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Mild androgen insensitivity syndrome

From Wikipedia, the free encyclopedia
Medical condition
Mild androgen insensitivity syndrome
Other namesUndervirilized male syndrome
AIS results when the function of theandrogen receptor (AR) is impaired. The AR protein (pictured) mediates the effects of androgens in the human body.
SpecialtyEndocrinology Edit this on Wikidata

Mild androgen insensitivity syndrome (MAIS) is a medical condition that results in a mild impairment of thecell's ability to respond toandrogens.[1][2][3] The degree of impairment is sufficient to impairspermatogenesis and / or the development ofsecondary sexual characteristics atpuberty in males, but does not affectgenital differentiation ordevelopment. Female genital and sexual development is not significantly affected by the insensitivity to androgens;[3][4] as such, MAIS is only diagnosed in males.[1] The clinicalphenotype associated with MAIS is a normalmale habitus with mildspermatogenic defect and / or reduced secondaryterminal hair.[1][5][6][7][8][9]

MAIS is one of three types ofandrogen insensitivity syndrome, which is divided into three categories that are differentiated by the degree ofgenital masculinization:complete androgen insensitivity syndrome (CAIS) is indicated when the external genitalia is phenotypically female, mild androgen insensitivity syndrome (MAIS) is indicated when the external genitalia is phenotypically male, andpartial androgen insensitivity syndrome (PAIS) is indicated when the external genitalia is partially, but not fully masculinized.[1][2][5][6][7][10][11][12][13]

Androgen insensitivity syndrome is the largest single entity that leads to 46,XYundermasculinization.[14]

Signs and symptoms

[edit]
Mild androgen insensitivity syndrome (MAIS) presenting with a mild impairment of virilization in a 23-year-old man.[15]

Individuals with mild (or minimal) androgen insensitivity syndrome (grade 1 on theQuigley scale) are bornphenotypically male, with fullymasculinized genitalia; this category of androgen insensitivity is diagnosed when the degree of androgen insensitivity in an individual with a46,XY karyotype is great enough to impairvirilization orspermatogenesis, but is not great enough to impair normal male genital development.[1][5][6][9] MAIS is the mildest and least known form of androgen insensitivity syndrome.[5][16]

The existence of a variant of androgen insensitivity that solely affectedspermatogenesis was theoretical at first.[17] Cases of phenotypically normal males withisolated spermatogenic defect due to AR mutation were first detected as the result ofmale infertility evaluations.[1][13][18][19] Until then, early evidence in support of the existence of MAIS was limited to cases involving a mild defect invirilization,[15][20] although some of these early cases made allowances for some degree of impairment ofgenital masculinization, such ashypospadias ormicropenis.[21][22][23] It is estimated that 2-3% of infertile men have AR gene mutations.[6] It is also estimated that MAIS is responsible for 40% of male infertility.[24]

Examples of MAIS phenotypes include isolated infertility (oligospermia or azoospermia),[5][7] mildgynecomastia in young adulthood, decreasedsecondaryterminal hair, high pitched voice, or minorhypospadias repair in childhood.[1][25] Theexternal male genitalia (penis andscrotum) are otherwise normal in individuals with MAIS.[1][5][6][9]Internal genitalia, includingWolffian structures (theepididymides,vasa deferentia, andseminal vesicles) and theprostate, is also normal, although thebitesticular volume of infertile men (both with and without MAIS) is diminished;[6]male infertility is associated with reduced bitesticular volume,varicocele,retractile testes, lowejaculate volume,male accessory gland infections (MAGI), andmumpsorchitis.[6] The incidence of these features in infertile men with MAIS is similar to that of infertile men without MAIS.[6] MAIS is not associated withMüllerian remnants.

Spinal and bulbar muscular atrophy

[edit]

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a severeneurodegenerative syndrome that is associated with a particular mutation of theandrogen receptor'spolyglutamine tract called atrinucleotide repeat expansion.[26][27] SBMA results when the length of the polyglutamine tract exceeds 40 repetitions.[28]

Although technically a variant of MAIS, SBMA's presentation is not typical of androgen insensitivity; symptoms do not occur until adulthood and includeneuromuscular defects as well as signs of androgen inaction.[26] Neuromuscular symptoms include progressive proximal muscle weakness,atrophy, andfasciculations. Symptoms of androgen insensitivity experienced by men with SBMA are also progressive[26] and include testicular atrophy, severeoligospermia orazoospermia,gynecomastia, and feminized skin changes[29] despite elevated androgen levels.[1] Disease onset, which usually affects theproximal 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 musclecreatine kinase.[30] SBMA is often misdiagnosed asamyotrophic lateral sclerosis (ALS) (also known as Lou Gehrig's disease).[27]

The symptoms of SBMA are thought to be brought about by two simultaneous pathways involving the toxicmisfolding of proteins and loss of AR functionality.[1] The polyglutamine tract in affected pedigrees tends to increase in length over generations, a phenomenon known as "anticipation",[31] 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.[26]

Comorbidity

[edit]
Histopathology of testicular tissue showing immature germ cells andspermatogonia with decreased tubular diameter. Scattered groups of Leydig cells appearing immature.[32]

All forms of androgen insensitivity are associated withinfertility, though exceptions have been reported for both the mild and partial forms.[4][5][7][33][34][35] Lifespan is not thought to be affected by AIS.[1]

Trinucleotide satellite lengths and AR transcriptional activity

[edit]
Main article:Genetics of androgen insensitivity syndrome

Theandrogen receptor gene contains twopolymorphictrinucleotidemicrosatellites in exon 1.[2] The first microsatellite (nearest the5' end) contains 8[36] to 60[27][30] repetitions of theglutaminecodon "CAG" and is thus known as thepolyglutamine tract.[3] The second microsatellite contains 4[37] to 31[38] repetitions of theglycine codon "GGC" and is known as thepolyglycine tract.[39] The average number of repetitions varies by ethnicity, with Caucasians exhibiting an average of 21 CAG repeats, and Blacks 18.[40] Disease states are associated with extremes in polyglutamine tract length;prostate cancer,[26]hepatocellular carcinoma,[41] andintellectual disabilities[36] are associated with too few repetitions, whilespinal and bulbar muscular atrophy (SBMA) is associated with a CAG repetition length of 40 or more.[28] Some studies indicate that the length of the polyglutamine tract is inversely correlated withtranscriptional activity in the AR protein, and that longer polyglutamine tracts may be associated withinfertility[42][43][44] andundermasculinized genitalia.[45] However, other studies have indicated that no such correlation exists.[46][47][48][49][50][51] A comprehensivemeta-analysis of the subject published in 2007 supports the existence of the correlation, and concluded that these discrepancies could be resolved whensample size and study design are taken into account.[11] Longer polyglycine tract lengths have also been associated with genital masculinization defects in some,[52][53] but not all,[54] studies.

Diagnosis

[edit]
Main article:Diagnosis of androgen insensitivity syndrome

MAIS is only diagnosed in normal phenotypic males, and is not typically investigated except in cases ofmale infertility.[18] MAIS has a mild presentation that often goes unnoticed and untreated;[15] 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 anAR genemutation.[5] Theandrogen sensitivity index (ASI), defined as the product ofluteinizing hormone (LH) andtestosterone (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.[5] Testosterone levels may be elevated despite normal levels of luteinizing hormone.[15][20][25] Conversion of testosterone (T) todihydrotestosterone (DHT) may be impaired, although to a lesser extent than is seen in5α-reductase deficiency.[3] A high ASI in a normal phenotypic male,[46] especially when combined withazoospermia oroligospermia,[5][7] decreasedsecondaryterminal hair,[27] and/or impaired conversion of T to DHT,[3] can be indicative of MAIS, and may warrantgenetic testing.

Management

[edit]

Due to its mild presentation, MAIS often goes unnoticed and untreated.[15] Management of MAIS is currently limited tosymptomatic management; methods to correct a malfunctioningandrogen receptor protein that result from an AR genemutation are not currently available. Treatment includes surgical correction of mildgynecomastia, minorhypospadias repair, andtestosterone supplementation.[1][15][55] Supraphysiological doses of testosterone have been shown to correct diminishedsecondary sexual characteristics in men with MAIS,[15] as well as to reverseinfertility due to low sperm count.[55][56] As is the case with PAIS, men with MAIS will experience side effects fromandrogen therapy (such as the suppression of thehypothalamic-pituitary-gonadal axis) at a higher dosage than unaffected men. Careful monitoring is required to ensure the safety and efficacy of treatment.[15][57][58] Regularbreast[57] andprostate[59] examinations may be necessary due tocomorbid association withbreast andprostate cancers.

References

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External links

[edit]
Classification
External resources
Ovarian
Testicular
Enzymatic
Androgen receptor
Other
General
X-linked disorders
Immune
Hematologic
Endocrine
Metabolic
Nervous system
Skin and related tissue
Neuromuscular
Urologic
Bone/tooth
No primary system
Genetic disorders relating to deficiencies oftranscription factor or coregulators
(1) Basic domains
1.2
1.3
(2) Zinc finger
DNA-binding domains
2.1
2.2
2.3
2.5
(3) Helix-turn-helix domains
3.1
3.2
3.3
3.5
(4) β-Scaffold factors
with minor groove contacts
4.2
4.3
4.7
4.11
(0) Other transcription factors
0.6
Ungrouped
Transcription coregulators
Coactivator:
Corepressor:
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