Mild androgen insensitivity syndrome
Encyclopedia
Mild androgen insensitivity syndrome (MAIS) is a condition that results in a mild impairment of the cell's ability to respond to androgen
s. The degree of impairment is sufficient to impair spermatogenesis
and / or the development of secondary sexual characteristics at puberty
in males, but does not affect genital differentiation
or development. Female genital and sexual development is not significantly affected by the insensitivity to androgens; as such, MAIS is only diagnosed in males. The clinical phenotype
associated with MAIS is a normal male habitus
with mild spermatogenic
defect and / or reduced secondary terminal hair
.
MAIS is one of three types of androgen insensitivity syndrome
, which 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 undermasculinization .
male, with fully masculinized genitalia; this category of androgen insensitivity is diagnosed when the degree of androgen insensitivity in an individual with a 46,XY karyotype
is great enough to impair virilization or spermatogenesis
, but is not great enough to impair normal male genital development . MAIS is the mildest and least known form of androgen insensitivity syndrome .
The existence of a variant of androgen insensitivity that solely affected spermatogenesis
was theoretical at first . Cases of phenotypically normal males with isolated spermatogenic defect
due to AR mutation were first detected as the result of male infertility
evaluations . Until then, early evidence in support of the existence of MAIS was limited to cases involving a mild defect in virilization , although some of these early cases made allowances for some degree of impairment of genital masculinization, such as hypospadias
or micropenis
. It is estimated that 2-3% of infertile men have AR gene mutations .
Examples of MAIS phenotypes include isolated infertility (oligospermia or azoospermia) , mild gynecomastia
in young adulthood, decreased secondary
terminal hair
, high pitched voice, or minor hypospadias
repair in childhood . The external male genitalia
(penis
, scrotum
, and urethra
) are otherwise normal in individuals with MAIS . Internal genitalia
, including Wolffian structures
(the epididymides
, vasa deferentia
, and seminal vesicles) and the prostate
, is also normal, although the bitesticular volume of infertile men (both with and without MAIS) is diminished ; male infertility
is associated with reduced bitesticular volume, varicocele
, retractile testes, low ejaculate volume, male accessory gland
infections (MAGI), and mumps
orchitis
. The incidence of these features in infertile men with MAIS is similar to that of infertile men without MAIS . MAIS is not associated with Müllerian
remnants.
, also known as spinal and bulbar muscular atrophy (SBMA), is a severe neurodegenerative
syndrome that is associated with a particular mutation of the androgen receptor
's polyglutamine tract
called a trinucleotide repeat expansion . SBMA results when the length of the polyglutamine tract exceeds 40 repetitions .
Although technically a variant of MAIS, SBMA's presentation is not typical of androgen insensitivity; symptoms do not occur until adulthood and include neuromuscular
defects as well as signs of androgen inaction . Neuromuscular symptoms include progressive proximal muscle weakness, atrophy
, and fasciculations. Symptoms of androgen insensitivity experienced by men with SBMA are also progressive and include testicular atrophy, severe oligospermia
or azoospermia
, gynecomastia
, and feminized skin changes despite elevated androgen levels . Disease onset, which usually affects the proximal musculature first, occurs in the third to fifth decades of life, and is often preceded by muscular cramps on exertion, tremor of the hands, and elevated muscle creatine kinase
. SBMA is often misdiagnosed as amyotrophic lateral sclerosis
(ALS) (aka. Lou Gehrig's disease) .
The symptoms of SBMA are thought to be brought about by two simultaneous pathways involving the toxic misfolding of proteins and loss of AR functionality . The polyglutamine tract in affected pedigrees tends to increase in length over generations, a phenomenon known as "anticipation
" , leading to an increase in the severity of the disease as well as a decrease in the age of onset for each subsequent generation of a family affected by SBMA .
, though exceptions have been reported for both the mild and partial forms . Lifespan is not thought to be affected by AIS .
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 . 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 infertility
and undermasculinized genitalia . 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 . Longer polyglycine tract lengths have also been associated with genital masculinization defects in some , but not all , studies.
. MAIS has a mild presentation that often goes unnoticed and untreated ; even with semenological, clinical and laboratory data, it can be difficult to distinguish between men with and without MAIS, and thus a diagnosis of MAIS is not usually made without confirmation of an AR gene
mutation
. The androgen
sensitivity index (ASI), defined as the product of luteinizing hormone
(LH) and testosterone
(T), is frequently raised in individuals with all forms of AIS, including MAIS, although many individuals with MAIS have an ASI in the normal range . Testosterone levels may be elevated despite normal levels of luteinizing hormone . Conversion of testosterone (T) to dihydrotestosterone
(DHT) may be impaired, although to a lesser extent than is seen in 5α-reductase deficiency
. A high ASI in a normal phenotypic male , especially when combined with azoospermia
or oligospermia
, decreased secondary
terminal hair
, and / or impaired conversion of T to DHT , can be indicative of MAIS, and may warrant genetic testing
.
; methods to correct a malfunctioning androgen receptor
protein that result from an AR gene mutation
are not currently available. Treatment includes surgical correction of mild gynecomastia
, minor hypospadias
repair, and testosterone supplementation
. Supraphysiological doses of testosterone have been shown to correct diminished secondary sexual characteristics in men with MAIS , as well as to reverse infertility
due to low sperm count . As is the case with PAIS, men with MAIS will experience side effects from androgen
therapy (such as the suppression of the hypothalamic-pituitary-gonadal axis
) at a higher dosage than unaffected men. Careful monitoring is required to ensure the safety and efficacy of treatment . Regular breast and prostate
examinations may be necessary due to comorbid
association with breast
and prostate
cancers.
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 degree of impairment is sufficient to impair spermatogenesis
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...
and / or the development of 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...
in males, but does not affect genital differentiation
Sexual differentiation
Sexual differentiation is the process of development of the differences between males and females from an undifferentiated zygote...
or development. Female genital and sexual development is not significantly affected by the insensitivity to androgens; as such, MAIS is only diagnosed in males. The clinical 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...
associated with MAIS is 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 and / 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...
.
MAIS is one of three types of androgen insensitivity syndrome
Androgen insensitivity syndrome
Androgen insensitivity syndrome is a condition that results in the partial or complete inability of the cell to respond to androgens. 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...
, which is divided into three categories that are differentiated by the degree of genital masculinization: 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) 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
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) 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 undermasculinization .
Signs and symptoms
Individuals with mild (or minimal) androgen insensitivity syndrome (grade 1 on the Quigley scale) are born phenotypicallyPhenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
male, with fully masculinized genitalia; this category of androgen insensitivity is diagnosed when the degree of androgen insensitivity in an individual 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...
is great enough to impair virilization or spermatogenesis
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...
, but is not great enough to impair normal male genital development . MAIS is the mildest and least known form of androgen insensitivity syndrome .
The existence of a variant of androgen insensitivity that solely affected spermatogenesis
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...
was theoretical at first . Cases of phenotypically normal males with isolated spermatogenic defect
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...
due to AR mutation were first detected as the result 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...
evaluations . Until then, early evidence in support of the existence of MAIS was limited to cases involving a mild defect in virilization , although some of these early cases made allowances for some degree of impairment of genital masculinization, such as hypospadias
Hypospadias
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...
or 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...
. It is estimated that 2-3% of infertile men have AR gene mutations .
Examples of MAIS phenotypes include isolated infertility (oligospermia or azoospermia) , mild 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"...
in young adulthood, decreased 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...
, high pitched voice, or minor hypospadias
Hypospadias
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...
repair in childhood . The external male genitalia
Male external genitalia
The male external genitalia refers to the portion of the male reproductive system consisting of penis, urinary tract, and scrotum....
(penis
Penis
The penis is a biological feature of male animals including both vertebrates and invertebrates...
, 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...
, and 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...
) are otherwise normal in individuals with MAIS . Internal genitalia
Male internal genitalia
The male internal genitalia refers to the portion of the male reproductive system consisting of seminal tract and prostate....
, including Wolffian structures
Wolffian structures
In anatomy, Wolffian structures are male urogenital structures that include the epididymis, vas deferens, and seminal vesicles. They are often referred to in cases of androgen insensitivity syndrome.-See also:...
(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) and the prostate
Prostate
The prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals....
, is also normal, although the bitesticular volume of infertile men (both with and without MAIS) is diminished ; 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...
is associated with reduced bitesticular volume, varicocele
Varicocele
Varicocele , also known as varicoscele or varicose seal, is an abnormal enlargement of the vein that is in the scrotum draining the testicles. The testicular blood vessels originate in the abdomen and course down through the inguinal canal as part of the spermatic cord on their way to the testis...
, retractile testes, low ejaculate volume, male accessory gland
Male accessory gland
Male accessory glands in humans are the seminal vesicles, prostate gland, and the bulbourethral glands.In insects, male accessory glands produce products that mix with the sperm to protect and preserve them. Some insecticides can induce an increase in the protein content of the male accessory...
infections (MAGI), and mumps
Mumps
Mumps is a viral disease of the human species, caused by the mumps virus. Before the development of vaccination and the introduction of a vaccine, it was a common childhood disease worldwide...
orchitis
Orchitis
Orchitis or orchiditis is a condition of the testes involving inflammation. It can also involve swelling and frequent infection.-Symptoms:Symptoms of orchitis are similar to those of testicular torsion...
. The incidence of these features in infertile men with MAIS is similar to that of infertile men without MAIS . MAIS is not associated with Müllerian
Müllerian duct
Müllerian ducts are paired ducts of the embryo that run down the lateral sides of the urogenital ridge and terminate at the Müllerian eminence in the primitive urogenital sinus. In the female, they will develop to form the Fallopian tubes, uterus, cervix, and the upper two-third of the vagina; in...
remnants.
Kennedy Disease
Kennedy diseaseKennedy disease
Kennedy's disease or X-linked Spinal and Bulbar Muscular Atrophy or Spinobulbar Muscular Atrophy or X-Linked Bulbo-Spinal Atrophy is an X-linked recessive, slow progressing, neurodegenerative disease associated with mutation of the androgen receptor...
, also known as spinal and bulbar muscular atrophy (SBMA), is a severe 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...
syndrome that is associated with a particular mutation of the 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 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....
called a trinucleotide repeat expansion . SBMA results when the length of the polyglutamine tract exceeds 40 repetitions .
Although technically a variant of MAIS, SBMA's presentation is not typical of androgen insensitivity; symptoms do not occur until adulthood and include neuromuscular
Neuromuscular junction
A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...
defects as well as signs of androgen inaction . Neuromuscular symptoms include progressive proximal muscle weakness, atrophy
Muscle atrophy
Muscle atrophy, or disuse atrophy, is defined as a decrease in the mass of the muscle; it can be a partial or complete wasting away of muscle. When a muscle atrophies, this leads to muscle weakness, since the ability to exert force is related to mass...
, and fasciculations. Symptoms of androgen insensitivity experienced by men with SBMA are also progressive and include testicular atrophy, severe oligospermia
Oligospermia
Oligospermia, also oligozoospermia, refers to semen with a low concentration of sperm and is a common finding in male infertility. Often semen with a decreased sperm concentration may also show significant abnormalities in sperm morphology and motility...
or azoospermia
Azoospermia
Azoospermia is the medical condition of a male not having any measurable level of sperm in his semen. It is associated with very low levels of fertility or even sterility, but many forms are amenable to medical treatment...
, 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"...
, and feminized skin changes despite elevated androgen levels . Disease onset, which usually affects the proximal musculature first, occurs in the third to fifth decades of life, and is often preceded by muscular cramps on exertion, tremor of the hands, and elevated muscle creatine kinase
Creatine kinase
Creatine kinase , also known as creatine phosphokinase or phospho-creatine kinase , is an enzyme expressed by various tissues and cell types. CK catalyses the conversion of creatine and consumes adenosine triphosphate to create phosphocreatine and adenosine diphosphate...
. SBMA is often misdiagnosed as amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
(ALS) (aka. Lou Gehrig's disease) .
The symptoms of SBMA are thought to be brought about by two simultaneous pathways involving the toxic misfolding of proteins and loss of AR functionality . The polyglutamine tract in affected pedigrees tends to increase in length over generations, a phenomenon known as "anticipation
Anticipation (genetics)
In genetics, anticipation is a phenomenon whereby the symptoms of a genetic disorder become apparent at an earlier age as it is passed on to the next generation. In most cases, an increase of severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders such as...
" , leading to an increase in the severity of the disease as well as a decrease in the age of onset for each subsequent generation of a family affected by SBMA .
Comorbidity
All forms of androgen insensitivity are associated with infertilityInfertility
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...
, though exceptions have been reported for both the mild and partial forms . Lifespan is not thought to be affected by AIS .
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 . 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 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 . 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 . Longer polyglycine tract lengths have also been associated with genital masculinization defects in some , but not all , studies.
Diagnosis
MAIS is only diagnosed in normal phenotypic males, and is not typically investigated except in cases of male infertilityMale 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...
. MAIS has a mild presentation that often goes unnoticed and untreated ; even with semenological, clinical and laboratory data, it can be difficult to distinguish between men with and without MAIS, and thus a diagnosis of MAIS is not usually made without confirmation of an AR gene
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...
. The 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...
sensitivity index (ASI), defined as the product of 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...
(LH) and 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...
(T), is frequently raised in individuals with all forms of AIS, including MAIS, although many individuals with MAIS have an ASI in the normal range . Testosterone levels may be elevated despite normal levels of luteinizing hormone . Conversion of testosterone (T) 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...
(DHT) may be impaired, although to a lesser extent than is seen in 5α-reductase deficiency
5-alpha-reductase deficiency
5-Alpha-reductase deficiency is an autosomal recessive intersex condition caused by a mutation of the 5-alpha reductase type 2 gene.-Normal function:...
. A high ASI in a normal phenotypic male , especially when combined with azoospermia
Azoospermia
Azoospermia is the medical condition of a male not having any measurable level of sperm in his semen. It is associated with very low levels of fertility or even sterility, but many forms are amenable to medical treatment...
or oligospermia
Oligospermia
Oligospermia, also oligozoospermia, refers to semen with a low concentration of sperm and is a common finding in male infertility. Often semen with a decreased sperm concentration may also show significant abnormalities in sperm morphology and motility...
, decreased 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...
, and / or impaired conversion of T to DHT , can be indicative of MAIS, and may warrant genetic testing
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...
.
Management
Due to its mild presentation, MAIS often goes unnoticed and untreated . Management of MAIS 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. Treatment includes surgical correction of mild 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"...
, minor hypospadias
Hypospadias
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...
repair, and testosterone supplementation
Androgen replacement therapy
Androgen replacement therapy is a hormone treatment often prescribed to counter the effects of male Hypogonadism. It is also prescribed to lessen the effects or delay the onset of normal male aging...
. Supraphysiological doses of testosterone have been shown to correct diminished secondary sexual characteristics in men with MAIS , as well as to reverse 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...
due to low sperm count . As is the case with PAIS, men with MAIS will experience side effects from 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...
therapy (such as the suppression of the hypothalamic-pituitary-gonadal axis
Hypothalamic-pituitary-gonadal axis
The hypothalamic–pituitary–gonadal axis refers to the effects of the hypothalamus, pituitary gland, and gonads as if these individual endocrine glands were a single entity as a whole...
) at a higher dosage than unaffected men. Careful monitoring is required to ensure the safety and efficacy of treatment . Regular breast and prostate
Rectal examination
A rectal examination or rectal exam is an internal examination of the rectum such as by a physician or other healthcare professional.-Procedure:...
examinations may be necessary due to comorbid
Comorbidity
In medicine, comorbidity is either the presence of one or more disorders in addition to a primary disease or disorder, or the effect of such additional disorders or diseases.- In medicine :...
association with breast
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
and prostate
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...
cancers.