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- Review -
Phenotypic heterogeneity of mutations in androgen receptor
Singh Rajender, Lalji Singh, Kumarasamy Thangaraj
Centre for Cellular and Molecular Biology, Hyderabad 500007, India
Androgen receptor (AR) gene has been extensively studied in diverse clinical conditions. In addition to the point
mutations, trinucleotide repeat (CAG and GGN) length polymorphisms have been an additional subject of interest and
controversy among geneticists. The polymorphic variations in triplet repeats have been associated with a number of
disorders, but at the same time contradictory findings have also been reported. Further, studies on the same disorder
in different populations have generated different results. Therefore, combined analysis or review of the published
studies has been of much value to extract information on the significance of variations in the gene in various clinical
conditions. AR genetics has been reviewed extensively but until now review articles have focused on individual
clinical categories such as androgen insensitivity, male infertility, prostate cancer, and so on. We have made the first
effort to review most the aspects of AR genetics. The impact of androgens in various disorders and polymorphic
variations in the AR gene is the main focus of this review. Additionally, the correlations observed in various studies
have been discussed in the light of in vitro evidences available for the effect of
AR gene variations on the action of androgens. (Asian J Androl 2007 Mar; 9: 147_179)
Keywords: androgen receptor; androgen insensitivity; prostate cancer; breast cancer; CAG repeat; GGN repeat
Correspondence to: Dr K. Thangaraj, Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, India.
Tel: +91-40-27192637 Fax: +91-40-27160591
Received 2006-05-02 Accepted 2006-09-01
Androgens, upon testes differentiation, drive male secondary sexual differentiation and maturation. Androgens
can be considered to function through an axis involving the testicular synthesis of testosterone, its transport to target
tissues, and the conversion by 5α-reductase to the more active metabolite
5α-dihydrotestosterone (DHT). Both the androgens in humans, testosterone (T) and dihydrotestosterone (DHT), complex with the androgen receptor (AR) for
their action but exert different biological functions. The receptor-testosterone complex signals differentiation of
Wolffian duct during embryonic life, regulation of secretion of leutinizing hormone by hypothalamic-pituitary axis and
spermatogenesis. The receptor-dihydrotestosterone complex promotes the development of external genitalia and
prostate during embryogenesis and is also responsible for changes that occur at puberty in males . Androgens are
important not only for secondary sexual differentiation in males but also have numerous other functions in both males
and females. Androgens promote the enlargement of the skeletal muscles  and affect human behavior ,
aggression  and libido . Recent studies have also indicated that androgens inhibit the ability of some fat cells to
store lipids by blocking a signal transduction pathway that normally supports adipocyte function . All these studies
emphasize multiple roles of androgens in the human body right from the embryonic stage to adulthood.
The AR gene has been mapped to the long arm
(Xq11-12) of the X-chromosome . The gene consists of eight
exons and encodes a protein with 919 amino acid residues.
Exon 1 of the gene consists of two polymorphic repeat
(CAG and GGN) motifs, encoding variable lengths of
polyglutamine and polyglycine stretches, respectively
(Figure 1), in the N-terminal region (transactivation
domain) of AR protein [7, 8]. The two repeat regions
are separated by 248 amino acids of non-polymorphic
sequence. CAG, a simple repeat, varies in length from
eight to 35 repeats, while GGN, a complex repeat
(GGT)3GGG(GGT)2(GGC)n , varies in length from 10 to 30 repeats . The CAG repeat length and
the AR transactivation potential are inversely correlated
[9, 10]. In in vitro studies, AR alleles with more than 40
CAG repeats showed reduced transcription activity in
comparison to the molecules with 25, 20 and no repeats
[9, 10]. Therefore, it seems that the increased length of
the CAG repeat should associate with decreased AR
activity and hence the disorders related to the reduced
androgen actions. Similarly, the deletion of GGN repeats
also resulted in 30% reduction in transactivation
potential . However, it needs to be determined whether
this trinucleotide repeat functions as a protein interaction
domain and there is a direct correlation between the GGN
repeat length and the AR transactivation function. If so,
the increased GGN repeats should associate with the
disorders related to higher androgen actions.
AR shares with other members of the nuclear
receptors superfamily: a signature-structural and functional
organization that includes an N-terminal transactivation
domain (TAD), a central DNA-binding domain (DBD), a
C-terminal ligand-binding domain (LBD), and a hinge
region connecting the LBD and the DBD (Figure 1).
Elucidation of the 3-D crystallographic structure of AR-LBD
has established twelve α helices and four β strands
arranged in two β sheets, which make a typical helical
sandwich to form ligand-binding pocket . The 12
helices of AR are folded into a three-layered sandwich.
Helices H1/2, H3, H7 and H10/11 form two outer layers
while inner layers consist of a ligand binding pocket and
a non-ligand binding hydrophobic core (helices H4/5, H8
and H9). In addition to ligand binding, LBD is also
involved in dimerization of the receptors, binding of
specific ligands, and contains a ligand-dependent activation
function (AF2) [4, 6, 7, 13]. Unlike many other nuclear
receptors, the NTD of AR harbors one or more transcriptional activation function (AF1) and exhibits strong
hormone-independent activity in isolation, but AR-LBD
in isolation exhibits only a weak hormone-dependent
activity. The actions of AR are subject to modulation,
either positively or negatively, by a number of
co-regulators [8_10]. The NTD of AR is known to strongly
interact with the LBD (N-C interaction) in a
hormone-dependent manner [6, 14, 15] and this interaction is important
for transcriptional regulation and interaction with
Androgen pathways are integrated with several other
pathways regulating metabolic processes in the human
body. Therefore, the disturbances in the androgen
pathways may lead to alteration not only in the secondary
sexual differentiation but also in the physiology of
numerous other organs. Further, the level of androgens
differs dramatically between males and females, hence
the differences in the incidence and course of many
disorders between males and females may be attributed to
the androgens. Therefore, the AR gene has been very
well studied in a number of clinical conditions in addition
to the reproductive disorders. In addition to the point
mutations, AR gene has been a subject of interest
because of the presence of two polymorphic trinucleotide
repeats and diverse roles of androgens in the human body.
Of the two repeats, CAG has been the most commonly
studied, while GGN repeat has been less commonly
studied because of technical problems in the amplification of
GC rich region of this repeat. Different phenotypes
associated with the AR gene mutations and trinucleotide
repeat length polymorphisms, along with the underlying
mechanisms and the phenotypic variations in the affected
individuals will be the focus of this review.
2 AR gene in reproductive disorders
2.1 Androgen insensitivity
2.1.1 Androgens and androgen insensitivity
The end organ resistance to the androgens as a
result of mutations in the AR gene results in mild to
complete androgen insensitivity. The phenotypic features of
complete androgen insensitivity syndrome (CAIS) are
female external genitalia, usually with small labial folds, a
short blind ending vagina, absence of Wolffian duct
derived structures and prostate, gynecomastia, scanty
pubic and axillary hair (Figure 2). The patients usually lack
uterus and ovaries, however sometimes a rudimentary
uterus may be present . Usually testosterone levels
are elevated at the time of puberty with or without
elevated levels of leutinizing hormone (LH). Elevated
testosterone levels also serve as substrate for estrogen
synthesis, which results in further feminization in CAIS
In partial androgen insensitivity syndrome (PAIS),
several different phenotypes are evident (Figure 2),
ranging from predominantly female phenotype (female
external genitalia, pubic hair with or without clitoromegaly
and partially to completely fused labia) through
ambiguous genitalia to predominantly male phenotype with
micropenis, perineal hypospadias and cryptorchidism
. The later phenotype is also termed as Reifenstein
syndrome . PAIS patients are assigned a grade (Figure
2) according to the severity of androgen insensitivity and
affinity of the phenotype with male or female pattern.
Individuals with MAIS usually have normal male genitals
and internal male structures and during puberty may have
breast enlargement, sparse facial and body hair, and small
penis . Some affected Individuals may also have
impaired sperm production resulting in oligozoospermia
or azoospermia .
2.1.2 AR gene in androgen insensitivity
A large number of mutations have been identified in
the AR gene worldwide and are available at
AR gene mutation database  (web:
http://www.mcgill.ca/androgendb/). Of these, approximately 90% have been
reported in androgen insensitivity. A significant number
of these mutations have been supported by functional
assays to result in lower ligand binding or transactivation
potential of the mutant receptor molecule. Most of the
mutations resulting in androgen insensitivity are the
substitutions along with a low frequency of
deletions/insertions. Structural_functional correlation of these
mutations is now possible because of the availability of
crystal structure for AR-LBD . Although almost
every kind of mutation has been reported in the
AR gene, certain generalizations have been made .
One of the first mutations was a group in which
single nucleotide substitutions resulted in the insertion of
premature termination codon within the open reading
frame of the AR gene. In different pedigrees, such
mutations have been localized to each of the eight exons of
the AR gene and associated uniformally with CAIS .
Mutations associated with normal androgen binding
represent another relatively homogenous class of defects.
Nucleotide sequencing in such patients localized the
mutations to DBD, which associated with a broad range
of androgen resistant phenotypes, including CAIS and
PAIS . Mutations that disrupt N and C-terminal
interactions of AR protein form another category of
AR mutations, which retain normal ligand binding . The
final category of mutations is associated with qualitative
abnormalities of ligand binding such as alterations of ligand
affinity, thermal instability of ligand-binding and rapid
dissociation of ligand from the receptor protein.
Uniformly, these defects have been traced to amino acid
substitution mutations within the LBD of the receptor
protein and associate with the entire range of
androgen-resistant phenotypes [22, 24].
Correlations between the site of the mutation in the
secondary structure of AR protein and the androgen
insensitivity phenotype have also been sought. Most of
the mutations in the α-helical and β-sheet regions of the
receptor result in CAIS and those in turns and linker
regions result in PAIS. Supporting this, our study on a
familial case of CAIS revealed L859F mutations in helix
10 of the AR protein . However, a general
correlation is difficult to derive because some mutations in
the α helices and β sheet regions associate with PAIS and
those in turns and linker region are responsible for CAIS
2.2 Genital abnormalities AR mutations in androgen insensitivity patients are
known to associate with variable development of the
Wolffian duct, micropenis, hypospadias and
cryptorchidism [15, 27]. However, screening of the
AR gene in patients with isolated cryptorchidism failed to find any
mutation [28, 29]. The study of AR gene for mutations
has been lacking in isolated hypospadias.
To the best of our knowledge, until now four studies
have examined the CAG repeat length in men with cryptorchidism. The earliest study on Japanese men (48
cryptorchid and 100 normal) suggested no significant
difference between cases and controls . However,
Lim et al.  found that longer repeats were associated
with severe genital abnormalities among men
(n = 175) in the UK. In another study, Aschim
et al.  analyzed both the CAG and GGN repeats in Caucasian men (51
hypospadiac, 23 cryptorchid and 201 controls). The
study revealed no difference in the CAG repeat between
cases and controls, but the GGN repeat was longer in
patients with hypospadiasis and cryptorchidism in
comparison to controls. Ferlin et al.  reported no
difference between ex-cryptorchid men (n = 105) and
controls (n = 115) in the mean and median values, and in the
distribution of CAG and GGC repeats when considered
independently. But the analysis of the joint distribution
of CAG and GGC repeats showed that some combinations were significantly more frequent in men with
bilateral cryptorchidism. In particular, men with a history of
bilateral cryptorchidism more frequently presented the
combination CAG = 21/ GGC = 18 and CAG ¡Ý 21/GGC
2.3 Male infertility
2.3.1 Androgens, spermatogenesis and fertility
The germ cells are nurtured by Sertoli cells for their
differentiation into sperms and Sertoli cells are in turn
dependent on Leydig cells for androgens. Although germ
cells themselves do not express AR, but are indirectly
dependent upon androgens for their differentiation into
sperms. Studies of a hypomorphic and conditional allele
of the AR gene, have uncovered a dual post-meiotic
requirement for AR activity during male germ cell
differentiation . Observations in AR hypomorphic
animals demonstrated that terminal differentiation of
spermatids and their release from the seminiferous
epithelium is AR dependent and maximally sensitive to AR
depletion within the testis. Cell-specific disruption of
AR in Sertoli cells of hypomorphic animals further showed that
progression of late-round spermatids to elongating steps
is sensitive to loss of Sertoli cell AR function .
Considering this, AR appears to play a role in the final stages
of sperm differentiation to attain elongated morphology,
and hence point mutations in the AR gene are more likely
to result in dysmorphic sperms (teratozoospermia or
oligoteratozoospermia) rather than no sperms
2.3.2 AR gene in male infertility
126.96.36.199 AR mutations
Although hundreds of mutations have been reported
in the AR gene in various disorders, only a few have
been reported in male infertility  (web:
http://www.mcgill.ca/androgendb/). Most of the mutations in
infertile men resulted in the reduction of transactivation
potential of the mutant protein. However, there has been
no correlation between the type of mutation and the
subtype of infertility (azoospermia, oligozoospermia or
oligoteratozoospermia). Gln58Leu substitution was
observed in one azoospermic and one oligoteratozoospermic
male . The specificity of these mutations and their
ultimate role in male infertility are unclear because many
of these mutations have been reported to exist in normal
populations as well. A synonymous Glu211Glu mutation
has been reported in both infertile and fertile males. The
polymorphism showed ethnic difference as it occurs in
10_15% of Caucasians but not in Chinese men . A
20% reduction in the transactivation potential of AR as a
result of Gly214Arg substitution resulted in severe
oligozoospermia, but the mutation was also observed in
a fertile man .
Further, there have been reports of mutations
showing no effect on AR activity in in
vitro assays, but associated with infertility or even androgen insensitivity in
certain other individuals . A study on a large cohort
of infertile males revealed Pro390Ser substitution in two
oligozoospermic patients. Although
in-vitro assays showed no gross change in the transactivation potential
but the importance of the above residue in AR function
was shown by the association of the proline replacement
with CAIS. However, the phenotype in certain other
mutations could well be correlated with the in
vitro observations. Asn756Ser substitution caused 62%
reduction in transactivation potential of AR resulting in
severe oligozoospermia. Similarly, Met886Val substitution
caused 50% reduction in transactivation resulting in
oligozoospermia . In our recent study, we sequenced
the complete coding region of AR gene in a total 399
infertile men, including 277 azoospermic, 100 oligozoospermic and 22 oligoteratozoospermic
individuals . The study revealed no mutation in the
AR gene in any of the infertile individuals demonstrating that the
AR gene mutations might contribute to a very low
percentage of infertility.
188.8.131.52 CAG repeat polymorphism
CAG repeat has been extensively studied in male
infertility in various populations, but the results vary greatly
between populations. Increased CAG-repeat length was
associated with male infertility in Japanese, American,
Australian, English, Singaporean, French and Chinese
populations but not in German, Belgian, Danish and Dutch
populations . Most of the studies on European
populations demonstrated no significant differences in CAG
repeat between cases and controls (Table 1) except two
studies reporting longer repeats in infertile men [40, 41].
However, the combined analysis of data from all the
studies showed no significant difference between fertile and
infertile European males .
Although most of the studies on Asian populations
showed increased repeat length to associate with infertility,
some studies showed no association with male infertility
(Table 1). Our study on infertile Indian men (280
azoospermic and 201 normozoospermic) revealed no
significant difference in the mean length or the range of the
repeat between azoospermic and normozoospermic men
. Later our finding was supported by another study
from India . Surprisingly, one study on Japanese
infertile men showed an association of shorter CAG
repeats with infertility . Similarly, another study on
Chinese infertile men showed the association of both the
longer and shorter repeats with infertility. However,
sample size in the later study was too small to interpret
the findings conclusively. But the combined analysis of
the data on Asian populations showed significantly longer
repeats in infertile men . Two studies on American
populations showed increased repeat length in the
infertile men [46, 47]. The studies on other populations showed
varied correlation of CAG repeat with male infertility
184.108.40.206 GGN repeat polymorphism
Few studies have analyzed GGN repeat length
polymorphisms in male infertility (Table 1). In contrast to the
varied association of CAG repeat length
polymorphisms, only three studies on GGN repeat have shown no
correlation with male infertility [48_50]. Our recent analysis
of GGN repeats in a large sample size (n = 595),
including azoospermic, oligozoospermic and
oligoteratozo-ospermic individuals, revealed no difference between
infertile and fertile men . Therefore, it appears that
the variation in the length of this repeat does not affect
the sperm count. However, sequence analysis of the
GGN repeat region revealed that mutations in this region
are common in both fertile and infertile men. 
Two studies analyzing both CAG and GGN repeats observed significant differences in the joint analysis but
not when the two repeats were considered independently.
Ferlin et al.  showed that the haplotypes with CAG
= 21/GGC = 18 and CAG ¡Ý 21/GGC ¡Ý 18 repeats were
associated with infertility while the haplotype with CAG
¡Ý 23/GGC ¡Ü 16 repeats provided protection against
infertility in Italian men. In another study on Swedish men,
haplotype with CAG < 21 and GGN = 23 combination of
repeats was shown to confer lower risk of infertility to
the carriers . However, the significance of this
observation is weakened by the fact that the two protective
haplotypes in the above studies had almost the same
number of GGC repeats but the CAG repeat number differed
substantially (¡Ý 23 in the former but < 21 repeats in the
2.4 Klinefelter's syndrome
The phenotype in Klinefelter's syndrome is highly
variable, but generally includes testicular failure,
androgen deficiency, small penis, sperm deficiency, tall stature,
and characteristic cognitive differences, such as
language-based learning disabilities and reading dysfunction [53,
54]. In an effort to study the factors influencing the
phenotype in Klinefelter's syndrome patients, Zinn
et al.  studied karyotype to detect mosaicism, genotyped
microsatellite markers to determine parental origin of the
supernumerary X-chromosome, and number of CAG repeats and methylation to look at X-inactivation ratio in
a cohort of white and black Klinefelter's syndrome boys
and men (n = 35). The study showed that the CAG
repeat was the only factor influencing the phenotype in
Klinefelter's syndrome. CAG repeat length and penile
length were inversely correlated in the affected individuals.
Given the inverse relation between CAG-repeat length
and the AR-transactivation function, this finding is not
surprising. However, further studies replicating these
results would strengthen the association.
2.5 Maleness, libido and depression
Testosterone (T) levels decline linearly with age and
approximately one fourth of elderly men have
mild-to-moderate T deficiency . Symptoms of profound T
deficiency in young adult men include loss of libido,
dysphoria, fatigue, and irritability . The development
of depressive symptoms in men with mild T deficiency
is not well studied but appears to be variable .
Seidman et al.  assessed the relation between AR
isotype, total T level, and depression in a large
community-based sample of middle-aged and elderly men
(n = 1 000), to understand the role of CAG repeat length
polymorphisms in the progression of the above symptoms.
The study revealed that depression was inversely
associated with total T in men with shorter CAG repeats but
not in men with moderate and longer CAG repeat lengths.
This observation is in accordance with the above
discussion on the relation of androgens with the
development of less libido, fatigue and dysphoria. It is possible
that in the men with higher T level, the presence of shorter
CAG repeats result in higher overall effects of
testosterone to maintain libido, physical and mental health. In a
similar study, Harkonen et al.  reported a direct
correlation between CAG repeat length and depression in
2.6 Prostate cancer
2.6.1 Androgens in prostate development
Androgens are required for prostate development and
normal prostate function . Therefore, AR and the
modulators of AR activity remain important in prostate
cancer (PC). Approximately 80_90% of PC are dependent on androgens at initial diagnosis, and endocrine
therapy of PC is directed towards the reduction of
serum androgens and inhibition of AR . However,
androgen ablation therapy ultimately fails, and PC progresses
to a hormone refractory state. AR is expressed
throughout PC progression and persists in the majority of
patients with hormone refractory disease [61, 62]. There
are reports stating that AR proliferates in PC showing
that androgens and AR are actively involved in PC
2.6.2 AR gene in prostate cancer
220.127.116.11 AR mutations
Newmark et al.  first reported an
AR mutation in a patient with PC. Thereafter, a number of mutations
have been identified in the AR gene in PC (web:
http://www.mcgill.ca/androgendb). The majority of the
mutations are substitutions predominantly localized to the
AR-LBD . There are relatively few reports of
tumors that contain multiple AR mutations. The effect of
many of the identified mutations has not yet been
investigated in vitro . The most frequent functional
consequences of AR mutations isolated from metastatic PC
are the ability of anti-androgens and adrenal androgens
to act as AR agonists. The AR T877A mutation allows
the antiandrogens (hydroxyflutamide and cyproterone
acetate) , DHEA , androstenediol , estradiol
and progesterone [61, 67] to activate AR transcription.
Excluding the AR T877A mutant, AR mutations that
confer enhanced transcriptional sensitivity to adrenal
androgens have been identified in up to 30% of metastatic PC
samples . The AR mutations reported in PC have
been reviewed, along with their mechanisms, in detail by
Heinlein and Chang .
18.104.22.168 CAG repeat polymorphisms
In a study on Australian (n = 50) and Chinese
(n = 50) men without known prostate disease, CAG repeat
length was not found to be related to the volume of the
central zone of the prostate , considered to be the
most hormonally sensitive prostatic region. Several
studies have shown an association of shorter CAG repeats
with prostate cancer, however, at the same time a
number of studies have failed to link AR-CAG repeat number
with sporadic or familial PC (Table 2). The majority of
studies on Caucasian men showed an association of shorter repeats with PC risk [69_71]. Similarly the studies
on Hispanic whites , non-Hispanic whites  and
black Americans  also showed the association of
shorter repeats with PC risk. However, an almost equal
number of the studies reported no association of CAG
repeat length with PC risk (Table 2). Out of the four
studies analyzing the age at diagnosis, two reported that
the shorter repeats were associated with younger age at
diagnosis [69, 75], while the other two mentioned no
correlation between the repeat length and the age at
diagnosis [76, 77].
Unlike Americans, not much data has been generated
for Asian and European populations. Studies on Asian
populations showed no association (with grade or age at
diagnosis) in Taiwanese men , shorter repeats in
Japanese , Chinese  and Indian men [81, 82] with
PC. Therefore, it seems that the shorter CAG repeats
correlate with the increased risk of PC among Asians.
The majority of studies on Europeans have shown no
association of CAG repeat length with the disease risk
[83_87]. One study showed the association of shorter
CAG repeats with the disease risk but did not find any
correlation with family history, disease stage or grade
prostate specific antigen level or the age at diagnosis .
Similarly, studies from other populations showed varied
correlation (Table 2). The above observation that the
short CAG repeats should increase the risk of prostate
cancer is further supported by the fact that the ethnic
differences in prostate cancer incidence are inversely
correlated to the predominant AR-CAG repeat length in each
group, with Europeans having the lowest prostate
cancer incidence and the longest AR-CAG repeats, whereas
Asians and black Americans have the highest incidence
and shortest CAG repeat length.
22.214.171.124 GGN repeat polymorphisms
Similar to CAG repeat, the studies on GGN repeat
have documented varying association with PC risk. Short
GGN repeat lengths have been found to be associated
with increased PC risk [71, 80, 89]. These results are in
contrast to the direct correlation observed between GGN
repeat length and transactivation in transfection assays
[9, 10]. However, an almost equal number of studies
showed no correlation between GGN repeat and PC risk
[83, 90, 91]. Similarly, our data from two case-control
studies showed no correlation between GGN repeat length and PC risk (unpublished data). Another study
found that longer GGN repeat lengths (GGN > 16) were
associated with an increased risk of PC recurrence and
death . In a completely different observation, Platz
et al.  found that PC risk was high in individuals
with 23 GGN repeat in comparison to all others. In a
combined analysis of GGN and CAG repeats on the American population, the subgroup with two shorter
repeats (CAG < 22; GGN ¡Ü 16) had a two-fold elevation in
odds relative to those with two longer repeats
(CAG ¡Ý 22; GGN > 16) . In a similar observation, Irvine
et al.  reported an excess of American white patients
with < 22 CAG and not-16 GGC repeats relative to the
white controls. In both the studies, the disease
associated haplotype consisted of CAG repeats less than 22,
but there was no consistency in GGN repeat length.
Therefore, the above haplotypes may be just a chance
2.7 Testicular cancer
2.7.1 Androgens and testicular cancer
The incidence of the most common form of
testicular cancer, that is, testicular germ cell cancer (TGCC),
is highest shortly after puberty . The sharp rise in
the levels of gonadotropins, luteinizing hormone (LH),
follicle stimulating hormone (FSH) and sex steroids
suggest that either one or a combination of these endocrine
factors might stimulate the progression of testicular
cancer . It has also been hypothesized that testicular
dysgenesis syndrome, including TGCC, is a result of an
imbalance in sex steroid action in favor of estrogens during
the fetal period. The high level of estrogens and the high
risk of testicular cancer in AIS patients strengthen the
above hypothesis. Epidemiological studies have indicated
that CAG length might also play a role in the risk of TGCC.
The shorter repeats in the black Americans than Asians
parallels with the low risk of TGCC in the former group
2.7.2 AR gene in testicular cancer
Mutations in the AR gene imply a dramatic loss of
receptor activity, but are extremely rare , and thus
not likely to be involved in most TGCC cases. A
Pubmed search using `androgen receptor CAG repeat' and
`testicular cancer' found only three studies. All three
studies were conducted on European populations. To our
knowledge, only one study has undertaken sequencing
of the complete coding region of AR gene (cases = 123,
controls = 115), revealing mutations in three out of 123
(2.3%) patients . Independent analysis of CAG and
GGC repeats did not show any significant difference
between cases and controls in this study. However,
the joint distribution of the two repeats showed that the
haplotype with CAG = 20/GGC = 17 repeats was significantly more frequent in testicular cancer patients with
and without cryptorchidism. In the second study, Rajpert
De-Meyts et al.  analyzed AR-CAG repeat on Danish
men with germ cell neoplasia (cases = 102, controls =
110) and reported no correlation between CAG repeat
length and germ cell neoplasia, type of the tumor and the
severity of the disease. In another study on TGCC in
Swedish patients (cases = 83, controls = 220) Giwercman
et al.  found that the CAG and GGN repeat length
polymorphisms as such were not associated with the
risk of developing TGCC, however, the CAG numbers exceeding 25 were more common in patients with
tumors that had no seminoma component. The length of
this trinucleotide repeat also seemed to correlate with the
presence or absence of metastases at diagnosis. Because
the AIS patients with AR mutations often develop
testicular tumors , it needs to be stressed that the
AR gene is a suitable candidate for testicular cancer and more
studies sequencing the AR gene should be conducted in
the future. However, the failure of testes descendence
in androgen insensitivity cases cannot be excluded as a
possible cause of the disorder in this group of individuals.
2.8 Ovarian cancer
2.8.1 Androgens and ovarian growth
Androgens are produced by ovarian theca lutein cells,
present in ovarian follicular fluid, and are one of the
principal sex steroids of growing follicles . There is
emerging evidence that androgens may be associated with
ovarian cancer risk . Interestingly, the
postmenopausal ovary is androgenic, as evidenced by 15-fold
higher testosterone concentration in the ovarian vein in
comparison to serum from peripheral veins . AR is
found in the normal surface epithelium of the ovaries
, suggesting that the androgens are active in the
organ. Most ovarian cancers express AR , and
anti-androgens inhibit ovarian cancer growth ,
indicating that androgens have mitogenic effects on ovarian cells.
Oral contraceptives, the most effective chemopreventive
agent against the disease, suppress ovarian testosterone
production by 35_70% . In contrast, there is
evidence that the AR gene may have an ovarian tumor
suppressor function because AR mRNA and protein are
down-regulated in ovarian cancer [105, 109].
2.8.2 AR gene in ovarian cancer
No study has reported the sequencing of
AR gene in ovarian cancer. However, trinucleotide repeat analysis
has been undertaken on few populations. The
AR-CAG repeat in ovarian cancer has been studied in two ways,
as a direct risk factor and as a modifier of the ovarian
cancer risk conferred by the BRCA mutations. Among
the ovarian cancer women without BRCA gene mutation,
an almost equal number of studies on both European and
American populations have shown an association between
the longer CAG repeats and disease risk [110, 111] and
no association between the two  (Table 3). A
related study on American women  did not show any
correlation between AR allelotype and age of diagnosis,
stage or grade at ovarian cancer; however, they reported
that patients with ¡Ü 19 CAG repeats had a shorter time to
recurrence and overall survival .
All studies on BRCA mutation carriers consistently
reported an earlier age at diagnosis with shorter repeat
size [114_116], while two studies mentioning the age of
diagnosis did not find any correlation of the repeat size
with the age at diagnosis of ovarian cancer [112, 113].
Taking into consideration the contrasting results of the
studies on ovarian cancer without BRCA mutations and
the consistent association of CAG repeat in BRCA
mutation carriers, it can be concluded that the CAG repeat
length alone does not affect the risk of ovarian cancer,
but a shorter repeat size may help the disease manifest at
an early stage in the presence of BRCA mutation. Surprisingly, no study has been conducted on GGN
repeat or joint analysis of CAG and GGN repeats in
ovarian cancer patients.
2.9 Polycystic ovary syndrome
2.9.1 Androgens, folliculogenesis and ovulation
Polycystic ovary syndrome (PCOS) is an endocrine
disorder characterized by abnormal androgen production and/or activity that leads to changes in the control of
follicle development and maturation . Evidences
from non-human primates  and transsexual women
 treated with high doses of androgens indicate that
the characteristic ovarian morphology (ovary with
numerous small follicular cysts), may be the result of direct,
receptor-mediated androgen activity. In women with
PCOS, this disruption often leads to chronic anovulation
and subsequent infertility.
2.9.2 AR gene in PCOS
None of the studies on PCOS to date have undertaken sequencing of the
AR gene. However, a few studies have analyzed CAG repeat in these patients and
generated contrasting results. Mifsud et
al.  reported no difference in the repeat length between cases
(n = 91) and controls (n = 112) from Singapore, although all the
women carrying the very shortest AR-CAG repeats
belonged to the PCOS group. Similarly, a later study on
Finnish women (cases = 106, controls = 112) showed no
correlation between CAG repeat length and PCOS .
Perhaps the most striking evidence on the role of CAG
repeat length as a mechanism of ovarian hyperandrogenism
comes from a study on Spanish girls . The authors
did follow-up studies on girls with premature pubarche
(n = 181) and found that the CAG repeat length is shorter
in these girls compared to healthy controls
(n = 124). They also showed that the girls developing ovarian
hyperandrogenism post menarche had shorter mean repeat length than those with normal ovarian function.
Hickey et al.  reported in Australian women (cases
= 122, controls = 83) that the patients exhibited a greater
frequency of AR alleles with more than 22 CAG repeats.
The results of the former two studies are supported by
the in vitro assays showing higher activity of the
AR alleles with shorter CAG repeats, while the results of the
latter study are contradictory to this observation.
2.10 Endometrial cancer
2.10.1 Androgens, endometrium and endometrial cancer
Steroid hormones are thought to influence the
origin and growth of endometrial tumors .
Estrogens induce cellular proliferation on endometrial cells,
whereas androgens have an anti-proliferative effect on
endometrial cells . Although no AR mutant mice
has yet been generated, a role for androgens has been
suggested in the female estrogen receptor null mutant
(ERKO), as androgens have been shown to increase the wet weight of the uterus of ERKO animals .
Studies have described an increase in androgens during
the menstrual cycle and in the early pregnancy of women
. The AR, like its counterpart estrogen receptors
(ER) and progesterone receptors
(PGR) is expressed in endometrial cells , and appear to be upregulated
by estrogen . After menopause, the ratio of
androgen to estrogen is high and the steroidal effect on
the endometrium is predominantly androgenic [125, 130].
2.10.2 AR gene in endometrial cancer
None of the studies on endometrial cancer have
attempted AR gene sequencing to date, but a few studies
have analyzed CAG repeat length polymorphisms. However, these studies have produced contrasting
results (Table 4) with few reporting the association of short
repeats [131, 132], while others have shown the
association of longer repeats with increased risk of the
disease [124, 133, 134]. Most of the studies on Asian
populations have shown the association of longer repeats with
endometrial cancer [124, 133, 134]. These results fit
the observation that androgens inhibit the endometrial
cancer and hence women with longer AR-CAG repeats
should be predisposed to endometrial cancer. In an
altogether different observation, Hsieh et
al.  reported a higher risk of developing endometriosis among
Chinese women with 21 CAG-repeats. Out of the two studies
conducted on European women, one has reported shorter
repeats in patients , while the other reported no
correlation between CAG repeat length and
susceptibility to endometrial cancer or its clinical manifestation .
Other studies showed varied correlation (Table 4). Of
the two studies on GGN repeat, one reported longer
repeats to associate with the risk of endometrial cancer
 while the other reported shorter repeats to
associate with more benign condition of endometrial cancer
. In the joint analysis of the two repeats, Rodriguez
et al.  observed that the relationship between the
short-short-CAG genotype and early stage remained
significant only in the presence of the short-short-GGN
genotype (43.9% vs. 0%).
2.11 Breast cancer
2.11.1 Androgens in breast development
Estrogen and progesterone act in an integrative
fashion to stimulate normal female breast development.
Estrogen receptor (ER), progesterone receptor
(PR) and AR expression were observed in 100% (30/30) of
gynecomastia cases  and breast cancer . Further,
it is well known that after menopause the level of
androgens goes up and the level of estrogens drops. Multiple
studies have reported a statistically significant increase
in postmenopausal breast cancer risk with increasing
levels of endogenous testosterone . The study of
premenopausal women  found no statistically
significant differences between cases and controls in mean
levels of testosterone. The disturbances in the level of these
hormones in coupling with the polymorphisms in the
receptor molecules may result in the altered physiology of
the reproductive organs. Several studies conducted to
examine the effects of androgens on the growth of
AR-positive breast cancer cell lines have reported both
inhibitory  and stimulatory  effects. In contrast
to the prostate, where androgens act as mitogenic agents,
in the breast the hormone probably acts as anti-mitogen
and hence, a higher risk and earlier onset of breast
cancer may be associated with long CAG repeats in the
2.11.2 AR gene in breast cancer
Very few studies have reported mutations in
AR gene in men and women with breast cancer  (web:
www.androgendb.mcgill.ca/). Wooster et al.  reported
the first AR mutation (R607Q substitution) in two
brothers with breast cancer and PAIS. Thereafter, Lobaccaro
et al.  reported R608L substitution in a male with
breast cancer. The only mutation reported till date in a
woman with breast cancer is the splice site variant in
the AR gene . However, a significant number of
studies have analyzed the nucleotide triplet repeat variations.
AR-CAG repeat length polymorphism in breast cancer has
been studied in two ways, as a risk factor for breast
cancer by itself and as a risk factor in the background of
BRCA mutations. All the studies on American women
with breast cancer have shown a consistent association
of increased CAG repeats with breast cancer risk to
smaller or greater extent (Table 5), irrespective of the
BRCA mutation carrier status. However, all the studies
on Asian women showed no correlation between the
disease risk and CAG repeat length [115, 146, 147]. Only
one study showed early onset of disease in women with
shorter repeats . Similarly, all the studies on
European men and women with breast cancer have shown
no correlation with the disease risk [148, 149] or disease
risk and age at onset [112, 149]. A study on Australian
men reported increased CAG repeat in patients  while
another two studies on Australian women reported no
association with  and without BRCA mutation .
The contrasting outcome of the two studies on men [148,
150] may be because the Australian men carried a BRCA
mutation , while the European men did not carry
BRCA mutations .
Steroid hormone pathways regulate BRCA1
expression . Therefore, the allelic variation in
AR gene may be involved in modification of
BRCA1-associated breast cancer risk. Hence, few studies have analyzed
AR-CAG repeat in the BRCA mutation carriers. In one
of the earliest studies on breast cancer, Rebbeck
et al.  found that women carrying at least one allele with
¡Ý 28 CAG repeats were at higher risk of breast cancer
than those carrying shorter alleles. Women with at least
one allele of ¡Ý 28, ¡Ý 29 or ¡Ý 30 repeats were diagnosed
earlier by 0.8, 1.8, or 6.3 years, respectively, than women
who did not carry at least one such allele. Thus,
AR appeared to be a modifier gene for breast cancer risk in
BRCA1 mutation carriers. But three later studies did not
support this finding [112, 115, 151]. One reason for this
contradiction may be the ethnic differences between the
patients, given the fact that former study involved
American patients while the later three studies involved
Australian/British, Israeli and Italian women. Therefore, it can
be concluded that AR-CAG repeat may be a risk factor
for breast cancer by itself but it does not act as a
modifier of the breast cancer risk associated with the
BRCA mutations. Analysis of GGN repeat on American women
showed association of longer GGN repeat with decreased
risk of breast cancer  but till date no study has
analyzed both the repeats jointly.
Preeclampsia is characterized by high blood pressure,
swelling, sudden weight gain, headache, changes in
vision and the presence of protein in the urine associated
with elevated androgen levels . Saarela et
al.  first examined children born after preeclamptic pregnancy
(cases = 59, controls = 58) and found that they had
significantly shorter AR polyglutamine tracts compared to
the control children born to normotensive mothers. The
study fits the in vitro observation that shorter CAG
repeats confer higher AR activity. The difference was more
pronounced in the subgroup of boys. Theoretically,
knowing the location of the AR gene on the X-chromosome,
also the preeclamptic mothers of the boys would be
expected to have relatively short polyglutamine tracts.
With this priori information and the evidence of the role of
AR polyglutamine tract in androgen response, the authors
investigated whether the length of CAG repeats is altered
in an unrelated group of women with preeclampsia (cases
=133, controls = 112). But no significant differences
were observed between preeclamptic women and controls, however, the shortest CAG repeats were
observed only in the preeclmaptic women.
2.13 Androgen levels in women
As discussed above, the pathophysiological roles of
androgens in women are gaining increasing attention given
its role in ovary function, PCOS, libido, diabetes, breast
cancer, and so on. Further, as evidenced above, the
level of androgens goes up after menopause [125, 130].
Parallel to the observation in men , the inhibitory
feedback of AR may affect the serum level of androgens
in women. To test this hypothesis, analysis on a cohort
of Swedish premenopausal women (n = 270) revealed
that women with relatively few CAG repeats displayed
higher levels of serum androgens . A later study on
postmenopausal Brazilian women (n = 39) reported that
the biallelic CAG repeat mean was significantly less in
the cases with high level of androgens .
3 AR gene in neurological disorders
3.1 Spinal and bulbar muscular atrophy (SBMA)
Spinal and bulbar muscular atrophy (Kennedy's disease) is a disorder affecting specialized nerve cells
that control muscle movement (motor neurons). The
condition, which mainly affects males, is characterized
by muscle weakness and wasting that usually begins in
adulthood and worsens slowly over time. Muscle
wasting in the arms and legs results in cramping, difficulty in
walking and a tendency to fall. Certain muscles in the
face and throat (bulbar muscles) are also affected, which
causes progressive problems with swallowing and speech. Additionally, muscle twitches (fasciculations)
are common. Some men with the disorder experience
unusual breast development (gynecomastia) and may even
be infertile. The sexual differentiation is normal in initial
stages of life but the abnormalities appear with time .
The disorder is caused by abnormal increase in the
AR-CAG repeat length . The CAG repeat length in all
the SBMA patients have been found to be above the
average range and varies from 38_75 repeats  The
abnormally expanded CAG repeat disrupts the normal
function of motor neurons in the brain and spinal cord.
These nerve cells gradually die, leading to the muscle
weakness and wasting seen in this condition. People
with a higher number of CAG repeats tend to develop
signs and symptoms of SBMA at an earlier age 163].
Evidences suggested that aggregate formation and
proteolytic processing of the AR protein can occur in a
polyglutamine repeat length dependent manner and
abnormal metabolism of the AR protein with expanded
repeat is coupled to cellular toxicity . Thus, the loss
of function of the AR gene contributes to the androgen
insensitivity in SBMA, the pivotal cause of
neurode-generation has been believed to be a gain of toxic function of
the pathogenic AR as a result of expansion of the
polyglutamine tract . Finally, it has been evidenced
that Caspase-3 cleavage of an AR displaying an expanded
poly-glutamine tract can play a role in the induction of
neural cell death . The correlation of the expanded
CAG repeat with SBMA has been proven beyond doubts
and multiple studies have consistently reported the CAG
repeat expansion in SBMA patients with various ethnic
backgrounds. Unlike most other trinucleotide repeat
associated diseases, SBMA shows limited meiotic instability,
and evidences so far indicate the absence of somatic
repeat instability in adults . Therefore, the
determination of the CAG repeat length has been used for
prenatal screening of the disorder in case of positive family
history . The determination of the CAG repeat length
in the prenatal samples not only helps in detecting the
risk but also helps in estimating the probable age of onset
of the disease.
3.2 Alzheimer's disease
Hogorvorst et al.  reported that men with
Alzheimer's disease (AD) had lower serum levels of
total testosterone than control males, independent of
potentiasl confounds. Also, many other reports have shown
that testosterone exerts neuroprotective actions, against
oxidative stress , apoptosis  and toxicity of
β-amyloid . A recent study has found an interaction
between the apolipoprotein E 14 allele (APOE14) and AR
and testosterone levels affecting the memory of mice
. Therefore, Lehmann et al.  examined the
potential association of the AR-CAG repeat polymorphism
separately in an Oxford cohort of men and women (cases
= 49 women and 50 men, controls = 50 women and 50 men), both in early- and late-onset AD. The study showed
that the shorter CAG repeats were associated with AD in
men but not in women .
The AR gene is a potentially attractive candidate gene
for schizophrenia for several reasons. First, gender
comparisons in epidemiological surveys of schizophrenia have
demonstrated consistently that women show a later age
of onset (10_25 years for men and 25_35 years for women)
, less severe manifestation and a slightly better course
. Second, an apparent excess of sex chromosome aneuploidies (XXY and XXX) have been
reported in populations of patients with schizophrenia
and schizophrenic sib-pairs are more often of the same
than of the opposite sex . Finally, in families that
included at least two siblings with schizophrenia, Crow
et al.  reported that male-male pairs shared alleles
at the AR gene above the rate expected by chance,
although a later study did not replicate this finding .
Tsai et al.  conducted an association study on
schizophrenia in Taiwanese patients (cases = 225,
controls = 247) to test the hypothesis that the
AR-CAG repeat polymorphism was associated with susceptibility to
schizophrenia and/or its onset. However, the study
revealed no association of the repeat length with
Schizophrenia or its age of onset in either sex.
3.5 Cognitive function
Several recent studies suggested that testosterone and
other androgens might improve cognitive function in older
men . AR is expressed in the brain in areas critical
for learning and memory such as the thalamus, hippocampus, and in the deep layers of the cerebral
cortex [182, 183]. Therefore, Yaffe et al.  analyzed
AR-CAG repeat in community dwelling American white
men (n = 301) and found that longer CAG repeat length
was associated with lower cognitive functioning in older
The CAG repeat analysis for the three disorders
discussed above have produced different results: short
repeats associated with Alzheimer's disease, longer with
decrease in cognitive function while no association was
observed with schizophrenia. These disorders share many
features such as memory loss and impaired thinking.
Although, individually, no more than one study has
addressed CAG repeat in the above disorders, the
comparative analysis of CAG repeat in these disorders raises
doubt about the associations observed. This
observation warrants the need for classification of the subjects
with various symptoms in subgroups and analysis of data
Psychoticism, characterized by externalizing
behavior problems, including impulsivity, aggression, and
nonconformity to social rules has been correlated with
androgens . Similarly, T administration to eugonadal
men has psychiatric effects only in susceptible
sub-populations . Turakulov et al.  studied the
AR-CAG repeat on an Australian population (781 males and
890 females) in Canberra. The study found a modest
but statistically significant association of short repeats
with high P scores (score used for psychoticism) for
men but no significant association in women. Another
study on Brisbane women (n = 588) supported the
relationship between P scores and short CAG sequences,
but the adolescent boys showed differences, which
although small but tended to lie in the opposite direction
. The results of the above two studies on
psycho-ticism have produced contrasting results and need
There is no gender difference in migraine occurrence
prior to puberty; however, migraine develops in three
times as many women than men during the adult years
. In many women, migraine worsens around the
time of menstruation, and may cease altogether after
menopause or during pregnancy . In a study on
Australian patients (cases = 275, controls = 275),
CAG repeats length was found not to associate with migraine
3.8 Criminal activities
From the twin and adoption studies, it was
demonstrated that genetic components as well as
environmental factors might affect the development of antisocial
behavior . The androgen-related signaling molecules
may be altered as a part of the neurobiological substrate
of antisocial or violent criminal behavior for several
reasons. First, testosterone has been linked to male
aggression in several studies [191, 192]. Second,
significant psychiatric symptoms, including aggression and
violence, have been associated with androgen-related
drug abuse . Finally, through surveys of the
general population, it has been demonstrated that antisocial
personality disorder (ASPD), a psychopathy characterized by continual antisocial or criminal acts, is more
common in males (4.2%) than in females (1.9%) .
Therefore, Cheng et al.  studied criminal Chinese
males (146 extremely violent criminals and 108 normal
controls) and found no association between CAG repeat length and violent convicts, although more of
violent criminals than controls presented with the shorter
(< 17) repeats. Therefore, the tendency to be criminal
appears to be influenced much more by environmental
factors than genetic. However, more studies on this
aspect will bring forward the role of genetics in
4 AR gene in the disorders of aero-digestive tract
and digestive system
4.1 Head and neck cancer
Squamous cell carcinoma of the mucosa of the upper aerodigestive tract (oral cavity, larynx, oropharynx
and hypopharynx) showed an impressive higher incidence
of head and neck tumors in males compared to females
. Further, expression studies showed that
laryngeal tumors were positive for AR . These studies
indicate that the relatively higher incidence of the
disorder in males could be attributed to the androgens.
Therefore, a study on Brazilian males (cases = 103,
controls = 100) revealed an increased relative risk of head
and neck cancer in men with a CAG repeat length > 20
. Higher incidence of the disorder in men indicates
that androgen and hence shorter CAG repeats should
promote the disease, but the above study has produced
4.2 Esophageal cancer
The prognosis of esophageal cancer is worse in males
than in females, possibly because of the difference in
hormonal environments . Worldwide, two-thirds
of the disease occurs in men , suggesting that
X-chromosome linked genes may be involved in the disease.
A high proportion (22 of 29) of tumors analyzed by
comparative genomic hybridization (CGH) revealed changes
involving the X chromosome , including the site of
the AR gene. With this background, Dietzsch
et al.  by analysis on African males (29 patients and 109
controls), African females (14 patients and 59 controls)
and Colored (black people) males (15 patients and 58
controls), reported that CAG triplet length did not differ
significantly between cases and controls, but the short
(GGC)n alleles were implicated in esophageal cancer in
African males. When the two alleles were considered
jointly, additional information on predisposition was
gained, revealing two haplotypes (CAG > 21, GGC <
16) and (CAG < 21, GGC > 16) conferring a protective
effect. The results are, however, contradictory to the
observation that the incidence of the disorder is higher in
males and the shorter GGN repeats should produce more
active AR molecules.
4.3 Colorectal cancer
Androgens are essential for the regulation of cell
growth and differentiation in several tissues, including
colorectal tissue . Clinical studies have found that
women had different tumor locations than men ,
are more often associated with peritoneal metastases and
poorly differentiated lesions , and have significantly
increased 5-year survival rates in colorectal cancer .
Slattery et al.  on the basis of data from
case-control studies of colon (1 580 cases and 1 968 controls)
and rectal (797 cases and 1 016 controls) cancers
reported association of increased number of CAG repeats
with colon cancer among men, but not women. The same authors on the basis of a later study on colon (1 580
cases and 1 968 controls) and rectal (797 cases and 1 016
controls) cancer reported that men with low vitamin D
intake or low levels of sunshine exposure, who had more
than 23 CAG repeats of the AR gene had the greatest
risk of colon cancer. Men with high levels of sunshine
exposure were at reduced risk of developing rectal
cancer if they had 23 or more CAG repeats than if they had
fewer than 23 CAG repeats . According to the
survival rates in colorectal cancer between the two genders,
androgens and hence shorter CAG repeats should promote colorectal cancer, but none of the above studies
5 AR gene in disorders related to general body
health and fitness
5.1 Bone and mineral density
5.1.1 Androgens and bone metabolism
Hypogonadism results in low bone mass and
significant increase in the risk of osteoporosis in both sexes.
The estrogen and the androgen receptor genes are
therefore obvious candidates for mediating the genetic
influence on bone mass and risk of osteoporosis. Previously,
many studies have reported associations between
polymorphisms in the estrogen receptor gene and reduced
bone mass and increased risk of osteoporotic fractures
. Subsequently, a significant number of studies
have analyzed the AR gene in relation to bone and
mineral density (BMD). Although no study has reported
mutation in the AR gene, but trinucleotide repeats have
been analyzed in multiple studies.
5.1.2 AR gene in BMD
Given the fact that androgens help in the
development of bones and the maintenance of BMD , an
inverse correlation is expected between CAG repeat length
and BMD. Studies on European populations have produced all the three possible patterns: no correlation
[210_212], inverse correlation [213, 214] and direct
correlation  between AR-CAG repeat and BMD, but
studies on Asian populations showed inverse correlation [215,
216]. If we look at all the studies irrespective of the
origin, an almost equal number of studies on women have
shown the inverse correlation [214_216] and no
correlation [211, 212] between the CAG repeat length and BMD.
Yamada et al.  observed the inverse correlation in
premenopausal women but not in post-menopausal women. Out of four studies on men, two have shown
no correlation [210, 217], one has shown inverse
correlation  and still another has shown direct relation
 between the CAG repeat length and BMD. None
of the studies on BMD in men or women has analyzed
GGN repeat (Table 6). Hence, the role of variation in
this repeat remains inconclusive.
The incidence of rheumatoid arthritis (RA) is higher
in women than in men (2:1 to approximately 3:1). This
difference suggests an influence of reproductive and
hormonal factors in the occurrence of the disease .
The role of androgens in the pathogenesis of RA has
been discussed in multiple studies [219, 220]. In men, a
number of studies have suggested an etiological role of
lower serum testosterone levels in developing RA .
In view of the possible role of androgens in developing
RA, Kawasaki et al.  conducted a study on
Japanese men and women (cases = 90 men and 276 women,
controls = 305 men and 332 women) and reported
association of shorter CAG repeats with younger age of
onset in men. A later study on a cohort of Greek women
(cases = 158, controls = 193) showed that only women
with long-long genotype had a 2-fold lower risk of
osteoarthritis compared to individuals with short-short
genotype. In women, when odds ratio were adjusted
for age, sex, BMI, age of menarche, age of menopause,
and grade of physical demand, it was observed that those
with long-long genotype had a significantly increased risk
for knee osteoarthritis compared to those with
short-short genotype .
In men serum testosterone concentrations were
frequently found to have inverse correlations with body
mass index (BMI), waist circumference, waist-hip-ratio
(WHR), amount of visceral fat, serum levels of leptin,
insulin and free fatty acids . A study by Zitzmann
et al.  on German men (n = 106) reported an
association of short CAG repeats with protective parameters
(low body fat mass and plasma insulin) and adverse
parameters (low high density lipoprotein cholesterol
concentrations). The results of this study fit the
observation that the levels of androgens in the human body are
inversely proportional to the body fat content and BMI.
5.4 Type 1 diabetes
It has been shown that androgen treatment prevents
diabetes in non-obese diabetic mice . Moreover,
testosterone increased the circulating insulin levels .
Mice transgenic to expanded CAG triplet repeats were
prone to diabetes . Therefore it would be expected
that expanded repeats would be associated with diabetes.
In light of the above facts, Gombos et al. 
investigated the association of CAG repeat polymorphism with
type 1 diabetes (T1D) in a German population of affected
sibling pair families (n = 120), nuclear families
(n = 645) and cohorts of sporadic cases
(n = 208) and controls (n = 1381). However, no significant difference in the
distribution of CAG repeat alleles was observed between
the patients and the controls.
5.5 Cardiac diseases
It has been suggested that the difference in the
incidence of ischaemic heart disease between men and women
is a result of sex steroids, as estrogens are believed to be
protective in women  and androgen harmful in men.
Several reports have shown that the androgens are
atherogenic when administered to women in high doses ,
while androgenic steroids are believed to be responsible
for premature cardiovascular disease in athletes .
Considering this, Alevizaki et al.  investigated
coronary artery patients (n = 131) and reported short CAG
repeats in more severe forms of the disease. Later, in
two independent case-control studies on white men (N
= 544), Hersberger et al.  showed no association
of short CAG repeats with coronary heart disease or
5.6 Hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is more prevalent
in men than in women throughout the world .
Prospective studies have demonstrated a positive
association between circulating levels of testosterone and HCC
risk in relation to chronic HBV or HCV infection among
men . AR has been detected in both HCC and
non-tumorous liver tissues from men and women . Yu
et al.  on the basis of their case-control study on
Taiwanese women (cases = 238, controls = 354) demonstrated that the women harboring both
AR alleles with more than 23 CAG repeats had an increased risk of HCC.
A higher incidence of HCC in men suggests that higher
androgens levels and hence shorter CAG repeats should
associate with the disease risk, but the above study
produced contradicting results.
5.7 Muscle development and strength
AR is highly expressed in skeletal muscles ,
with expression being upregulated in response to muscle
overload . Animal and clinical studies have
indicated that the androgen-AR signaling pathway is required
for both skeletal muscle development and increases in
muscle mass, strength, and muscle protein synthesis in
response to androgens . Based on their two
independent studies on white men and women
(n = 294 men, 112 men and 90 women), Walsh
et al.  suggested that greater number of CAG repeats associated with
higher total fat free mass in men but not in women.
5.8 Lateralization and Handedness
It has been proposed that exposure to high levels of
testosterone in utero results in decreased lateralization
and an increased likelihood of left-handedness .
Conversely, Witelson and Nowakowski  proposed
that low testosterone levels are associated with
increased left-handedness. Two linkage studies have
mapped the region for handedness to DXS990  and between DXS993 and DXS991 .
The AR gene on Xp11 is therefore a strong candidate for
influencing handedness. Taking the above facts into consideration,
Medland et al.  demonstrated that in females the
probability of left-handedness was greater in those with
a greater number of CAG repeats while in males the
risk of left-handedness was greater in those with fewer
5.9 Male pattern baldness
Finasteride is a drug used to treat male pattern
baldness (MPB). It works by blocking the conversion of the
male hormone testosterone to dihydrotestosterone; high
levels of which are linked to baldness. Finasteride is not
necessarily effective on all of the MPB patients. To know
any factor, which correlates with the effectiveness of
finasteride, Wakisaka et al.  analyzed the CAG and
GGN repeat polymorphism in MPB patients. The study
indicated that the smaller the number of repeats (CAG +
GGC) the more effective was the drug.
5.10 Acne, hirsutism and alopecia
Similar to many other disorders, acne (pimples or
zits on face, chest, etc. especially during puberty),
hirsutism (male pattern of hair distribution in a female) and
alopecia (lacking hair where it would normally grow,
especially on the head) are thought to have their etiology
in the androgens action. In the light of the above facts,
Sawaya et al. , studied CAG repeats in androgen
related disorders such as acne, hirsutism and
androgenetic alopecia on American men (n = 48) and women
(n = 60), revealing that shorter CAG repeat lengths were
associated with these disorders in both males and females.
The results of the study fit the experimental
observations that shorter CAG repeats result in higher activity of
the AR protein.
6 Variable association of AR gene variations with
From the above discussion it is clear that mutations
in the AR gene are responsible for varied phenotypes
including androgen insensitivity syndrome, male infertility, prostate cancer and breast cancer. Apart from
point mutations, trinucleotide repeat polymorphisms in
the AR gene have been correlated with numerous other
disorders. Drastically different observations in
mutation/polymorphism studies in the same disorders in
different populations have been quite interesting. However,
the factors contributing to the differences between the
studies involving AR mutations and trinucleotide repeat
polymorphisms have been different and remain scarcely
6.1 Trinucleotide repeat length polymorphisms
Triplet repeat length polymorphisms associate
variably with the same disorder in different populations;
showing direct, inverse or no association at all. The
well-established differences in the CAG repeat length range
between different populations is the first source of
variations in the results. Americans and Asians have the
shortest CAG repeats (8_30 and 11_31 repeats, respectively),
while Europeans have the longest repeats (8_39 repeats).
Apart from the ethnic differences, it is likely that the
differing study designs may contribute to the differing
results. For example, the contrasting results of two studies
on ovarian cancer [110, 247] may be because of the
differences in the selection of controls. In one study, the
control samples were recruited from general population
, while in the other, controls were recruited from
women donating blood at the hospital from which the
cases were identified . In both the studies, the mean
age of the controls was significantly lower than that of
the cases. In particular, while the distribution of allele
lengths was almost identical for both studies' case groups,
the distribution of allele lengths between the two studies'
control groups differed substantially.
Another factor contributing to the variations in the
results of the studies on female subjects may be the
variations in data analysis methods. The data analysis on
female subjects becomes complex because of the
presence of two AR alleles in each subject. The data on
female subjects have been analyzed by taking the mean
of two alleles , counting both the alleles
independently  and taking into consideration the long-long,
long-short or short-short allele combinations for all the
subjects . The data analysis becomes further
complex because of the phenomenon of X-inactivation. Most
of the studies to date did not take X-inactivation into
account; however, some studies mention the analysis by
taking only the active AR alleles into consideration. The
best method of data analysis is taking into consideration
the X-inactivation pattern followed by analysis for the
active alleles of all the cases.
To understand the mechanism by which the length
of CAG repeats should contribute to various disorders
and variability in the association studies, it is important
to study the co-regulator milieu of AR. More than 70
proteins are known to interact with the AR protein .
The CAG repeat region is located in the AR domain that
is known to interact with some AR co-regulators .
It is possible that variation in the CAG repeat length
affects its interaction with co-regulator milieu.
Transfection assays have demonstrated that the interaction
between AR and the co-activator ARA24 decreases with
increasing AR-CAG repeat length, resulting in decreased
AR transactivation . Similarly, AR alleles with
shorter CAG repeats are better co-activated by members
of the steroid receptor co-activators (SRC) family of
co-regulators (SRC-1, transcriptional intermediary factor 2
[TIF-2], and SRC-3) . Alternatively, polymorphisms in the promoters of` AR target genes in
combination with short AR-CAG alleles may contribute to the
susceptibility to various disorders.
6.2 Single nucleotide mutations
In the AR gene it is not only the trinucleotide repeats
that show varying associations with various disorders,
but also the single nucleotide substitutions . The
study on phenotypic variation was conducted on patients
with familial AIS, having received the X-linked
AR mutation from their carrier mother and having it in all their
cells. No phenotypic variation was observed in families
with CAIS, except one family with coexistence of CAIS
and PAIS cases sharing M780I substitution . However, distinct phenotypic variation was observed in
one-third of the families with PAIS. D695N substitution
was reported in both, PAIS and CAIS. A645D mutation,
with proven pathogenicity in PAIS and CAIS patients
was also found to be present in a totally normal individual.
Another interesting example is E211E mutation, which
was reported in MAIS, PAIS, and CAIS, and also in 8%
of the normal population. W751STOP mutation has been
reported not only in PAIS, CAIS but also in prostate
cancer patients  (www.androgendb.mcgill.ca/). The
later observation seems more surprising if we look at the
mechanism by which AR mutations contribute to
androgen insensitivity and prostate cancer. Mutations in AIS
are mostly loss of function mutations, while mutations
in prostate cancer result in gain of function and
broadened specificity of the receptor for the ligands. Therefore,
we need to understand the mechanism by which
AR gene contributes to the development of AIS or prostate
cancer and the factors that influence the ultimate phenotype
in AR mutations, before the variability in the phenotype
can be satisfactorily explained.
Some studies have suggested the role of genetic
background or modifiers, in varying manifestations of
androgen insensitivity syndrome [26, 252, 253]. The
nature and exact role of the so-called `genetic background'
remains largely unknown; however certain components
of this background have been identified. Holterhus
et al.  reported a family with four affected individuals,
displaying strikingly different external genitalia:
ambiguous (first brother), severe micropenis (second brother),
slight micropenis (third brother) and micropenis and
penoscrotal hypospadias (uncle). All had been assigned
a male gender and shared the same mutation in the
AR gene. Taking into account the well-documented individual
and time-dependent variation in testosterone
concentration in early fetal development, the authors concluded that
their observations illustrated the potential impact of
varying ligand concentrations on phenotypic variability in
different AIS cases. In another study, a 5-α reductase 2
deficiency in genital skin fibroblasts of the subject was
found to be the cause of the more severely impaired
viri-lization in a family with R846H mutation . Affected
members of another family with AR gene mutation M771I
 also showed phenotypic variation, ranging from a
female to a Reifenstein phenotype. The M771I mutation
introduced qualitative defects in AR and also resulted in
decreased expression of the AR protein in Scatchard
analysis of GSF  and in in vitro expression studies
. However, the phenotypic variability could not be
Somatic mosaicism was first shown to play a role in
variable expressivity with the identification of L172STOP
mutation in a patient with PAIS [257, 258]. The
mutation had previously been reported in a CAIS patient and
showed absent ligand binding upon functional assays
. Even more intriguing was the fact that cells from
the PAIS individual exhibited measurable
androgen-binding activity, although the stop mutation would be
expected to preclude any AR activity. Sequencing of the
gene in the mother's blood leukocytes showed that the
patient had initially inherited the mutation from their
mother, but some of the AR genes in their genital skin
fibroblasts had reverted to normal . In a related
study using kinetic analysis, the authors identified two
different AR alleles within a single biopsy, indicating the
presence of a heterogeneous AR population resulting from
the somatic mosaicism . Their conclusion was that
in these cases some of the mutant genes had undergone
a back mutation to produce wild-type receptors [258,
259]. It will be interesting to see whether somatic
mosaicism can be found in more than 20 cases of variable
expressivity reported in AIS to date. Currently, only five
cases of variable AIS phenotypes are confirmed to be
caused by somatic mosaicism [253, 259].
Highly variable results have been generated in the
association studies of triplet repeat polymorphisms with
various disorders and similar variations have been
reported in AR mutations as well. Studies on the disorders,
except for male infertility, prostate cancer and breast
cancer, lack support from multiple studies and hence it
would be premature to make conclusions on the association of the
AR gene with these disorders. The CAG repeat has been analyzed
in vitro [9, 10] and hence the outcome of various studies should be analyzed in view
of in vitro observations. However, GGN repeat has been
comparatively less studied and most of the studies on
GGN repeat lack in vitro evidences. Therefore, more
in vitro investigations on GGN repeat are anticipated
before the results of various association studies can be
Furthermore, very few studies have analyzed CAG
and GGN repeats jointly. Joint analyses have shown
certain differences between the cases and controls in
male infertility [49, 50], prostate cancer [71, 93],
testicular cancer , endometrial cancer  and
esophageal cancer . The AR-CAG repeat may be in
linkage disequilibrium with other polymorphisms, including
the StuI mutation  and the GGC (GGN) repeat in
exon 1 [32, 49, 93], however, these associations need
confirmation by in vitro methods using specific
combinations of CAG and GGN repeats in AR constructs.
Therefore, the joint analyses of major polymorphic sites
in the AR gene will not only help in understanding the
association of these polymorphisms with various
disorders but also help in understanding the variability in the
The variation in the eventual phenotypes between
individuals sharing the same AR mutation has been
interesting. Studies to date have suggested variation in
embryonic androgens concentration, 5-a reductase 2
deficiency and somatic mosaicism in the androgen
target tissues contributing to variable phenotype. But these
variations cannot account for phenotypic variability in all
the known cases. Polymorphism studies on
AR interacting genes may further help to understand the
phenotypic variability. Analyses of these
AR-interacting genes will help in further uncovering the mechanism of
The role of AR in diverse phenotypes makes it an
interesting candidate for prenatal screening. Prenatal
screening has already been used in SBMA and androgen
insensitivity in the families at high risk. Once the
information on the potential effects of mutation(s) at each
nucleotide position of the gene is clear, the screening of
the AR mutations in prenatal samples may be helpful in
preventing the transmission of the mutant X-chromosome to the coming generations. The assignment of the
gender in the PAIS cases has been quite difficult and
does not always depend on the type of the mutation.
Individuals with the same mutation in AR gene have been
raised both as males and females. The determination of
the triplet repeat length and other polymorphisms in the
gene along with the understanding of the mechanism of
phenotypic variability will help in proper management and
rearing of the sex in the cases of androgen insensitivity.
In addition, determination of the number of CAG and
GGN repeats in these samples will also help in
determining the risk of prostate cancer, infertility, breast cancer
or other disorders related to variations in the triplet repeats.
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