.
- AR stability is thought to be aided by type II coregulatorsTranscription coregulatorIn molecular biology and genetics, transcription coregulators are proteins that interact with transcription factors to either activate or repress the transcription of specific genes. Transcription coregulators that activate gene transcription are referred to as coactivators while those that...
, which modulate protein foldingProtein foldingProtein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
and androgen binding, or facilitate NH2/carboxyl-terminal interaction.
- The hormone-activated androgen receptor is phosphorylatedProtein phosphorylationProtein phosphorylation is a post-translational modification of proteins in which a serine, a threonine or a tyrosine residue is phosphorylated by a protein kinase by the addition of a covalently bound phosphate group. Regulation of proteins by phosphorylation is one of the most common modes of...
.
- Receptor phosphorylation can occur before androgen binding, although the presence of androgen promotes hyperphosphorylation.
- The biological ramifications of receptor phosphorylation are unknown.
- Receptor phosphorylation can occur before androgen binding, although the presence of androgen promotes hyperphosphorylation.
- The hormone-activated androgen receptor translocates to the nucleus.
- Nucleocytoplasmic transport is in part facilitated by an amino acidAmino acidAmino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence on the ARAndrogen receptorThe androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
called the nuclear localization signalNuclear localization signalA nuclear localization signal or sequence is an amino acid sequence which 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines or arginines exposed on the protein surface. Different...
.
- The AR's nuclear localization signal is primarily encoded in the hinge region of the AR gene.
- Nucleocytoplasmic transport is in part facilitated by an amino acid
- HomodimerizationProtein dimerIn biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
occurs.
- Dimerization is mediated by the second (nearest the 3' end) zinc fingerZinc fingerZinc fingers are small protein structural motifs that can coordinate one or more zinc ions to help stabilize their folds. They can be classified into several different structural families and typically function as interaction modules that bind DNA, RNA, proteins, or small molecules...
.
- Dimerization is mediated by the second (nearest the 3' end) zinc finger
- DNA binding to regulatory androgen response elementsHormone response elementA hormone response element is a response element for hormones, a short sequence of DNA within the promoter of a gene that is able to bind a specific hormone receptor complex and therefore regulate transcription...
occurs.
- Target genes contain (or are flanked by) transcriptionTranscription (genetics)Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
al enhancer nucleotide sequences that interact with the first zinc finger.
- These areas are called androgen response elements.
- Target genes contain (or are flanked by) transcription
- CoactivatorsCoactivator (genetics)A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....
are recruited by the AR.
- Type I coactivators (i.e., coregulators) are thought to influence AR transcriptional activity by facilitating DNA occupancy, chromatin remodelingChromatin remodelingChromatin remodeling is the enzyme-assisted movement of nucleosomes on DNA.This is performed by chromatin remodeling complexes like SWI/SNF , RSC and Imitation SWI complexes ....
, or the recruitment of general transcription factorTranscription factorIn molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s associated with RNA polymerase IIRNA polymerase IIRNA polymerase II is an enzyme found in eukaryotic cells. It catalyzes the transcription of DNA to synthesize precursors of mRNA and most snRNA and microRNA. A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase...
holocomplex.
- Type I coactivators (i.e., coregulators) are thought to influence AR transcriptional activity by facilitating DNA occupancy, chromatin remodeling
- Target gene transcription ensues.
In this way, androgens bound to androgen receptors regulate the expression
Regulation of gene expression
Gene modulation redirects here. For information on therapeutic regulation of gene expression, see therapeutic gene modulation.Regulation of gene expression includes the processes that cells and viruses use to regulate the way that the information in genes is turned into gene products...
of target genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
, and thus produce androgenic effects.
It is theoretically possible for certain mutant
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
androgen receptors to 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
Transactivation
In molecular biology and genetics, transactivation is an increased rate of gene expression triggered either by biological processes or by artificial means.- Natural transactivation :...
domain, perhaps due to the AR's unliganded
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
conformation.
Androgens in fetal development
Human embryos develop similarly for the first six weeks, regardless of genetic sex (46,XX or 46,XY karyotypeKaryotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
); 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
Gonadal ridge
In embryology, the gonadal ridge is the precursor to the gonads. The gonadal ridge initially consists mainly of mesenchyme and cells of underlying mesonephric origin. Once oogonia enter this area they attempt to associate with these somatic cells...
at the back of the abdominal cavity
Abdominal cavity
The abdominal cavity is the body cavity of the human body that holds the bulk of the viscera. It is located below the thoracic cavity, and above the pelvic cavity. Its dome-shaped roof is the thoracic diaphragm , and its oblique floor is the pelvic inlet...
, near the midline. By the fifth week, the genital ridges differentiate
Sexual differentiation
Sexual differentiation is the process of development of the differences between males and females from an undifferentiated zygote...
into an outer cortex
Cortex (anatomy)
In anatomy and zoology the cortex is the outermost layer of an organ. Organs with well-defined cortical layers include kidneys, adrenal glands, ovaries, the thymus, and portions of the brain, including the cerebral cortex, the most well-known of all cortices.The cerebellar cortex is the thin gray...
and an inner medulla
Medulla
Medulla refers to the middle of something and derives from the Latin word for marrow. Its anatomical uses include:* Medulla oblongata, a part of the brain stem* Renal medulla, a part of the kidney* Adrenal medulla, a part of the adrenal gland...
, and are called indifferent gonads
Development of the gonads
The prenatal development of the gonads is a part of the development of reproductive system and ultimately forms the testes in males and ovaries in females. They initially develop from the mesothelial layer of the peritoneum....
. 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
Y chromosome
The Y chromosome is one of the two sex-determining chromosomes in most mammals, including humans. In mammals, it contains the gene SRY, which triggers testis development if present. The human Y chromosome is composed of about 60 million base pairs...
’s SRY gene. This process does not require the presence of androgen
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
, nor a functional androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
.
Until approximately 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. The testes secrete anti-Müllerian hormone
Anti-müllerian hormone
Anti-Müllerian hormone also known as AMH is a protein that, in humans, is encoded by the AMH gene. It inhibits the development of the Müllerian ducts in the male embryo. It has also been called Müllerian inhibiting factor , Müllerian-inhibiting hormone , and Müllerian-inhibiting substance...
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
Female internal genitalia
The female internal genitalia refers to the portion of the female reproductive system consisting of the adnexa, uterus, and vagina....
(uterus
Uterus
The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
, cervix
Cervix
The cervix is the lower, narrow portion of the uterus where it joins with the top end of the vagina. It is cylindrical or conical in shape and protrudes through the upper anterior vaginal wall...
, 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
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
and functional androgen receptors, the Wolffian ducts develop into the epididymides
Epididymis
The epididymis is part of the male reproductive system and is present in all male amniotes. It is a narrow, tightly-coiled tube connecting the efferent ducts from the rear of each testicle to its vas deferens. A similar, but probably non-homologous, structure is found in cartilaginous...
, vasa deferentia
Vas deferens
The vas deferens , also called ductus deferens, , is part of the male anatomy of many vertebrates; they transport sperm from the epididymis in anticipation of ejaculation....
, 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 external genitalia
Male external genitalia
The male external genitalia refers to the portion of the male reproductive system consisting of penis, urinary tract, and scrotum....
(the penis
Penis
The penis is a biological feature of male animals including both vertebrates and invertebrates...
, penile urethra
Urethra
In anatomy, the urethra is a tube that connects the urinary bladder to the genitals for the removal of fluids out of the body. In males, the urethra travels through the penis, and carries semen as well as urine...
, and scrotum
Scrotum
In some male mammals the scrotum is a dual-chambered protuberance of skin and muscle containing the testicles and divided by a septum. It is an extension of the perineum, and is located between the penis and anus. In humans and some other mammals, the base of the scrotum becomes covered with curly...
), as well as the prostate
Prostate
The prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals....
, are dependent on the androgen dihydrotestosterone
Dihydrotestosterone
Dihydrotestosterone is an androgen or male sex hormone. The enzyme 5α-reductase synthesises DHT in the prostate, testes, hair follicles, and adrenal glands...
. Testosterone is converted into dihydrotestosterone by the 5-alpha reductase
5-alpha reductase
5α-reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in 3 metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism, and prostate cancer....
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
. If this enzyme is absent or deficient, then dihydrotestosterone will not be created, and the external male genitalia will not develop properly. As is the case with the internal male genitalia
Male internal genitalia
The male internal genitalia refers to the portion of the male reproductive system consisting of seminal tract and prostate....
, a functional androgen receptor is needed in order for dihydrotestosterone to regulate the transcription of target genes involved in development.
Pathogenesis of Androgen Insensitivity Syndrome
Mutations in the androgen receptorAndrogen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
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
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
of the dimerized
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
, androgen-AR complex. AIS can result if even one of these steps is significantly disrupted, as each step is required in order for androgens to successfully activate the AR and regulate gene expression
Regulation of gene expression
Gene modulation redirects here. For information on therapeutic regulation of gene expression, see therapeutic gene modulation.Regulation of gene expression includes the processes that cells and viruses use to regulate the way that the information in genes is turned into gene products...
. 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
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
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
DNA-binding domain
A DNA-binding domain is an independently folded protein domain that contains at least one motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence or have a general affinity to DNA...
have been known to affect dimerization and binding to target DNA, and mutations in the transactivation
Transactivation
In molecular biology and genetics, transactivation is an increased rate of gene expression triggered either by biological processes or by artificial means.- Natural transactivation :...
domain have been known to affect target gene transcription regulation. Unfortunately, even when the affected functional domain is known, it is difficult to predict the phenotypical
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
consequences of a particular mutation (see Correlation of genotype and phenotype).
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
Upstream and downstream (DNA)
In molecular biology and genetics, upstream and downstream both refer to a relative position in DNA or RNA. Each strand of DNA or RNA has a 5' end and a 3' end, so named for the carbons on the deoxyribose ring. Relative to the position on the strand, downstream is the region towards the 3' end of...
functional domains if a premature stop codon
Nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in a truncated, incomplete, and usually nonfunctional protein product. It differs from a missense mutation, which is a point mutation...
or framing error
Frameshift mutation
A frameshift mutation is a genetic mutation caused by indels of a number of nucleotides that is not evenly divisible by three from a DNA sequence...
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
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, 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
Male breast cancer
Male breast cancer is a relatively rare cancer in men that originates from the breast. As it presents a similar pathology as female breast cancer, assessment and treatment relies on experiences and guidelines that have been developed in female patients. The optimal treatment is currently not...
, prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
, or in the case of spinal and bulbar muscular atrophy, disease of the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. The form of breast cancer that is seen in some men with partial androgen insensitivity syndrome is caused by a mutation in the AR's DNA-binding domain. It has been hypothesized that this mutation causes 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 receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
protein, to cause cancerous growth. The etiology
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
of spinal and bulbar muscular atrophy (SBMA) demonstrates that even the mutant AR protein itself can result in pathology
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
. The trinucleotide repeat expansion of the polyglutamine tract
Polyglutamine tract
A polyglutamine tract or polyQ tract is a portion of a protein consisting of a sequence of several glutamine units. A tract typically consists of about 10 to a few hundred such units....
of the AR gene that is associated with SBMA results in the synthesis of a misfolded AR protein that the cell fails to properly proteolyze
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
and disperse. These misfolded AR proteins form aggregates in the cell cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
and nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
. Over the course of 30 to 50 years, these aggregates accumulate and have a cytotoxic
Cytotoxicity
Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are a chemical substance, an immune cell or some types of venom .-Cell physiology:...
effect, eventually resulting in the neurodegenerative
Neurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
symptoms associated with SBMA.
Diagnosis
The phenotypes that result from the insensitivity to androgens are not unique to AIS, and 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 spermatogenesisSpermatogenesis
Spermatogenesis is the process by which male primary germ cells undergo division, and produce a number of cells termed spermatogonia, from which the primary spermatocytes are derived. Each primary spermatocyte divides into two secondary spermatocytes, and each secondary spermatocyte into two...
and / or virilization. Laboratory findings include a 46,XY karyotype
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
and normal or elevated postpubertal testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
, luteinizing hormone
Luteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
, and estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
levels. The androgen binding activity of genital skin fibroblasts is typically diminished, although exceptions have been reported. Conversion of testosterone to dihydrotestosterone
Dihydrotestosterone
Dihydrotestosterone is an androgen or male sex hormone. The enzyme 5α-reductase synthesises DHT in the prostate, testes, hair follicles, and adrenal glands...
may be impaired. The diagnosis of AIS is confirmed if androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
gene sequencing
DNA sequencing
DNA sequencing includes several methods and technologies that are used for determining the order of the nucleotide bases—adenine, guanine, cytosine, and thymine—in a molecule of DNA....
reveals a mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
, 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. Depending on the form of AIS that is suspected, the list of differentials can include:
- Chromosomal anomalies:
- Klinefelter syndrome (47,XXY karyotype)
- Turner syndromeTurner syndromeTurner syndrome or Ullrich-Turner syndrome encompasses several conditions in human females, of which monosomy X is most common. It is a chromosomal abnormality in which all or part of one of the sex chromosomes is absent...
(45,XO karyotype) - Mixed gonadal dysgenesisMixed gonadal dysgenesisMixed gonadal dysgenesis is a condition of unusual and asymmetrical gonadal development leading to an unassigned sex differentiation. A number of differences have been reported in the karyotype, most commonly a mosaicism 45,X/ 46, XY...
(45,XO/46,XY karyotype) - Tetragametic chimerism (46,XX/46,XY karyotype)
- AndrogenAndrogenAndrogen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
biosyntheticBiosynthesisBiosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
dysfunction in 46,XY individualsKaryotypeA karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
: - Luteinizing hormone (LH) receptor mutations
- Smith-Lemli-Opitz syndromeSmith-Lemli-Opitz syndromeSmith-Lemli-Opitz syndrome is an autosomal recessive metabolic and developmental congenital disorder that causes the inability to correctly produce or synthesize cholesterol due to a low occurrence of the 7-DHC reductace enzyme.-Symptoms:The signs and symptoms of SLOS syndrome vary widely...
(associated with mental retardation) - Lipoid congenital adrenal hyperplasiaLipoid congenital adrenal hyperplasiaLipoid congenital adrenal hyperplasia is an endocrine disorder that is an uncommon and potentially lethal form of congenital adrenal hyperplasia...
- 3β-hydroxysteroid dehydrogenase 2 deficiencyCongenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency3β-Hydroxysteroid dehydrogenase II deficient congenital adrenal hyperplasia is an uncommon form of CAH resulting from a mutation in the gene for one of the key enzymes in cortisol synthesis by the adrenal gland, 3β-hydroxysteroid dehydrogenase type II...
- 17α-hydroxylase deficiencyCongenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiencyCongenital adrenal hyperplasia due to 17α-hydroxylase deficiency is an uncommon form of congenital adrenal hyperplasia resulting from a defect in the gene for the enzyme CYP17A1. It produces decreased synthesis of both cortisol and sex steroids, with resulting increase in mineralocorticoid production...
- 17,20 lyase deficiency
- 17β-hydroxysteroid dehydrogenase deficiency17-beta-hydroxysteroid dehydrogenase deficiency17-beta-hydroxysteroid dehydrogenase III deficiency is a rare disorder of sexual development affecting testosterone biosynthesis, which can produce impaired virilization of genetically male infants and children and excessive virilization of female adults.It is an autosomal recessive condition and...
- 5α-reductase deficiency5-alpha-reductase deficiency5-Alpha-reductase deficiency is an autosomal recessive intersex condition caused by a mutation of the 5-alpha reductase type 2 gene.-Normal function:...
- Androgen excess in 46,XX individuals:
- 21-hydroxylase deficiencyCongenital adrenal hyperplasia due to 21-hydroxylase deficiencyCongenital adrenal hyperplasia due to 21-hydroxylase deficiency , in all its forms, accounts for over 95% of diagnosed cases of congenital adrenal hyperplasia, and "CAH" in most contexts refers to 21-hydroxylase deficiency...
- 3β-hydroxysteroid dehydrogenase 2 deficiencyCongenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency3β-Hydroxysteroid dehydrogenase II deficient congenital adrenal hyperplasia is an uncommon form of CAH resulting from a mutation in the gene for one of the key enzymes in cortisol synthesis by the adrenal gland, 3β-hydroxysteroid dehydrogenase type II...
- Cytochrome P450 oxidoreductase deficiency (disorder in mother causes 46,XX fetal virilization)
- 11β-hydroxylase deficiency
- Aromatase deficiencyAromatase deficiencyAromatase deficiency is a condition resulting from insufficient production of the enzyme aromatase, which can lead to inappropriate virilization.One notable feature is that it can also affect the mother during gestation that resolves after birth...
- Glucocorticoid receptor mutations
- Maternal virilizing tumor (e.g. luteomaLuteomaLuteoma is a rare tumor of the ovaries.It can be associated with female pseudohermaphroditism.-Presentation:This type of ovarian tumor produces progesterone. The excess of this hormone produces the symptoms that accompany this disease....
) - Increased androgen exposure in utero, not otherwise specified (e.g. androgenic drugsAnabolic steroidAnabolic steroids, technically known as anabolic-androgen steroids or colloquially simply as "steroids", are drugs that mimic the effects of testosterone and dihydrotestosterone in the body. They increase protein synthesis within cells, which results in the buildup of cellular tissue ,...
) - Developmental
- Mayer-Rokitansky-Küster-Hauser syndrome (46,XX karyotype)
- Swyer syndromeSwyer syndromeSwyer syndrome, or XY gonadal dysgenesis, is a type of hypogonadism in a person whose karyotype is 46,XY. The person is externally female with streak gonads, and left untreated, will not experience puberty...
(46,XY karyotype) - XX gonadal dysgenesisXX gonadal dysgenesisThis syndrome is inherited as an autosomal disease. It affects both males and females but the phenotype differs. In both sexes sensorineural deafness occurs but in females ovarian dysgenesis also occurs....
(46,XX karyotype) - Leydig cellLeydig cellLeydig cells, also known as interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle. They produce testosterone in the presence of luteinizing hormone...
agenesisAgenesisIn medicine, agenesis refers to the failure of an organ to develop during embryonic growth and development due to the absence of primordial tissue...
or hypoplasiaHypoplasiaHypoplasia is underdevelopment or incomplete development of a tissue or organ. Although the term is not always used precisely, it properly refers to an inadequate or below-normal number of cells. Hypoplasia is similar to aplasia, but less severe. It is technically not the opposite of hyperplasia...
, not otherwise specified (46,XY karyotype) - Absent (vanishing) testes syndromeAnorchiaAnorchia is a medical condition where both testes are absent at birth. Within a few weeks of fertilization, the embryo develops rudimentary sex organs, which are crucial to the development of the reproductive system...
- Ovotesticular DSDTrue hermaphroditismTrue hermaphroditism is a medical term for an intersex condition in which an individual is born with ovarian and testicular tissue.There may be an ovary on one side and a testis on the other, but more commonly one or both gonads is an ovotestis containing both types of tissue.It is rare—so...
- Testicular DSD (i.e. 46,XX sex reversalIntersexIntersex, in humans and other animals, is the presence of intermediate or atypical combinations of physical features that usually distinguish female from male...
) - Teratogenic causes (e.g. estrogens, antiestrogenAntiestrogenAn antiestrogen is a substance that blocks the production or utilization of estrogens, or inhibits their effects....
s) - Other causes:
- Frasier syndromeFrasier syndromeFrasier syndrome is a urogenital anomaly associated with WT1.It was first characterized in 1964.-Presentation:Frasier syndrome presents at birth with male pseudohermaphroditism , streak gonads and progressive glomerulonephropathy...
(associated with progressive glomerulopathy) - Denys-Drash syndromeDenys-Drash syndromeDenys-Drash syndrome is a syndrome characterized by the following conditions:* gonadal dysgenesis* nephropathy* Wilms tumorDenys-Drash Syndrome is a very rare disorder.- Etiology :...
(associated with nephropathy and Wilms tumor) - WAGR syndromeWAGR syndromeWAGR syndrome is a rare genetic syndrome in which affected children are predisposed to develop Wilms tumour , Aniridia , Genitourinary anomalies, and mental Retardation...
(associated with Wilms tumor and aniridia) - McKusick-Kaufman syndromeMcKusick-Kaufman syndromeMcKusick–Kaufman syndrome is a genetic condition associated with MKKS.It is named for Robert Kaufman and Victor McKusick.-External links:*...
(associated with postaxial polydactyly) - Robinow syndromeRobinow syndromeRobinow syndrome is an extremely rare genetic disorder characterized by short-limbed dwarfism, abnormalities in the head, face, and external genitalia, as well as vertebral segmentation. The disorder was first described in 1969 by human geneticist Meinhard Robinow, along with physicians Frederic N....
(associated with dwarfism) - Aarskog-Scott syndromeAarskog-Scott syndromeAarskog–Scott syndrome is an inherited disease characterized by short stature, facial abnormalities, skeletal and genital anomalies.The Aarskog–Scott syndrome is also known as the Aarskog syndrome, faciodigitogenital syndrome, shawl scrotum syndrome and faciogenital dysplasia.-Signs and...
(associated with facial anomalies) - Hand-foot-genital syndromeHand-Foot-Genital SyndromeHand-foot-genital syndrome is characterized by limb malformations and urogenital defects. Mild bilateral shortening of the thumbs and great toes, caused primarily by shortening of the distal phalanx and/or the first metacarpal or metatarsal, is the most common limb malformation and results in...
(associated with limb malformations) - Popliteal pterygium syndromePopliteal pterygium syndromePopliteal pterygium syndrome is an inherited condition affecting the face, limbs, and genitalia. The syndrome goes by a number of names including the popliteal web syndrome and, more inclusively, the facio-genito-popliteal syndrome...
(associated with extensive webbing behind knees) - Kallmann syndromeKallmann syndromeKallmann syndrome is a genetic disorder marked by anosmia and hypogonadism - the decreased functioning of the glands that produce sex hormones. Abnormalities in various genes may cause a defect in the hypothalamus, causing a deficiency of gonadotropin-releasing hormone ; this in turn causes...
(often associated with anosmia) - HypospadiasHypospadiasHypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...
not otherwise specified - CryptorchidismCryptorchidismCryptorchidism is the absence of one or both testes from the scrotum. It is the most common birth defect regarding male genitalia. In unique cases, cryptorchidism can develop later in life, often as late as young adulthood. About 3% of full-term and 30% of premature infant boys are born with at...
not otherwise specified - vaginal atresiaVaginal atresiaVaginal Atresia is a birth defect or congenital abnormality of the female genitourinary system that manifests itself in the absence of a vagina , or a deformed and nonfunctional vagina ....
not otherwise specified
CAIS
PAIS
MAIS
Management
Management of AIS is currently limited to symptomatic managementSymptomatic treatment
Symptomatic treatment is any medical therapy of a disease that only affects its symptoms, not its cause, i.e., its etiology. It is usually aimed at reducing the signs and symptoms for the comfort and well-being of the patient, but it also may be useful in reducing organic consequences and sequelae...
; methods to correct a malfunctioning androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
protein that result from an AR gene mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
are not currently available. Areas of management include sex assignment
Sex assignment
Sex assignment refers to the assigning of the biological sex at the birth of a baby. In the majority of births, a relative, midwife, or physician inspects the genitalia when the baby is delivered, sees ordinary male or female genitalia, and declares, "it's a girl" or "it's a boy" without the...
, genitoplasty, gonadectomy in relation to tumor
Germ cell tumor
A germ cell tumor is a neoplasm derived from germ cells. Germ cell tumors can be cancerous or non-cancerous tumors. Germ cells normally occur inside the gonads...
risk, hormone replacement therapy
Hormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
, and genetic
Genetic counseling
Genetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
and psychological counseling
Psychotherapy
Psychotherapy is a general term referring to any form of therapeutic interaction or treatment contracted between a trained professional and a client or patient; family, couple or group...
.
CAIS
PAIS
MAIS
Epidemiology
Estimates for the incidenceIncidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
of androgen insensitivity syndrome are based on a relatively small population
Statistical population
A statistical population is a set of entities concerning which statistical inferences are to be drawn, often based on a random sample taken from the population. For example, if we were interested in generalizations about crows, then we would describe the set of crows that is of interest...
size, and thus are known to be imprecise. CAIS is estimated to occur in 1 out of every 20,400 46,XY births. A nationwide survey in The Netherlands based on patients with genetic confirmation
Genetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
of the diagnosis estimates that the minimal incidence of CAIS is 1 in 99,000. The incidence of PAIS is estimated to be 1 in 130,000. Due to its subtle presentation, MAIS is not typically investigated except in the case of male infertility
Male infertility
Male infertility refers to the inability of a male to achieve a pregnancy in a fertile female. In humans it accounts for 40-50% of infertility. Male infertility is commonly due to deficiencies in the semen, and semen quality is used as a surrogate measure of male fecundity.-Pre-testicular...
, and thus its true prevalence is unknown.
History
Recorded descriptions of the effects of androgen insensitivity syndrome date back for hundreds of years, although significant understanding of its underlying histopathologyHistopathology
Histopathology refers to the microscopic examination of tissue in order to study the manifestations of disease...
would not occur until the 1950s. The taxonomy
Taxonomy
Taxonomy is the science of identifying and naming species, and arranging them into a classification. The field of taxonomy, sometimes referred to as "biological taxonomy", revolves around the description and use of taxonomic units, known as taxa...
and nomenclature
Nomenclature
Nomenclature is a term that applies to either a list of names or terms, or to the system of principles, procedures and terms related to naming - which is the assigning of a word or phrase to a particular object or property...
associated with androgen insensitivity went through a significant evolution that paralleled this understanding.
Timeline of major milestones
- 1950: Lawson WilkinsLawson Wilkins-References:...
administers daily methyltestosteroneMethyltestosteroneMethyltestosterone is a 17-alpha-alkylated anabolic steroid used to treat men with a testosterone deficiency. It is also used in women to treat breast cancer, breast pain, swelling due to pregnancy, and with the addition of estrogen it can treat symptoms of menopause...
to a 46,XYKaryotypeA karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
female patient, who shows no signs of virilization. His experiment is the first documented demonstration of the pathophysiologyPathophysiologyPathophysiology is the study of the changes of normal mechanical, physical, and biochemical functions, either caused by a disease, or resulting from an abnormal syndrome...
of androgen insensitivity syndrome. - 1970: Mary F. LyonMary F. LyonMary Frances Lyon, FRS is an English geneticist, who is best known for her discovery of X-chromosome inactivation, an important cytogenetic phenomenon.-Childhood and education:...
and Susan Hawkes report that a geneGeneA gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
on the X chromosomeX chromosomeThe X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
caused complete insensitivity to androgens in mice. - 1981: Barbara Migeon et al. narrow down the locusLocus (genetics)In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
of the human androgen receptorAndrogen receptorThe androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
geneGeneA gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
(or a factor controlling the androgen receptor gene) to somewhere between Xq11 and Xq13. - 1988: The human androgen receptor gene is first clonedMolecular cloningMolecular cloning refers to a set of experimental methods in molecular biology that are used to assemble recombinant DNA molecules and to direct their replication within host organisms...
and partially analyzedGenetic analysisGenetic analysis can be used generally to describe methods both used in and resulting from the sciences of genetics and molecular biology, or to applications resulting from this research....
by multiple parties. Terry Brown et al. report the first mutations proven to cause AIS. - 1989: Terry Brown et al. reports the exact locus of the AR gene (Xq11-Xq12), and Dennis Lubahn et al. publishes its intronIntronAn intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
-exonExonAn exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
boundaries. - 1994: The androgen receptor gene mutations databaseDatabaseA database is an organized collection of data for one or more purposes, usually in digital form. The data are typically organized to model relevant aspects of reality , in a way that supports processes requiring this information...
is created to provide a comprehensive listing of mutations published in journalsMedical journalA public health journal is a scientific journal devoted to the field of public health, including epidemiology, biostatistics, and health care . Public health journals, like most scientific journals, are peer-reviewed...
and conference proceedingsProceedingsIn academia, proceedings are the collection of academic papers that are published in the context of an academic conference. They are usually distributed as printed books either before the conference opens or after the conference has closed. Proceedings contain the contributions made by researchers...
.
Early terminology
The first descriptions of the effects of androgen insensitivity appeared in the medical literatureMedical literature
Medical literature refers to articles in journals and texts in books devoted to the field of medicine.Contemporary and historic views regarding diagnosis, prognosis and treatment of medical conditions have been documented for thousands of years. The Edwin Smith papyrus is the first known medical...
as individual case reports or as part of a comprehensive description of intersex
Intersex
Intersex, in humans and other animals, is the presence of intermediate or atypical combinations of physical features that usually distinguish female from male...
physicalities. In 1839, Scottish obstetrician Sir James Young Simpson
James Young Simpson
Sir James Young Simpson was a Scottish doctor and an important figure in the history of medicine. Simpson discovered the anaesthetic properties of chloroform and successfully introduced it for general medical use....
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
Taxonomy
Taxonomy is the science of identifying and naming species, and arranging them into a classification. The field of taxonomy, sometimes referred to as "biological taxonomy", revolves around the description and use of taxonomic units, known as taxa...
, however, was far from the first; taxonomies / descriptions for the classification of intersexuality were developed by Italian physician and physicist Fortuné Affaitati in 1549, French surgeon Ambroise Paré
Ambroise Paré
Ambroise Paré was a French surgeon. He was the great official royal surgeon for kings Henry II, Francis II, Charles IX and Henry III and is considered as one of the fathers of surgery and modern forensic pathology. He was a leader in surgical techniques and battlefield medicine, especially the...
in 1573, French physician and sexology pioneer Nicolas Venette in 1687 (under the pseudonym Vénitien Salocini), and French Zoologist Isidore Geoffroy St. Hilaire
Isidore Geoffroy Saint-Hilaire
Isidore Geoffroy Saint-Hilaire was a French zoologist and an authority on deviation from normal structure. He coined the term ethology.He was born in Paris, the son of Étienne Geoffroy Saint-Hilaire...
in 1832. All five of the aforementioned authors used the colloquial term "hermaphrodite" 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
Nomenclature
Nomenclature is a term that applies to either a list of names or terms, or to the system of principles, procedures and terms related to naming - which is the assigning of a word or phrase to a particular object or property...
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
"PseudohermaphroditismPseudohermaphroditism
Pseudohermaphroditism, or pseudo-hermaphroditism, is the condition in which an organism is born with secondary sex characteristics or a phenotype that is different from what would be expected on the basis of the gonadal tissue ....
" has, until very recently, been the term used in the medical literature
Medical literature
Medical literature refers to articles in journals and texts in books devoted to the field of medicine.Contemporary and historic views regarding diagnosis, prognosis and treatment of medical conditions have been documented for thousands of years. The Edwin Smith papyrus is the first known medical...
to describe the condition of an individual whose gonads and karyotype
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
do not match the external genitalia in the gender binary
Gender binary
The gender binary is the classification of sex and gender into two distinct and disconnected forms of masculine and feminine. It is one general type of a gender system. It can describe a social boundary that discourages people from crossing or mixing gender roles, or from creating other third ...
sense. For example, 46,XY
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
individuals that have a female phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
, but also have testes instead of ovaries --- a group that includes all individuals with complete androgen insensitivity (CAIS), as well as some individuals with partial androgen insensitivity (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
True hermaphroditism
True hermaphroditism is a medical term for an intersex condition in which an individual is born with ovarian and testicular tissue.There may be an ovary on one side and a testis on the other, but more commonly one or both gonads is an ovotestis containing both types of tissue.It is rare—so...
.". Usage of the word in the medical literature predates the discovery of the chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
, and 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
Edwin Klebs
Theodor Albrecht Edwin Klebs was a German-Swiss pathologist. He is mainly known for his work on infectious diseases. He is the father of Arnold Klebs.-Life:...
is sometimes noted for using the word "pseudohermaphroditism" in his taxonomy
Taxonomy
Taxonomy is the science of identifying and naming species, and arranging them into a classification. The field of taxonomy, sometimes referred to as "biological taxonomy", revolves around the description and use of taxonomic units, known as taxa...
of intersex
Intersex
Intersex, in humans and other animals, is the presence of intermediate or atypical combinations of physical features that usually distinguish female from male...
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 Frederik Ruysch
Frederik Ruysch
Frederik Ruysch was a Dutch botanist and anatomist, remembered for his developments in anatomical preservation and the creation of dioramas or scenes incorporating human parts...
used it in a publication describing a subject with testes and a mostly female phenotype. "Pseudohermaphrodite" also appeared in the Acta Eruditorum
Acta Eruditorum
Acta Eruditorum was the first scientific journal of the German lands, published from 1682 to 1782....
later that same year, in a review of Ruysch's work. There is also evidence that the word was already being used by the German and French medical community long before Klebs used it; German physiologist Johannes Peter Müller
Johannes Peter Müller
Johannes Peter Müller , was a German physiologist, comparative anatomist, and ichthyologist not only known for his discoveries but also for his ability to synthesize knowledge.-Early years and education:...
equated "pseudohermaphroditism" with a sub-class of hermaphroditism from St. Hilaire's
Isidore Geoffroy Saint-Hilaire
Isidore Geoffroy Saint-Hilaire was a French zoologist and an authority on deviation from normal structure. He coined the term ethology.He was born in Paris, the son of Étienne Geoffroy Saint-Hilaire...
taxonomy in a publication dated 1834, and by the 1840s "pseudo-hermaphroditism" 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 literatureMedical literature
Medical literature refers to articles in journals and texts in books devoted to the field of medicine.Contemporary and historic views regarding diagnosis, prognosis and treatment of medical conditions have been documented for thousands of years. The Edwin Smith papyrus is the first known medical...
, including 2 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 that is now understood to be due to the inaction of androgens, and subsequent aromatization of testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
into estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
. A few years before Morris published his landmark paper, Lawson Wilkins
Lawson Wilkins
-References:...
had shown through his own experiments that unresponsiveness of the target cell to the action of androgenic hormones was a cause of "male pseudohermaphroditism
Pseudohermaphroditism
Pseudohermaphroditism, or pseudo-hermaphroditism, is the condition in which an organism is born with secondary sex characteristics or a phenotype that is different from what would be expected on the basis of the gonadal tissue ....
". Wilkins' work, which clearly demonstrated the lack of a therapeutic effect when 46,XY
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
women 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 androgen insensitivity syndrome, 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 receptorAndrogen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, 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
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
of AIS, it has been demonstrated that these disorders are different phenotypic expressions of one syndrome caused by molecular defects in the androgen receptor gene.
Androgen insensitivity syndrome (AIS) is now the accepted terminology
Terminology
Terminology is the study of terms and their use. Terms are words and compound words that in specific contexts are given specific meanings, meanings that may deviate from the meaning the same words have in other contexts and in everyday language. The discipline Terminology studies among other...
for the syndromes resulting from unresponsiveness of the target cell to the action of androgenic hormones. AIS is broken down into three classes based on phenotype: complete androgen insensitivity syndrome
Complete androgen insensitivity syndrome
Complete androgen insensitivity syndrome is a condition that results in the complete inability of the cell to respond to androgens. The unresponsiveness of the cell to the presence of androgenic hormones prevents the masculinization of male genitalia in the developing fetus, as well as the...
(CAIS), partial androgen insensitivity syndrome
Partial androgen insensitivity syndrome
Partial androgen insensitivity syndrome is a condition that results in the partial inability of the cell to respond to androgens. The partial unresponsiveness of the cell to the presence of androgenic hormones impairs the masculinization of male genitalia in the developing fetus, as well as the...
(PAIS), and mild androgen insensitivity syndrome
Mild androgen insensitivity syndrome
Mild androgen insensitivity syndrome is a condition that results in a mild impairment of the cell's ability to respond to androgens. The degree of impairment is sufficient to impair spermatogenesis and / or the development of secondary sexual characteristics at puberty in males, but does not...
(MAIS). 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 androgen receptor gene. These diagnoses were used to describe a variety of mild defects in virilization; as a result, the phenotypes of some men that have been diagnosed as such are better described by PAIS (e.g. micropenis
Micropenis
Micropenis is an unusually small penis. A common criterion is a dorsal erect penile length of at least 2.5 standard deviations smaller than the mean human penis size. The condition is usually recognized shortly after birth...
, hypospadias
Hypospadias
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...
and undescended testes
Cryptorchidism
Cryptorchidism is the absence of one or both testes from the scrotum. It is the most common birth defect regarding male genitalia. In unique cases, cryptorchidism can develop later in life, often as late as young adulthood. About 3% of full-term and 30% of premature infant boys are born with at...
), while others are better described by MAIS (e.g. isolated infertility
Male infertility
Male infertility refers to the inability of a male to achieve a pregnancy in a fertile female. In humans it accounts for 40-50% of infertility. Male infertility is commonly due to deficiencies in the semen, and semen quality is used as a surrogate measure of male fecundity.-Pre-testicular...
or gynecomastia
Gynecomastia
Gynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...
).
Popular culture
The 1991 novel RingRing (Suzuki novel)
is a Japanese horror novel by Koji Suzuki, first published in 1991, and set in modern day Japan. It was the basis for a film of the same name , and two remakes: a Korean version and an American version ....
(later adopted into English "The Ring" series) describes that the central antagonist Sadako) has this syndrome.
In Season 2 Episode 13 "Skin Deep" of House
House (TV series)
House is an American television medical drama that debuted on the Fox network on November 16, 2004. The show's central character is Dr. Gregory House , an unconventional and misanthropic medical genius who heads a team of diagnosticians at the fictional Princeton-Plainsboro Teaching Hospital in...
Information
,- An Australian parent/patient booklet on CAIS
- The Secret of My Sex news article
- Women With Male DNA All Female news article at ABCnews.com