This web only provides the extract of this article. If you want to read the figures and tables, please reference the PDF full text on Blackwell Synergy. Thank you.

- Review -

Phenotypic heterogeneity of mutations in androgen receptor

Singh Rajender, Lalji Singh, Kumarasamy Thangaraj

Centre for Cellular and Molecular Biology, Hyderabad 500007, India

Abstract

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
E-mail: thangs@ccmb.res.in
Received 2006-05-02 Accepted 2006-09-01

DOI: 10.1111/j.1745-7262.2007.00250.x

1 Introduction

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 [1]. 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 [2] and affect human behavior [3], aggression [4] and libido [5]. 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 [6]. 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 [7]. 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 represented by (GGT)₃GGG(GGT)₂(GGC)_n , varies in length from 10 to 30 repeats [8]. 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 [11]. 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 [12]. 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 coactivators [16].

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 [17]. 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 patients [18].

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 [18]. The later phenotype is also termed as Reifenstein syndrome [18]. 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 [19]. Some affected Individuals may also have impaired sperm production resulting in oligozoospermia or azoospermia [20].

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 [21] (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 [12]. Although almost every kind of mutation has been reported in the AR gene, certain generalizations have been made [22].

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 [22]. 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 [22]. Mutations that disrupt N and C-terminal interactions of AR protein form another category of AR mutations, which retain normal ligand binding [23]. 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 [25]. 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 [21, 26].

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 [30]. However, Lim et al. [16] found that longer repeats were associated with severe genital abnormalities among men (n = 175) in the UK. In another study, Aschim et al. [31] 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. [32] 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 ≥ 21/GGC ≥ 18.

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 [33]. 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 [33]. 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 (azoosper-mia) [34].

2.3.2 AR gene in male infertility

2.3.2.1 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 [21] (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 [35]. 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 [36]. 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 [37].

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 [21]. 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 [38]. 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 [34]. 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.

2.3.2.2 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 [39]. 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 [42].

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 [43]. Later our finding was supported by another study from India [44]. Surprisingly, one study on Japanese infertile men showed an association of shorter CAG repeats with infertility [45]. 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 [39]. 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 (Table 1).

2.3.2.3 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 [51]. 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. [52]

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. [49] showed that the haplotypes with CAG = 21/GGC = 18 and CAG ≥ 21/GGC ≥ 18 repeats were associated with infertility while the haplotype with CAG ≥ 23/GGC ≤ 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 [50]. 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 (≥ 23 in the former but < 21 repeats in the later study).

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. [53] 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 [55]. Symptoms of profound T deficiency in young adult men include loss of libido, dysphoria, fatigue, and irritability [5]. The development of depressive symptoms in men with mild T deficiency is not well studied but appears to be variable [56]. Seidman et al. [57] 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. [58] reported a direct correlation between CAG repeat length and depression in Finnish men.

2.6 Prostate cancer

2.6.1 Androgens in prostate development

Androgens are required for prostate development and normal prostate function [59]. 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 [60]. 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 progression [61].

2.6.2 AR gene in prostate cancer

2.6.2.1 AR mutations

Newmark et al. [63] 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 [61]. 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 [61]. 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) [64], DHEA [65], androstenediol [66], 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 [61]. The AR mutations reported in PC have been reviewed, along with their mechanisms, in detail by Heinlein and Chang [61].

2.6.2.2 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 [68], 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 [72], non-Hispanic whites [73] and black Americans [74] 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 [78], shorter repeats in Japanese [79], Chinese [80] 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 [88]. 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.

2.6.2.3 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 [85]. In a completely different observation, Platz et al. [92] 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 ≤ 16) had a two-fold elevation in odds relative to those with two longer repeats (CAG ≥ 22; GGN > 16) [71]. In a similar observation, Irvine et al. [93] 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 finding.

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 [94]. 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 [95]. 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 [96].

2.7.2 AR gene in testicular cancer

Mutations in the AR gene imply a dramatic loss of receptor activity, but are extremely rare [97], 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 [98]. 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. [99] 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. [100] 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 [101], 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 [102]. There is emerging evidence that androgens may be associated with ovarian cancer risk [103]. 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 [104]. AR is found in the normal surface epithelium of the ovaries [105], suggesting that the androgens are active in the organ. Most ovarian cancers express AR [106], and anti-androgens inhibit ovarian cancer growth [107], 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% [108]. 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 [112] (Table 3). A related study on American women [113] did not show any correlation between AR allelotype and age of diagnosis, stage or grade at ovarian cancer; however, they reported that patients with ≤ 19 CAG repeats had a shorter time to recurrence and overall survival [113].

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 [117]. Evidences from non-human primates [118] and transsexual women [119] 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. [120] 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 [121]. 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 [122]. 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. [123] 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 [124]. Estrogens induce cellular proliferation on endometrial cells, whereas androgens have an anti-proliferative effect on endometrial cells [125]. 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 [126]. Studies have described an increase in androgens during the menstrual cycle and in the early pregnancy of women [127]. The AR, like its counterpart estrogen receptors (ER) and progesterone receptors (PGR) is expressed in endometrial cells [128], and appear to be upregulated by estrogen [129]. 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. [135] 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 [131], while the other reported no correlation between CAG repeat length and susceptibility to endometrial cancer or its clinical manifestation [136]. 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 [137] while the other reported shorter repeats to associate with more benign condition of endometrial cancer [131]. In the joint analysis of the two repeats, Rodriguez et al. [131] 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 [138] and breast cancer [139]. 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 [139]. The study of premenopausal women [140] 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 [141] and stimulatory [142] 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 receptor gene.

2.11.2 AR gene in breast cancer

Very few studies have reported mutations in AR gene in men and women with breast cancer [21] (web: www.androgendb.mcgill.ca/). Wooster et al. [143] reported the first AR mutation (R607Q substitution) in two brothers with breast cancer and PAIS. Thereafter, Lobaccaro et al. [144] 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 [145]. 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 [115]. 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 [150] while another two studies on Australian women reported no association with [151] and without BRCA mutation [152]. The contrasting outcome of the two studies on men [148, 150] may be because the Australian men carried a BRCA mutation [150], while the European men did not carry BRCA mutations [148].

Steroid hormone pathways regulate BRCA1 expression [153]. 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. [154] found that women carrying at least one allele with ≥ 28 CAG repeats were at higher risk of breast cancer than those carrying shorter alleles. Women with at least one allele of ≥ 28, ≥ 29 or ≥ 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 [155] but till date no study has analyzed both the repeats jointly.

2.12 Preeclampsia

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 [156]. Saarela et al. [157] 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 [158], 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 [159]. 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 [160].

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 [161]. The disorder is caused by abnormal increase in the AR-CAG repeat length [162]. The CAG repeat length in all the SBMA patients have been found to be above the average range and varies from 38_75 repeats [162] 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 [164]. 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 [165]. 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 [166]. 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 [167]. Therefore, the determination of the CAG repeat length has been used for prenatal screening of the disorder in case of positive family history [168]. 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. [169] 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 [170], apoptosis [171] and toxicity of β-amyloid [172]. A recent study has found an interaction between the apolipoprotein E 14 allele (APOE14) and AR and testosterone levels affecting the memory of mice [173]. Therefore, Lehmann et al. [174] 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 [174].

3.4 Schizophrenia

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) [175], less severe manifestation and a slightly better course [176]. 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 [177]. Finally, in families that included at least two siblings with schizophrenia, Crow et al. [178] 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 [179]. Tsai et al. [180] 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 [181]. 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. [181] 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 white men.

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 thereafter.

3.6 Psychoticism

Psychoticism, characterized by externalizing behavior problems, including impulsivity, aggression, and nonconformity to social rules has been correlated with androgens [3]. Similarly, T administration to eugonadal men has psychiatric effects only in susceptible sub-populations [184]. Turakulov et al. [185] 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 [186]. The results of the above two studies on psycho-ticism have produced contrasting results and need validation.

3.7 Migraine

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 [187]. In many women, migraine worsens around the time of menstruation, and may cease altogether after menopause or during pregnancy [188]. In a study on Australian patients (cases = 275, controls = 275), CAG repeats length was found not to associate with migraine [189].

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 [190]. 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 [192]. 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%) [193]. Therefore, Cheng et al. [194] 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 criminal behavior.

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 [195]. Further, expression studies showed that laryngeal tumors were positive for AR [196]. 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 [197]. 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 contrasting results.

4.2 Esophageal cancer

The prognosis of esophageal cancer is worse in males than in females, possibly because of the difference in hormonal environments [198]. Worldwide, two-thirds of the disease occurs in men [199], 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 [200], including the site of the AR gene. With this background, Dietzsch et al. [201] 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 [202]. Clinical studies have found that women had different tumor locations than men [203], are more often associated with peritoneal metastases and poorly differentiated lesions [204], and have significantly increased 5-year survival rates in colorectal cancer [205]. Slattery et al. [206] 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 [207]. 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 confirmed it.

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 [208]. 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 [209], 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 [214] 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. [216] 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 [213] and still another has shown direct relation [214] 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.

5.2 Arthritis

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 [218]. 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 [219]. In view of the possible role of androgens in developing RA, Kawasaki et al. [221] 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 [222].

5.3 Obesity

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 [223]. A study by Zitzmann et al. [224] 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 [225]. Moreover, testosterone increased the circulating insulin levels [226]. Mice transgenic to expanded CAG triplet repeats were prone to diabetes [227]. Therefore it would be expected that expanded repeats would be associated with diabetes. In light of the above facts, Gombos et al. [228] 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 [229] and androgen harmful in men. Several reports have shown that the androgens are atherogenic when administered to women in high doses [230], while androgenic steroids are believed to be responsible for premature cardiovascular disease in athletes [231]. Considering this, Alevizaki et al. [232] 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. [233] showed no association of short CAG repeats with coronary heart disease or myocardial infarction.

5.6 Hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is more prevalent in men than in women throughout the world [234]. 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 [235]. AR has been detected in both HCC and non-tumorous liver tissues from men and women [236]. Yu et al. [237] 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 [236], with expression being upregulated in response to muscle overload [237]. 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 [238]. Based on their two independent studies on white men and women (n = 294 men, 112 men and 90 women), Walsh et al. [239] 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 [240]. Conversely, Witelson and Nowakowski [241] proposed that low testosterone levels are associated with increased left-handedness. Two linkage studies have mapped the region for handedness to DXS990 [242] and between DXS993 and DXS991 [243]. The AR gene on Xp11 is therefore a strong candidate for influencing handedness. Taking the above facts into consideration, Medland et al. [244] 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 repeats.

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. [245] 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. [246], 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 various disorders

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 known.

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 [247], while in the other, controls were recruited from women donating blood at the hospital from which the cases were identified [110]. 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 [169], counting both the alleles independently [169] and taking into consideration the long-long, long-short or short-short allele combinations for all the subjects [185]. 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 [21]. The CAG repeat region is located in the AR domain that is known to interact with some AR co-regulators [248]. 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 [249]. 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) [250]. 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 [21]. 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 [251]. 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 [21] (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. [254] 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 [255]. Affected members of another family with AR gene mutation M771I [251] 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 [251] and in in vitro expression studies [256]. However, the phenotypic variability could not be satisfactorily explained.

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 [258]. 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 [253]. 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 [259]. 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].

7 Conclusion

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 analyzed.

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 [98], endometrial cancer [131] and esophageal cancer [201]. The AR-CAG repeat may be in linkage disequilibrium with other polymorphisms, including the StuI mutation [260] 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 eventual phenotypes.

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 phenotypic variability.

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.

References

1 Haqq CM, Donahoe PK. Regulation of sexual dimorphism in mammals. Physiol Rev 1998; 78: 1_33.

2 Sinha-Hikim I, Taylor WE, Gonzalez-Cadavid NF, Zheng W, Bhasin S. Androgen receptor in human skeletal muscle and cultured muscle satellite cells: up-regulation by androgen treatment. J Clin Endocrinol Metab 2004; 89: 5245_55.

3 Eysenck HJ, Eysenck SBG. Psychoticism as a Dimension of Personality. London: Hodder and Stoughton.

4 Giammanco M, Tabacchi G, Giammanco S, Di Majo D, La Guardia M. Testosterone and aggressiveness. Med Sci Monit 2005; 11: RA136_45.

5 Wang C, Alexander G, Berman N, Salehian B, Davidson T, McDonald V, et al. Testosterone replacement therapy improves mood in hypogonadal men _ a clinical research center study. J Clin Endocrinol Metab 1996; 81: 3578_83.

6 Singh R, Artaza JN, Taylor WE, Braga M, Yuan X, Gonzalez-Cadavid NF, et al. Testosterone inhibits adipogenic differentiation in 3T3-L1 cells: nuclear translocation of androgen receptor complex with beta-catenin and T-cell factor 4 may bypass canonical Wnt signaling to down-regulate adipogenic transcription factors. Endocrinology 2006; 147: 141_54.

7 Lubahn DB, Joseph DR, Sullivan PM, Willard HF, French FS, Wilson EM. Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science 1988; 240: 327_30.

8 Faber PW, Kuiper GG, van Rooij HC, van der Korput JA, Brinkmann AO, Trapman J. The N-terminal domain of the human androgen receptor is encoded by one, large exon. Mol Cell Endocrinol 1989; 61: 257_62.

9 Chamberlain NL, Driver ED, Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 1994; 22: 3181_6.

10 Kazemi-Esfarjani P, Trifiro MA, Pinsky L. Evidence for a repressive function of the long polyglutamine tract in the human androgen receptor: possible pathogenetic relevance for the (CAG)n-expanded neuronopathies. Hum Mol Genet 1995; 4: 523_7.

11 Gao T, Marcelli M, McPhaul MJ. Transcriptional activation and transient expression of the human androgen receptor. J Steroid Biochem Mol Biol 1996; 59: 9_20.

12 Matias PM, Donner P, Coelho R, Thomaz M, Peixoto C, Macedo S, et al. Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations. J Biol Chem 2000; 275: 26164_71.

13 Brinkmann AO, Faber PW, van Rooij HC, Kuiper GG, Ris C, Klaassen P, et al. The human androgen receptor domain structure, genomic organization and regulation of expression. J Steroid Biochem 1989; 34: 307_10.

14 Ivell R, Hartung S. The molecular basis of cryptorchidism. Mol Hum Reprod 2003; 9: 175_81.

15 Brinkmann AO. Molecular basis of androgen insensitivity. Mol Cell Endocrinol 2001; 179: 105_9.

16 Lim HN, Nixon RM, Chen H, Hughes IA, Hawkins JR. Evidence that longer androgen receptor polyglutamine repeats are a causal factor for genital abnormalities. J Clin Endocrinol Metab 2001; 86: 3207_10.

17 Dapunt O, Platzer W, Gleispach H, Millonig-Ganner B. Rudimentary uterus in testicular feminization (author's transl). Wien Klin Wochenschr 1975; 87: 498_506.

18 Quigley CA, De Bellis A, Marschke KB, el-Awady MK, Wilson EM, French FS. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocrine Rev 1995; 16: 271_321. Erratum in: Endocr Rev 1995;16: 546.

19 Tsukada T, Inoue M, Tachibana S, Nakai Y, Takebe H. An androgen receptor mutation causing androgen resistance in undervirilized male syndrome. J Clin Endocrinol Metab 1994; 79: 1202_7.

20 Yong EL, Lim LS, Wang Q, Mifsud A, Lim J, Ong YC, et al. Androgen receptor polymorphisms and mutations in male infertility. J Endocrinol Invest 2000; 23: 573_7.

21 Gottlieb B, Beitel LK, Wu JH, Trifiro M. The androgen receptor gene mutations database (ARDB): 2004 update. Hum Mutat 2004; 23: 527_33.

22 McPhaul MJ. Androgen receptor mutations and androgen insensitivity. Mol Cell Endocrinol 2002; 198: 61_7.

23 Langley E, Kemppainen JA, Wilson EM. Intermolecular NH2-/carboxyl-terminal interactions in androgen receptor dimerization revealed by mutations that cause androgen insensitivity. J Biol Chem 1998; 273: 92_101.

24 Grino PB, Griffin JE, Cushard WG Jr, Wilson JD. A mutation of the androgen receptor associated with partial androgen resistance, familial gynecomastia, and fertility. J Clin Endocr Metab 1988; 66: 754_61.

25 Singh R, Shastry PK, Rasalkar AA, Singh L, Thangaraj K. A novel androgen receptor mutation resulting in complete androgen insensitivity syndrome and bilateral Leydig cell hyperplasia. J Androl 2006; 27: 510_6.

26 Yong EL, Tut TG, Ghadessy FJ, Prins G, Ratnam SS. Partial androgen insensitivity and correlations with the predicted three dimensional structure of the androgen receptor ligand-binding domain. Mol Cell Endocrinol 1998; 137: 41_50.

27 Sultan C, Paris F, Terouanne B, Balaguer P, Georget V, Poujol N, et al. Disorders linked to insufficient androgen action in male children. Hum Reprod Update 2001; 7: 314_22.

28 Wiener JS, Marcelli M, Gonzales ET Jr, Roth DR, Lamb DJ. Androgen receptor gene alterations are not associated with isolated cryptorchidism. J Urol 1998; 160: 863_5.

29 Suzuki Y, Sasagawa I, Ashida J, Nakada T, Muroya K, Ogata T. Screening for mutations of the androgen receptor gene in patients with isolated cryptorchidism. Fertil Steril 2001; 76: 834_6.

30 Sasagawa I, Suzuki Y, Tateno T, Nakada T, Muroya K, Ogata T. CAG repeat length of the androgen receptor gene in Japanese males with cryptorchidism. Mol Hum Reprod 2000; 6: 973_5.

31 Aschim EL, Nordenskjold A, Giwercman A, Lundin KB, Ruhayel Y, Haugen TB, et al. Linkage between cryptorchidism, hypospadias, and GGN repeat length in the androgen receptor gene. J Clin Endocrinol Metab 2004; 89: 5105_9.

32 Ferlin A, Garolla A, Bettella A, Bartoloni L, Vinanzi C, Roverato A, et al. Androgen receptor gene CAG and GGC repeat lengths in cryptorchidism. Eur J Endocrinol 2005; 152: 419_25.

33 Holdcraft RW, Braun RE. Androgen receptor function is required in Sertoli cells for the terminal differentiation of haploid spermatids. Development 2004; 131: 459_67.

34 Singh R, Deepa SR, Madhavi S, Gupta NJ, Chakravarty B, Singh L, et al. Male infertility: no evidence of involvement of androgen receptor gene among Indian men. J Androl 2006; 27: 102_5.

35 Lund A, Juvonen V, Lahdetie J, Aittomaki K, Tapanainen JS, Savontaus ML. A novel sequence variation in the transactivation regulating domain of the androgen receptor in two infertile Finnish men. Fertil Steril 2003; 79:1647_8.

36 Hiort O, Holterhus PM, Horter T, Schulze W, Kremke B, Bals-Pratsch M, et al. Significance of mutations in the androgen receptor gene in males with diopathic infertility. J Clin Endocrinol Metab 2000; 85: 2810_5.

37 Wang Q, Ghadessy FJ, Yong EL. Analysis of the transactivation domain of the androgen receptor in patients with male infertility. Clin Genet 1998; 54: 185_92.

38 Ghadessy FJ, Lim J, Abdullah AA, Panet-Raymond V, Choo CK, Lumbroso R, et al. Oligospermic infertility associated with an androgen receptor mutation that disrupts interdomain and coactivator (TIF2) interactions. J Clin Invest 1999; 103: 1517_25.

39 Yong EL, Loy CJ, Sim KS. Androgen receptor gene and male infertility. Hum Reprod Update 2003; 9: 1_7.

40 Wallerand H, Remy-Martin A, Chabannes E, Bermont L, Adessi GL, Bittard H. Relationship between expansion of the CAG repeat in exon 1 of the androgen receptor gene and idiopathic male infertility. Fertil Steril 2001; 76: 769_74.

41 Mengual L, Oriola J, Ascaso C, Ballesca JL, Oliva R. An increased CAG repeat length in the androgen receptor gene in azoospermic ICSI candidates. J Androl 2003; 24: 279_84.

42 Rajpert-De Meyts E, Leffers H, Petersen JH, Andersen AG, Carlsen E, Jorgensen N, et al. CAG repeat length in androgen-receptor gene and reproductive variables in fertile and infertile men. Lancet 2002; 359: 44_6.

43 Thangaraj K, Joshi MB, Reddy AG, Gupta NJ, Chakravarty B, Singh L. CAG repeat expansion in the androgen receptor gene is not associated with male infertility in Indian populations. J Androl 2002; 23: 815_8.

44 Dhillon VS, Husain SA. Cytogenetic and molecular analysis of the Y chromosome: absence of a significant relationship between CAG repeat length in exon 1 of the androgen receptor gene and infertility in Indian men. Int J Androl 2003; 26: 286_95.

45 Komori S, Kasumi H, Kanazawa R, Sakata K, Nakata Y, Kato H, et al. CAG repeat length in the androgen receptor gene of infertile Japanese males with oligozoospermia. Mol Hum Reprod 1999; 5: 14_6.

46 Mifsud A, Sim CK, Boettger-Tong H, Moreira S, Lamb DJ, Lipshultz LI, et al. Trinucleotide (CAG) repeat polymorphisms in the androgen receptor gene: molecular markers of male infertility risk. Fertil Steril 2001; 75: 275_81.

47 Patrizio P, Leonard DG, Chen KL, Hernandez-Ayup S, Trounson AO. Larger trinucleotide repeat size in the androgen receptor gene of infertile men with extremely severe oligozoospermia. J Androl 2001; 22: 444_8.

48 Tut TG, Ghadessy FJ, Trifiro MA, Pinsky L, Yong EL. Long polyglutamine tracts in the androgen receptor are associated with reduced transactivation, impaired sperm production and male infertility. J Clin Endocrinol Metab 1997; 82: 3777_82.

49 Ferlin A, Bartoloni L, Rizzo G, Roverato A, Garolla A, Foresta C. Androgen receptor gene CAG and GGC repeat lengths in idiopathic male infertility. Mol Hum Reprod 2004; 10: 417_21.

50 Ruhayel Y, Lundin K, Giwercman Y, Hallden C, Willen M, Giwercman A. Androgen receptor gene GGN and CAG polymorphisms among severely oligozoospermic and azoospermic Swedish men. Hum Reprod 2004; 19: 2076_83.

51 Rajender S, Rajani V, Gupta NJ, Chakravarty B, Singh L, Thangaraj K. No association of androgen receptor GGN repeat length polymorphism with infertility in Indian Men. J Androl 2006; 27: 785_9.

52 Lundin KB, Giwercman A, Richthoff J, Abrahamsson PA, Giwercman YL. No association between mutations in the human androgen receptor GGN repeat and inter-sex conditions. Mol Hum Reprod 2003; 9: 375_9.

53 Zinn AR, Ramos P, Elder FF, Kowal K, Samango-Sprouse C, Ross JL. Androgen receptor CAGn repeat length influences phenotype of 47,XXY (Klinefelter) syndrome. J Clin Endocrinol Metab 2005; 90: 5041_6.

54 Kamischke A, Baumgardt A, Horst J, Nieschlag E. Clinical and diagnostic features of patients with suspected Klinefelter syndrome. J Androl 2003; 24: 41_8.

55 Vermeulen A, Kaufman JM. Ageing of the hypothalamo_pituitary_testicular axis in men. Horm Res 1995; 43: 25_8.

56 Morales A, Heaton JP, Carson CC. Andropause: A misnomer for a true clinical entity. J Urol 2000; 163: 705_12.

57 Seidman SN, Araujo AB, Roose SP, McKinlay JB. Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men. Biol Psychiatry 2001; 50: 371_6.

58 Harkonen K, Huhtaniemi I, Makinen J, Hubler D, Irjala K, Koskenvuo M, et al. The polymorphic androgen receptor gene CAG repeat, pituitary-testicular function and andropausal symptoms in ageing men. Int J Androl 2003; 26: 187_94.

59 Roy AK, Lavrovsky Y, Song CS, Chen S, Jung MH, Velu NK, et al. Regulation of androgen action. Vit Horm 1999; 55: 309_52.

60 Denis LJ, Griffiths K. Endocrine treatment in prostate cancer. Sem Surg Oncol 2000; 18: 52_74.

61 Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev 2004; 25: 276_308.

62 van der Kwast TH, Schalken J, Ruizeveld de Winter JA, vanVroonhoven CCJ, Mulder E, Boersma W, et al. Androgen receptors in endocrine-therapy-resistant human prostate cancer. Int J Cancer 1991; 48: 189_93.

63 Newmark JR, Hardy DO, Tonb DC, Carter BS, Epstein JI, Isaacs WB, et al. Androgen receptor gene mutations in human prostate cancer. Proc Natl Acad Sci USA 1992; 89: 6319_23.

64 Wilding G, Chen M, Gelmann EP. Aberrant response in vitro of hormone-responsive prostate cancer cells to antiandrogens. Prostate 1989; 14: 103_15.

65 Shi XB, Ma AH, Xia L, Kung HJ, de Vere White RW. Functional analysis of 44 mutant androgen receptors from human prostate cancer. Cancer Res 2002; 62: 1496_502.

66 Miyamoto H, Yeh S, Lardy H, Messing E, Chang C. 5-Androstenediol is a natural hormone with androgenic activity in human prostate cancer cells. Proc Natl Acad Sci USA 1998; 95: 11083_8.

67 Yeh S, Miyamoto H, Shima H, Chang C. From estrogen to androgen receptor: a new pathway for sex hormones in prostate. Proc Natl Acad Sci USA 1998; 95: 5527_32.

68 Jin B, Beilin J, Zajac J, Handelsman DJ. Androgen receptor gene polymorphism and prostate zonal volumes in Australian and Chinese men. J Androl 2000; 21: 91_8.

69 Hardy DO, Scher HI, Bogenreider T, Sabbatini P, Zhang ZF, Nanus DM, et al. Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset. J Clin Endocrinol Metab 1996; 81: 4400_5.

70 Giovannucci E, Stampfer MJ, Krithivas K, Brown M, Dahl D, Brufsky A, et al. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci USA 1997; 94: 3320_3. Erratum in: Proc Natl Acad Sci USA 1997; 94: 8272.

71 Stanford JL, Just JJ, Gibbs M, Wicklund KG, Neal CL, Blumenstein BA, et al. Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk. Cancer Res 1997; 57: 1194_8.

72 Balic I, Graham ST, Troyer DA, Higgins BA, Pollock BH, Johnson-Pais TL, et al. Androgen receptor length polymorphism associated with prostate cancer risk in Hispanic men. J Urol 2002; 168: 2245_8.

73 Ingles SA, Ross RK, Yu MC, Irvine RA, La Pera G, Haile RW, et al. Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J Natl Cancer Inst 1997; 89: 166_70.

74 Bennett CL, Price DK, Kim S, Liu D, Jovanovic BD, Nathan D, et al. Racial variation in CAG repeat lengths within the androgen receptor gene among prostate cancer patients of lower socioeconomic status. J Clin Oncol 2002; 20: 3599_604.

75 Santos ML, Sarkis AS, Nishimoto IN, Nagai MA. Androgen receptor CAG repeat polymorphism in prostate cancer from a Brazilian population. Cancer Detect Prev 2003; 27: 321_6.

76 Lange EM, Chen H, Brierley K, Livermore H, Wojno KJ, Langefeld CD, et al. The polymorphic exon 1 androgen receptor CAG repeat in men with a potential inherited predisposition to prostate cancer. Cancer Epidemiol Biomarkers Prev 2000; 9: 439_42.

77 Cude KJ, Montgomery JS, Price DK, Dixon SC, Kincaid RL, Kovacs KF, et al. The role of an androgen receptor polymorphism in the clinical outcome of patients with metastatic prostate cancer. Urol Int 2002; 68: 16_23.

78 Huang SP, Chou YH, Chang WS, Wu MT, Yu CC, Wu T, et al. Androgen receptor gene polymorphism and prostate cancer in Taiwan. J Formos Med Assoc 2003; 102: 680_6.

79 Suzuki H, Akakura K, Komiya A, Ueda T, Imamoto T, Furuya Y, et al. CAG polymorphic repeat lengths in androgen receptor gene among Japanese prostate cancer patients: potential predictor of prognosis after endocrine therapy. Prostate 2002; 51: 219_24.

80 Hsing AW, Gao YT, Wu G, Wang X, Deng J, Chen YL, et al. Polymorphic CAG and GGN repeat lengths in the androgen receptor gene and prostate cancer risk: a population-based case-control study in China. Cancer Res 2000; 60: 5111_6.

81 Mishra D, Thangaraj K, Mandhani A, Kumar A, Mittal R. Is reduced CAG repeat length in androgen receptor gene associated with risk of prostate cancer in Indian population. Clin Genet 2005; 68: 55_60.

82 Krishnaswamy V, Kumarasamy T, Venkatesan V, Shroff S, Jayanth VR, Paul SF. South Indian men with reduced CAG repeat length in the androgen receptor gene have an increased risk of prostate cancer. J Hum Genet 2006; 51: 254_7.

83 Correa-Cerro L, Wohr G, Haussler J, Berthon P, Drelon E, Mangin P, et al. (CAG)nCAA and GGN repeats in the human androgen receptor gene are not associated with prostate cancer in a French-German population. Eur J Hum Genet 1999; 7: 357_62.

84 Bratt O, Borg A, Kristoffersson U, Lundgren R, Zhang QX, Olsson H. CAG repeat length in the androgen receptor gene is related to age at diagnosis of prostate cancer and response to endocrine therapy, but not to prostate cancer risk. Br J Cancer 1999; 81: 672_6.

85 Edwards SM, Badzioch MD, Minter R, Hamoudi R, Collins N, Ardern-Jones A, et al. Androgen receptor polymorphisms: association with prostate cancer risk, relapse and overall survival. Int J Cancer 1999; 84: 458_65.

86 Mir K, Edwards J, Paterson PJ, Hehir M, Underwood MA, Bartlett JM. The CAG trinucleotide repeat length in the androgen receptor does not predict the early onset of prostate cancer. BJU Int 2002; 90: 573_8.

87 Tayeb MT, Clark C, Murray GI, Sharp L, Haites NE, McLeod HL. Length and somatic mosaicism of CAG and GGN repeats in the androgen receptor gene and the risk of prostate cancer in men with benign prostatic hyperplasia. Ann Saudi Med 2004; 24: 21_6.

88 Mononen N, Ikonen T, Autio V, Rokman A, Matikainen MP, Tammela TL, et al. Androgen receptor CAG polymorphism and prostate cancer risk. Hum Genet 2002; 111: 166_71.

89 Chang BL, Zheng SL, Hawkins GA, Isaacs SD, Wiley KE, Turner A, et al. Polymorphic GGC repeats in the androgen receptor gene are associated with hereditary and sporadic prostate cancer risk. Hum Genet 2002; 110: 122_9.

90 Miller EA, Stanford JL, Hsu L, Noonan E, Ostrander EA. Polymorphic repeats in the androgen receptor gene in high-risk sibships. Prostate 2001; 48: 200_5.

91 Chen C, Lamharzi N, Weiss NS, Etzioni R, Dightman DA, Barnett M, et al. Androgen receptor polymorphisms and the incidence of prostate cancer. Cancer Epidemiol Biomarkers Prev 2002; 11: 1033_40.

92 Platz EA, Giovannucci E, Dahl DM, Krithivas K, Hennekens CH, Brown M, et al. The androgen receptor gene GGN microsatellite and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 1998; 7: 379_84.

93 Irvine RA, Yu MC, Ross RK, Coetzee GA. The CAG and GGC microsatellites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res 1995; 55: 1937_40.

94 Prener A, Østerlind A. Cancer in Denmark. Copenhagen, Danish Cancer Registry, Copenhagen, 1985.

95 Skakkebæk NE, Berthelsen JG, Giwercman A, Muller J. Carcinoma-in situ of the testis: possible origin from gonocytes and precursor of all types of germ cell tumours except spermatocytoma. Int J Androl 1987, 10, 19_28.

96 Schottenfeld D, Warshauer ME, Sherlock S, Zauber AG, Leder M, Payne R. The epidemiology of testicular cancer in young adults. Am J Epidemiol 1980; 112: 232_46.

97 Bangsbøll S, Qvist I, Lebech PE, Lewinsky M. Testicuar feminization syndrome and associated gonadal tumors in Denmark. Acta Obstet Gynecol Scan 1992; 71: 63_6.

98 Garolla A, Ferlin A, Vinanzi C, Roverato A, Sotti G, Artibani W, et al. Molecular analysis of the androgen receptor gene in testicular cancer. Endocr Relat Cancer 2005; 12: 645_55.

99 Rajpert-De Meyts E, Leffers H, Daugaard G, Andersen CB, Petersen PM, Hinrichsen J, et al. Analysis of the polymorphic CAG repeat length in the androgen receptor gene in patients with testicular germ cell cancer. Int J Cancer 2002; 102: 201_4.

100 Giwercman A, Lundin KB, Eberhard J, Stahl O, Cwikiel M, Cavallin-Stahl E, et al. Linkage between androgen receptor gene CAG trinucleotide repeat length and testicular germ cell cancer histological type and clinical stage. Eur J Cancer 2004; 40: 2152_8.

101 Savage MO, Lowe DG. Gonadal neoplasia and abnormal sexual differentiation. Clin Endocrinol 1990; 32: 519_33.

102 McNatty KP, Makris A, Reinhold VN, et al. Metabolism of androstenedione by human ovarian tissues in vitro with particular reference to reductase and aromatase activity. Steroids 1979; 34: 429_43.

103 Risch HA. Hormonal etiology of epithelial ovarian cancer, with hypothesis concerning the role of androgens and progesterone. J Natl Cancer Inst 1998; 90: 1774_86.

104 Judd HL, Judd GE, Lucas WE, Yen SS. Endocrine function of the post-menopausal ovary: concentration of androgens and estrogens in ovarian and peripheral vein blood. J Clin Endocrinol Metab 1974; 39: 1020_4.

105 Lau KM, Mok SC, Ho SM. Expression of human estrogen receptor alpha and beta, progesterone receptor, and androgen receptor mRNA in normal and malignant ovarian epithelial cells. Proc Natl Acad Sci USA 1999; 96: 5722_7.

106 Chadha S, Rao BR, Slotman BJ, van Vroonhoven CC, van der Kwast TH. An immunohistochemical evaluation of androgen and progesterone receptors in ovarian cancer. Hum Pathol 1993; 24: 90_5.

107 Slotman BJ, Rao BR. Response to inhibition of androgen action of human ovarian cancer cells in vitro. Cancer Lett 1989; 45: 312_20.

108 Modugno F. Ovarian cancer and polymorphisms in the androgen and progesterone receptor genes: a HuGE review. Am J Epidemiol 2004; 159: 319_35.

109 van Doorn HC, Burger CW, van der Valk P, Bonfrer HM. Estrogen, progesterone, and androgen receptors in ovarian neoplasia: correlation between immunohistochemical and biochemical receptor analyses. J Clin Pathol 2000; 53: 201_5.

110 Santarosa M, Bidoli E, Gallo A, Steffan A, Boiocchi M, Viel A. Polymorphic CAG repeat length within the androgen receptor gene: identification of a subgroup of patients with increased risk of ovarian cancer. Oncol Rep 2002; 9: 639_44.

111 Terry KL, De Vivo I, Titus-Ernstoff L, Shih MC, Cramer DW. Androgen receptor cytosine, adenine, guanine repeats, and haplotypes in relation to ovarian cancer risk. Cancer Res 2005; 65: 5974_81.

112 Menin C, Banna GL, De Salvo G, Lazzarotto V, De Nicolo A, Agata S, et al. Lack of association between androgen receptor CAG polymorphism and familial breast/ovarian cancer. Cancer Lett 2001; 168: 31_6.

113 Li AJ, Baldwin RL, Karlan BY. Short androgen receptor allele length is a poor prognostic factor in epithelial ovarian carcinoma. Clin Cancer Res 2003; 9: 3667_73.

114 Levine DA, Boyd J. The androgen receptor and genetic susceptibility to ovarian cancer: results from a case series. Cancer Res 2001; 61: 908_11.

115 Dagan E, Friedman E, Paperna T, Carmi N, Gershoni-Baruch R. Androgen receptor CAG repeat length in Jewish Israeli women who are BRCA1/2 mutation carriers: association with breast/ovarian cancer phenotype. Eur J Hum Genet 2002; 10: 724_8.

116 Kim SC, Ju W, Mahavni V, Geisler JP, Buller RE. CAG repeat length in exon 1 of the androgen receptor gene is related to age of diagnosis but not germ line BRCA1 mutation status in ovarian cancer. Int J Gynecol Cancer 2006; 16: 190_4.

117 Franks S. Polycystic ovary syndrome. N Engl J Med 1995; 333: 853_61.

118 Vendola KA, Zhou J, Adesanya OO, Weil SJ, Bondy CA. Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest 1998; 101: 2622_9.

119 Chadha S, Pache TD, Huikeshoven JM, Brinkmann AO, van der Kwast TH. Androgen receptor expression in human ovarian and uterine tissue of long-term androgen-treated transsexual women. Hum Pathol 1994; 25: 1198_204.

120 Mifsud A, Ramirez S, Yong EL. Androgen receptor gene CAG trinucleotide repeats in anovulatory infertility and polycystic ovaries. J Clin Endocrinol Metab 2000; 85: 3484_8.

121 Jaaskelainen J, Korhonen S, Voutilainen R, Hippelainen M, Heinonen S. Androgen receptor gene CAG length polymorphism in women with polycystic ovary syndrome. Fertil Steril 2005; 83: 1724_8.

122 Ibanez L, Ong KK, Mongan N, Jaaskelainen J, Marcos MV, Hughes IA, et al. Androgen receptor gene CAG repeat polymorphism in the development of ovarian hyperandrogenism. J Clin Endocrinol Metab 2003; 88: 3333_8.

123 Hickey T, Chandy A, Norman RJ. The androgen receptor CAG repeat polymorphism and X-chromosome inactivation in Australian Caucasian women with infertility related to polycystic ovary syndrome. J Clin Endocrinol Metab 2002; 87: 161_5.

124 Sasaki M, Dahiya R, Fujimoto S, Ishikawa M, Oshimura M. The expansion of the CAG repeat in exon 1 of the human androgen receptor gene is associated with uterine endometrial carcinoma. Mol Carcinog 2000; 27: 237_44.

125 Hackenberg R, Beck S, Filmer A, Hushmandnia A, Kunzmann R, Koch M, et al. Androgen responsiveness of the new human endometrial cancer cell line MFE-296. Int J Cancer 1994; 57: 117_22.

126 Couse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev 1999; 20: 358_417. Erratum in: Endocr Rev 1999; 20: 459.

127 Endres S, Mayuga KA, Cristofaro A, Taneja T, Goldberger JJ, Kadish AH. Menstrual cycle and ST height. Ann Noninvasive Electrocardiol 2004; 9: 121_6.

128 Wang H, Isaksson E, von Schoultz B, Cline JM, Sahlin L. Effect of long-term treatment with steroid hormones or tamoxifen on the progesterone receptor and androgen receptor in the endometrium of ovariectomized cynomolgus macaques. Reprod Biol Endocrinol 2003; 1: 7.

129 Slayden OD, Brenner RM. Hormonal regulation and localization of estrogen, progestin and androgen receptors in the endometrium of nonhuman primates: effects of progesterone receptor antagonists. Arch Histol Cytol 2004; 67: 393_409.

130 GM Centla. Inhibition of endometrial carcinoma cell cultures by a synthetic androgen. Cancer Res 1985; 45: 6264_7.

131 Rodriguez G, Bilbao C, Ramirez R, Falcon O, Leon L, Chirino R, et al. Alleles with short CAG and GGN repeats in the androgen receptor gene are associated with benign endometrial cancer. Int J Cancer 2006; 118: 1420_5.

132 McGrath M, Lee IM, Hankinson SE, Kraft P, Hunter DJ, Buring J, et al. Androgen receptor polymorphisms and endometrial cancer risk. Int J Cancer 2006; 118: 1261_8.

133 Yaron M, Levy T, Chetrit A, Levavi H, Sabah G, Schneider D, et al. The polymorphic CAG repeat in the androgen receptor gene in Jewish Israeli women with endometrial carcinoma. Cancer 2001; 92: 1190_4.

134 Sasaki M, Sakuragi N, Dahiya R. The CAG repeats in exon 1 of the androgen receptor gene are significantly longer in endometrial cancer patients. Biochem Biophys Res Commun 2003; 305: 1105_8.

135 Hsieh YY, Chang CC, Tsai FJ, Wu JY, Tsai CH, Tsai HD. Androgen receptor trinucleotide polymorphism in endometriosis. Fertil Steril 2001; 76: 412_3.

136 Lattuada D, Vigano P, Somigliana E, Odorizzi MP, Vignali M, Di Blasio AM. Androgen receptor gene cytosine, adenine, and guanine trinucleotide repeats in patients with endometriosis. J Soc Gynecol Investig 2004; 11:237_40.

137 Sasaki M, Karube A, Karube Y, Watari M, Sakuragi N, Fujimoto S, et al. GGC and StuI polymorphism on the androgen receptor gene in endometrial cancer patients. Biochem Biophys Res Commun 2005; 329: 100_4.

138 Sasano H, Kimura M, Shizawa S, Kimura N, Nagura H. Aromatase and steroid receptors in gynecomastia and male breast carcinoma: an immunohistochemical study. J Clin Endocrinol Metab 1996; 81: 3063_7.

139 Lillie EO, Bernstein L, Ursin G. The role of androgens and polymorphisms in the androgen receptor in the epidemiology of breast cancer. Breast Cancer Res 2003; 5: 164_73.

140 Wysowski DK, Comstock GW, Helsing KJ, Lau HL. Sex hormone levels in serum in relation to the development of breast cancer. Am J Epidemiol 1987; 125: 791_9.

141 Ortmann J, Prifti S, Bohlmann MK, Rehberger-Schneider S, Strowitzki T, Rabe T. Testosterone and 5 alpha-dihydrotestosterone inhibit in vitro growth of human breast cancer cell lines. Gynecol Endocrinol 2002; 16: 113_20.

142 Hackenberg R, Hofmann J, Holzel F, Schulz KD. Stimulatory effects of androgen and antiandrogen on the in vitro proliferation of human mammary carcinoma cells. J Cancer Res Clin Oncol 1988; 114: 593_601.

143 Wooster R, Mangion J, Eeles R, Smith S, Dowsett M, Averill D, et al. A germline mutation in the androgen receptor gene in two brothers with breast cancer and Reifenstein syndrome. Nat Genet 1992; 2: 132_4.

144 Lobaccaro JM, Lumbroso S, Belon C, Galtier-Dereure F, Bringer J, Lesimple T, et al. Androgen receptor gene mutation in male breast cancer. Hum Mol Genet 1993; 2: 1799_802.

145 Zhu X, Daffada AA, Chan CM, Dowsett M. Identification of an exon 3 deletion splice variant androgen receptor mRNA in human breast cancer. Int J Cancer 1997; 72: 574_80.

146 Kasami M, Gobbi H, Dupont WD, Simpson JF, Page DL, Vnencak-Jones CL. Androgen receptor CAG repeat lengths in ductal carcinoma in situ of breast, longest in apocrine variety. Breast 2000; 9: 23_7.

147 Kadouri L, Easton DF, Edwards S, Hubert A, Kote-Jarai Z, Glaser B, et al. CAG and GGC repeat polymorphisms in the androgen receptor gene and breast cancer susceptibility in BRCA1/2 carriers and non-carriers. Br J Cancer 2001; 85: 36_40.

148 Young IE, Kurian KM, Mackenzie MA, Kunkler IH, Cohen BB, Hooper ML, et al. The CAG repeat within the androgen receptor gene in male breast cancer patients. J Med Genet 2000; 37: 139_40.

149 Syrjakoski K, Hyytinen ER, Kuukasjarvi T, Auvinen A, Kallioniemi OP, Kainu T, et al. Androgen receptor gene alterations in Finnish male breast cancer. Breast Cancer Res Treat 2003; 77: 167_70.

150 MacLean HE, Brown RW, Beilin J, Warne GL, Zajac JD. Increased frequency of long androgen receptor CAG repeats in male breast cancers. Breast Cancer Res Treat 2004; 88: 239_46.

151 Spurdle AB, Antoniou AC, Duffy DL, Pandeya N, Kelemen L, Chen X, et al. The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res 2005; 7: R176_83.

152 Spurdle AB, Dite GS, Chen X, Mayne CJ, Southey MC, Batten LE, et al. Androgen receptor exon 1 CAG repeat length and breast cancer in women before age forty years. J Natl Cancer Inst 1999; 91: 961_6.

153 Gudas JM, Nguyen H, Li T, Cowan KH. Hormonedependent regulation of BRCA1 in human breast cancer cells. Cancer Res 1995; 55: 4561_5.

154 Rebbeck TR, Kantoff PW, Krithivas K, Neuhausen S, Blackwood MA, Godwin AK, et al. Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat. Am J Hum Genet 1999; 64: 1371_7.

155 Suter NM, Malone KE, Daling JR, Doody DR, Ostrander EA. Androgen receptor (CAG)n and (GGC)n polymorphisms and breast cancer risk in a population-based case-control study of young women. Cancer Epidemiol Biomarkers Prev 2003; 12: 127_35.

156 Serin IS, Kula M, Basbug M, Unluhizarci K, Gucer S, Tayyar M. Androgen levels of preeclamptic patients in the third trimester of pregnancy and six weeks after delivery. Acta Obstet Gynecol Scand 2001; 80: 1009_13.

157 Saarela T, Jaaskelainen J, Tenhola S, Voutilainen R, Heinonen S. Preeclampsia and androgen receptor gene CAG repeat length: results from both children and women. J Assist Reprod Genet 2005; 22: 269_75.

158 Brufsky A, Fontaine-Rothe P, Berlane K, Rieker P, Jiroutek M, Kaplan I, et al. Finasteride and flutamide as potency-sparing androgen-ablative therapy for advanced adenocarcinoma of the prostate. Urology 1997; 49: 913_20.

159 Westberg L, Baghaei F, Rosmond R, Hellstrand M, Landen M, Jansson M, et al. Polymorphisms of the androgen receptor gene and the estrogen receptor beta gene are associated with androgen levels in women. J Clin Endocrinol Metab 2001; 86: 2562_8.

160 Brum IS, Spritzer PM, Paris F, Maturana MA, Audran F, Sultan C. Association between androgen receptor gene CAG repeat polymorphism and plasma testosterone levels in postmenopausal women. J Soc Gynecol Investig 2005; 12: 135_41.

161 Lee JH, Shin JH, Park KP, Kim IJ, Kim CM, Lim JG, et al. Phenotypic variability in Kennedy's disease: implication of the early diagnostic features. Acta Neurol Scand 2005; 112: 57_63.

162 La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. Androgen receptor gene mutations in Xlinked spinal and bulbar muscular atrophy. Nature 1991; 352: 77_9.

163 Doyu M, Sobue G, Mukai E, Kachi T, Yasuda T, Mitsuma T, et al. Severity of X-linked recessive bulbospinal neuronopathy correlates with size of the tandem CAG repeat in androgen receptor gene. Ann Neurol 1992; 32: 707_10.

164 Stenoien DL, Cummings CJ, Adams HP, Mancini MG, Patel K, DeMartino GN, et al. Polyglutamine-expanded androgen receptors form aggregates that sequester heat shock proteins, proteasome components and SRC-1, and are suppressed by the HDJ-2 chaperone. Hum Mol Genet 1999; 8: 731_41.

165 Katsuno M, Adachi H, Waza M, Banno H, Suzuki K, Tanaka F, et al. Pathogenesis, animal models and therapeutics in spinal and bulbar muscular atrophy (SBMA). Exp Neurol 2006; 200: 8_18.

166 Ellerby LM, Hackam AS, Propp SS, Ellerby HM, Rabizadeh S, Cashman NR, et al. Kennedy's disease: caspase cleavage of the androgen receptor is a crucial event in cytotoxicity. J Neurochem 1999; 72: 185_95.

167 Jedele KB, Wahl D, Chahrokh-Zadeh S, Wirtz A, Murken J, Holinski-Feder E. Spinaland bulbar muscular atrophy (SBMA): somatic stability of an expanded CAG repeat in fetal tissues. Clin Genet 1998; 54: 148_51.

168 Yapijakis C, Kapaki E, Boussiou M, Vassilopoulos D, Papageorgiou C. Prenatal diagnosis of X-linked spinal and bulbar muscular atrophy in a Greek family. Prenat Diagn 1996; 16: 262_5.

169 Hogervorst E, Williams J, Budge M, Barnetson L, Combrinck M, Smith AD. Serum total testosterone is lower in men with Alzheimer's disease. Neuroendocrinol Lett 2001; 3: 163_8.

170 Ahlbom E, Prins GS, Ceccatelli S. Testosterone protects cerebellar granule cells from oxidative stress-induced cell death through a receptor mediated mechanism. Brain Res 2001; 892: 255_62.

171 Hammond J, Le Q, Goodyer C, Gelfand M, Trifiro M, LeBlanc A. Testosterone-mediated neuroprotection through the androgen receptor in human primary neurons. J Neurochem 2001; 77: 1319_26.

172 Pike CJ. Testosterone attenuates b-amyloid toxicity in cultured hippocampal neurons. Brain Res 2001; 919: 160_5.

173 Raber J, Bongers G, LeFevour A, Buttini M, Mucke L. Androgens protect against apolipoprotein E4-induced cognitive deficits. J Neurosci 2002; 22: 5204_9.

174 Lehmann DJ, Butler HT, Warden DR, Combrinck M, King E, Nicoll JA, et al. Association of the androgen receptor CAG repeat polymorphism with Alzheimer's disease in men. Neurosci Lett 2003; 340: 87_90.

175 Angermeyer MC, Kuhn L. Gender differences in age at onset of schizophrenia. An overview. Eur Arch Psychiatry Neurol Sci 1988; 237: 351_64.

176 Roy MA, Maziade M, Labbe A, Merette C. Male gender is associated with deficit schizophrenia: a metaanalysis. Schizophr Res 2001; 47: 141_7.

177 DeLisi LE, Friedrich U, Wahlstrom J, Boccio-Smith A, Forsman A, Eklund K, et al. Schizophrenia and sex chromosome anomalies. Schizophr Bull 1994; 20: 495_505.

178 Crow TJ, Poulter M, Lofthouse R, Chen G, Shah T, Bass N, et al. Male siblings with schizophrenia share alleles at the androgen receptor above chance expectation. Am. J Med Genet 1993; 48: 159_60.

179 Arranz M, Sharma T, Sham P, Kerwin R, Nanko S, Owen M, et al. Schizophrenia and the androgen receptor gene: report of a sibship showing co-segregation with Reifenstein syndrome but no evidence for linkage in 23 multiply affected families. Am J Med Genet 1995; 60: 377_81.

180 Tsai SJ, Hong CJ, Liao DL, Chiang CH. Distribution of androgen receptor CAG repeat polymorphism in Chinese schizophrenia and its correlation with age at onset. Psychoneuroendocrinology 2006; 31: 270_4.

181 Yaffe K, Edwards ER, Lui LY, Zmuda JM, Ferrell RE, Cauley JA. Androgen receptor CAG repeat polymorphism is associated with cognitive function in older men. Biol Psychiatry 2003; 54: 943_6.

182 Beyenburg S, Watzka M, Clusmann H, Blumcke I, Bidlingmaier F, Elger CE, et al. Androgen receptor mRNA expression in the human hippocampus. Neurosci Lett 2000; 294: 25_8.

183 Sarrieau A, Mitchell JB, Lal S, Olivier A, Quirion R, Meaney MJ. Androgen binding sites in human temporal cortex. Neuroendocrinology 1990; 51: 713_6.

184 Pope HGJ, Kouri EM, Hudson JI. Effects of supraphysiologic doses of testosterone on mood and aggression in normal men. A randomized controlled trial. Arch Gen Psychiatry 2000; 57: 133_40.

185 Turakulov R, Jorm AF, Jacomb PA, TanX, Easteal S. Association of dopamine-b-hydroxylase and androgen receptor gene polymorphisms with Eysenck's P and other personality traits. Pers Individ Dif 2004; 37: 191_202.

186 Loehlin JC, Medland SE, Montgomery GW, Martin NG. Eysenck's Psychoticism and the X-linked androgen receptor gene CAG polymorphism in additional Australian samples. Pers Individ Dif 2005 (in press).

187 Silberstein SD, Merriam GR. Physiology of the menstrual cycle. Cephalalgia 2000; 20: 148_54.

188 MacGregor EA, Chia H, Vohrah RC, Wilkinson M. Migraine and menstruation: a pilot study. Cephalalgia 1990; 10: 305_10.

189 Colson NJ, Lea RA, Quinlan S, MacMillan J, Griffiths LR. Investigation of hormone receptor genes in migraine. Neurogenetics 2005; 6: 17_23.

190 Rhee SH, Waldman ID. Genetic and environmental influences on antisocial behavior: a meta-analysis of twin and adoption studies. Psychol Bull 2002; 128: 490_529.

191 Aluja A, Torrubia R. Hostility-aggressiveness, sensation seeking, and sex hormones in men: re-exploring their relationship. Neuropsychobiology 2004; 50: 102_7.

192 Trenton AJ, Currier GW. Behavioural manifestations of anabolic steroid use. CNS Drugs 2005; 19: 571_95.

193 Mulder RT, Wells JE, Joyce PR, Bushnell JA. Antisocial women. J Personal Disord 1994; 8: 279_87.

194 Cheng D, Hong CJ, Liao DL, Tsai SJ. Association study of androgen receptor CAG repeat polymorphism and male violent criminal activity. Psychoneuroendocrinology 2006; 31: 548_52.

195 Wunsch-Filho V. The epidemiology of oral and pharynx cancer in Brazil. Oral Oncol 2002; 38: 737_46.

196 Vecerina-Volic S, Romic-Stojkovic R, Krajina Z, Gamulin S. Androgen receptors in normal and neoplastic laryngeal tissue. Arch Otolaryngol Head Neck Surg 1987; 113: 411_3.

197 dos Santos ML, Sibov TT, Nishimoto IN, Kowalski LP, Miracca EC, Nagai MA. The CAG repeat polymorphism in the androgen receptor gene (AR) and its relationship to head and neck cancer. Oral Oncol 2004; 40: 177_82.

198 Yamashita Y, Hirai T, Mukaida H, Kawano K, Toge T, Niimoto M, et al. Detection of androgen receptors in human esophageal cancer. Jpn J Surg 1989; 19: 195_202.

199 Cannon G. Food, nutrition and the prevention of cancer: a global perspective. World Cancer Research Fund in association with the American Institute for Cancer Research. Menasha, USA: BANTA Book Group; 1997. p670.

200 Du Plessis L, Dietzsch E, Van Gele M, Van Roy N, Van Helden P, Parker MI, et al. Mapping of novel regions of DNA gain and loss by comparative genomic hybridization in esophageal carcinoma in the African and Colored populations of South Africa. Cancer Res 1999; 59: 1877_83.

201 Dietzsch E, Laubscher R, Parker MI. Esophageal cancer risk in relation to GGC and CAG trinucleotide repeat lengths in the androgen receptor gene. Int J Cancer 2003; 107: 38_45.

202 Berta L, Fronticelli Baldelli C, Fazzari A, Radice E, Bargoni A, Frairia R, et al. Sex steroid receptors, secondary bile acids and colorectal cancer. A possible mechanism of interaction. Panminerva Med 2003; 45: 261_6.

203 DeCosse JJ, Ngoi SS, Jacobson JS, et al. Gender and colorectal cancer. Eur J Cancer Prev 1993; 2: 105_15.

204 Alley PG, McNee RK. Age and sex differences in right colon cancer. Dis Colon Rectum 1986; 29: 227_9.

205 McArdle CS, McMillan DC, Hole DJ. Male gender adversely affects survival following surgery for colorectal cancer. Br J Surg 2003; 90: 711_5.

206 Slattery ML, Sweeney C, Murtaugh M, Ma KN, Wolff RK, Potter JD, et al. Associations between ERalpha, ERbeta, and AR genotypes and colon and rectal cancer. Cancer Epidemiol Biomarkers Prev 2005; 14: 2936_42.

207 Slattery ML, Sweeney C, Murtaugh M, Ma KN, Caan BJ, Potter JD, et al. Associations between vitamin D, vitamin D receptor gene and the androgen receptor gene with colon and rectal cancer. Int J Cancer 2006; 118: 3140_6.

208 Albagha OM, McGuigan FE, Reid DM, Ralston SH. Estrogen receptor alpha gene polymorphisms and bone mineral density: haplotype analysis in women from the United Kingdom. J Bone Miner Res 2001; 16: 128_34.

209 Oursler MJ, Kasem M, Riggs BL, Spelsberg TC. Androgen. In: Marcus R, Feldman D, Kelsey J, editors. Osteoporosis. New York: Academic Press; 1996. p237_60.

210 Van Pottelbergh I, Lumbroso S, Goemaere S, Sultan C, Kaufman JM. Lack of influence of the androgen receptor gene CAG-repeat polymorphism on sex steroid status and bone metabolism in elderly men. Clin Endocrinol 2001; 55: 659_66.

211 Salmen T, Heikkinen AM, Mahonen A, Kroger H, Komulainen M, Pallonen H, et al. Relation of androgen receptor gene polymorphism to bone mineral density and fracture risk in early postmenopausal women during a 5-year randomized hormone replacement therapy trial. J Bone Miner Res 2003; 18: 319_24.

212 Tofteng CL, Kindmark A, Brandstrom H, Abrahamsen B, Petersen S, Stiger F, et al. Polymorphisms in the CYP19 and AR genes—relation to bone mass and longitudinal bone changes in postmenopausal women with or without hormone replacement therapy: Calcif Tissue Int 2004; 74: 25_34.

213 Zitzmann M, Brune M, Kornmann B, Gromoll J, Junker R, Nieschlag E. The CAG repeat polymorphism in the androgen receptor gene affects bone density and bone metabolism in healthy males. Clin Endocrinol 2001; 55: 649_57.

214 Langdahl BL, Stenkjaer L, Carstens M, Tofteng CL, Eriksen EF. A CAG repeat polymorphism in the androgen receptor gene is associated with reduced bone mass and increased risk of osteoporotic fractures. Calcif Tissue Int 2003; 73: 237_43.

215 Chen HY, Chen WC, Wu MC, Tsai FJ, Tsai CH. Androgen receptor (AR) gene microsatellite polymorphism in postmenopausal women: correlation to bone mineral density and susceptibility to osteoporosis. Eur J Obstet Gynecol Reprod Biol 2003; 107: 52_6.

216 Yamada Y, Ando F, Niino N, Shimokata H. Association of polymorphisms of the androgen receptor and klotho genes with bone mineral density in Japanese women. J Mol Med 2005; 83: 50_7.

217 Kenny AM, McGee D, Joseph C, Covault J, Abreu C, Raisz LG. Lack of association between androgen receptor polymorphisms and bone mineral density or physical function in older men. Endocr Res 2005; 31: 285_93.

218 Alamanos Y, Drosos AA. Epidemiology of adult rheumatoid arthritis. Autoimmun Rev 2005; 4: 130_6.

219 Masi AT. Sex hormones and rheumatoid arthritis: cause and effect relationship in a complex pathophysiology? Clin Exp Rheumatol 1995; 13: 227_40.

220 Cutolo M, Masi AT. Do androgens influence the pathophysiology of rheumatoid arthritis? Facts and hypothesis. J Rheumatol 1998; 25: 1041_7.

221 Kawasaki T, Ushiyama T, Ueyama H, Inoue K, Mori K, Ohkubo I, et al. Polymorphic CAG repeats of the androgen receptor gene and rheumatoid arthritis. Ann Rheum Dis 1999; 58: 500_2.

222 Fytili P, Giannatou E, Papanikolaou V, Stripeli F, Karachalios T, Malizos K, et al. Association of repeat polymorphisms in the estrogen receptors alpha, beta, and androgen receptor genes with knee osteoarthritis. Clin Genet 2005; 68: 268_77.

223 Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB. Testosterone, sex hormone-binding globulin, and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care 2000; 23: 490_4.

224 Zitzmann M, Gromoll J, von Eckardstein A, Nieschlag E. The CAG repeat polymorphism in the androgen receptor gene modulates body fat mass and serum concentrations of leptin and insulin in men. Diabetologia 2003; 46: 31_9.

225 Fox HS. Androgen treatment prevents diabetes in nonobese diabetic mice. J Exp Med 1992; 175: 1409_12.

226 Morimoto S, Fernandez-Mejia C, Romero-Navarro G, Morales-Peza N, Diaz-Sanchez V. Testosterone effect on insulin content, messenger ribonucleic acid levels, promoter activity, and secretion in the rat. Endocrinology 2001; 142: 1442_7.

227 Hurlbert MS, Zhou W, Wasmeier C, Kaddis FG, Hutton JC, Freed CR. Mice transgenic for an expanded CAG repeat in the Huntington's disease gene develop diabetes. Diabetes 1999; 48: 649_51.

228 Gombos Z, Hermann R, Veijola R, Knip M, Simell O, Pollanen P, et al. Androgen receptor gene exon 1 CAG repeat polymorphism in Finnish patients with childhood-onset type 1 diabetes. Eur J Endocrinol 2003; 149: 597_600.

229 Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999; 340: 1801_11.

230 McCredie RJ, McCrohon JA, Turner L, Griffiths KA, Handelsman DJ, Celermajer DS. Vascular reactivity is impaired in genetic females taking high-dose androgens. J Am Coll Cardiol 1998; 32: 1331_5.

231 Sullivan ML, Martinez CM, Gennis P, Gallagher EJ. The cardiac toxicity of anabolic steroids. Prog Cardiovasc Dis 1998; 41: 1_15.

232 Alevizaki M, Cimponeriu AT, Garofallaki M, Sarika HL, Alevizaki CC, Papamichael C, et al. The androgen receptor gene CAG polymorphism is associated with the severity of coronary artery disease in men. Clin Endocrinol 2003; 59: 749_55.

233 Hersberger M, Muntwyler J, Funke H, Marti-Jaun J, Schulte H, Assmann G, et al. The CAG repeat polymorphism in the androgen receptor gene is associated with HDL-cholesterol but not with coronary atherosclerosis or myocardial infarction. Clin Chem 2005; 51: 1110_5.

234 Yu MW, Chen CJ. Hepatitis B and C viruses in the development of hepatocellular carcinoma. Crit Rev Oncol Hematol 1994; 17: 71_91.

235 Tanaka K, Sakai H, Hashizume M, Hirohata T. Serum testosterone: estradiol ratio and the development of hepatocellular carcinoma among male cirrhotic patients. Cancer Res 2000; 60: 5106_10.

236 Bhasin S, Woodhouse L, Storer TW. Proof of the effect of testosterone on skeletal muscle. J Endocrinol 2001; 170: 27_38.

237 Bamman MM, Shipp JR, Jiang J, Gower BA, Hunter GR, Goodman A, et al. Mechanical load increases muscle IGF-1 and androgen receptor mRNA concentrations in humans. Am J Physiol Endocrinol Metab 2001; 280: E383_E90.

238 Lee DK. Androgen receptor enhances myogenin expression and accelerates differentiation. Biochem Biophys Res Commun 2002; 294: 408_13.

239 Walsh S, Zmuda JM, Cauley JA, Shea PR, Metter EJ, Hurley BF, et al. Androgen receptor CAG repeat polymorphism is associated with fat-free mass in men. J Appl Physiol 2005; 98: 132_7.

240 Geschwind N, Galaburda A M In: Cerebral Lateralization. Cambridge, MA: MIT Press; 1987.

241 Witelson SF, Nowakowski RS. Left out axons make men right: A hypothesis for the origin of handedness and functional asymmetry. Neuropsychologia 1991; 29: 327_33.

242 Laval S, Dann J, Butler R, Loftus J, Rue J, Leask S, et al. Evidence for linkage to psychosis and cerebral asymmetry (relative hand skill) on the X chromosome. Am J Med Genet 1998; 7: 420_7.

243 Francks C, Fisher S, MacPhie L, Richardson A, Marlow A, Stein J, et al. A genome-wide linkage screen for relative hand skill in sibling pairs. Am J Human Genet 2002; 70: 800_5.

244 Medland SE, Duffy DL, Spurdle AB, Wright MJ, Geffen GM, Montgomery GW, et al. Opposite effects of androgen receptor CAG repeat length on increased risk of left handedness in males and females. Behav Genet 2005; 35: 735_44.

245 Wakisaka N, Taira Y, Ishikawa M, Nakamizo Y, Kobayashi K, Uwabu M, et al. Effectiveness of finasteride on patients with male pattern baldness who have different androgen receptor gene polymorphism. J Investig Dermatol Symp Proc 2005; 10: 293_4.

246 Sawaya ME, Shalita AR. Androgen receptor polymorphisms (CAG repeat lengths) in androgenetic alopecia, hirsutism, and acne. J Cutan Med Surg 1998; 3: 9_15.

247 Spurdle AB, Webb PM, Chen X, Martin NG, Giles GG, Hopper JL, et al. Androgen receptor exon 1 CAG repeat length and risk of ovarian cancer. Int J Cancer 2000; 87: 637_43.

248 Heinlein CA, Chang C. Androgen receptor (AR) coregulators: an overview. Endocr Rev 2002; 23: 175_200.

249 Hsiao PW, Lin DL, Nakao R, Chang C. The linkage of Kennedy's neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator. J Biol Chem 1999; 274: 20229_34.

250 Irvine RA, Ma H, Yu MC, Ross RK, Stallcup MR, CoetzeeGA. Inhibition of p160 mediated coactivation with increasing androgen receptor polyglutamine length. Hum Mol Genet 2000; 9: 267_74.

251 Rodien P, Mebarki F, Mowszowicz I, Chaussain JL, Young J, Morel Y, et al. Different phenotypes in a family with androgen insensitivity caused by the same M780I point mutation in the androgen receptor gene. J Clin Endocrinol Metab 1996; 81: 2994_8.

252 Gottlieb B, Beitel LK, Trifiro MA. Variable expressivity and mutation databases: The androgen receptor gene mutations database. Hum Mutat 2001; 17: 382_8.

253 Gottlieb B, Beitel LK, Trifiro MA. Somatic mosaicism and variable expressivity. Trends Genet 2001; 17: 79_82.

254 Holterhus PM, Sinnecker GH, Hiort O. Phenotypic diversity and testosterone-induced normalization of mutant L712F androgen receptor function in a kindred with androgen insensitivity. J Clin Endocrinol Metab 2000; 85: 3245_50.

255 Boehmer AL, Brinkmann AO, Nijman RM, Verleun-Mooijman MC, de Ruiter P, Niermeijer MF, et al. Phenotypic variation in a family with partial androgen insensitivity syndrome explained by differences in 5alpha dihydrotestosterone availability. J Clin Endocrinol Metab 2001; 86: 1240_6.

256 Bevan CL, Brown BB, Davies HR, Evans BA, Hughes IA, Patterson MN. Functional analysis of six androgen receptor mutations identified in patients with partial androgen insensitivity syndrome. Hum Mol Genet 1996; 5: 265_73.

257 Ackerman MJ. The long QT syndrome: ion channel diseases of the heart. Mayo Clin Proc 1998; 73: 250_69.

258 Holterhus PM, Bruggenwirth HT, Hiort O, Kleinkauf-Houcken A, Kruse K, Sinnecker GH, et al. Mosaicism due to a somatic mutation of the androgen receptor gene determines phenotype in the androgen insensitivity syndrome. J Clin Endocrinol Metab 1997; 82: 3584_9.

259 Holterhus PM, Wiebel J, Sinnecker GH, Bruggenwirth HT, Sippell WG, Brinkmann AO, et al. Clinical and molecular spectrum of somatic mosaicism in androgen insensitivity syndrome. Eur J Pediatr 1999; 158: 702_6.

260 Ross RK, Pike MC, Coetzee GA, Reichardt JK, Yu MC, Feigelson H, et al. Androgen metabolism and prostate cancer: establishing a model of genetic susceptibility. Cancer Res 1998; 58: 4497_504.

261 Giwercman, YL, Xu C, Arver S, Pousette A, Reneland R. No association between the androgen receptor gene CAG repeat and impaired sperm production in Swedish men. Clin Genet 1998; 54: 435_6.

262 Yoshida KI, Yano M, Chiba K, Honda M, Kitahara S. CAG repeat length in the androgen receptor gene is enhanced in patients with idiopathic azoospermia. Urology 1999; 54: 1078_81.

263 Dowsing AT, Yong EL, Clark M, McLachlan RI, de Kretser DM, Trounson AO. Linkage between male infertility and trinucleotide repeat expansion in the androgen-receptor gene. Lancet 1999; 354: 640_3.

264 Legius E, Vanderschueren D, Spiessens C, D'Hooghe T, Matthijs G. Association between CAG repeat number in the androgen receptor and male infertility in a Belgian study. Clin Genet 1999; 56: 166_7.

265 Dadze S, Wieland C, Jakubiczka S, Funke K, Schroder E, Royer-Pokora B, et al. The size of the CAG repeat in exon 1 of the androgen receptor gene shows no significant relationship to impaired spermatogenesis in an infertile Caucasoid sample of German origin. Mol Hum Reprod 2000; 6: 207_14.

266 Lim HN, Chen H, McBride S, Dunning AM, Nixon RM, Hughes IA, et al. Longer polyglutamine tracts in the androgen receptor are associated with moderate to severe undermasculinized genitalia in XY males. Hum Mol Genet 2000; 9: 829_34.

267 von Eckardstein S, Syska A, Gromoll J, Kamischke A, Simoni M, Nieschlag E. Inverse correlation between sperm concentration and number of androgen receptor CAG repeats in normal men. J Clin Endocrinol Metab 2001; 86: 2585_90.

268 Sasagawa I, Suzuki Y, Ashida J, Nakada T, Muroya K, Ogata T. CAG repeat length analysis and mutation screening of the androgen receptor gene in Japanese men with idiopathic azoospermia. J Androl 2001; 22: 804_8.

269 Van Golde R, Van Houwelingen K, Kiemeney L, Kremer J, Tuerlings J, Schalken J, et al. Is increased CAG repeat length in the androgen receptor gene a risk factor for male subfertility? J Urol 2002; 167: 621_3.

270 Casella R, Maduro MR, Misfud A, Lipshultz LI, Yong EL, Lamb DJ. Androgen receptor gene polyglutamine length is associated with testicular histology in infertile patients. J Urol 2003; 169: 224_7.

271 Asatiani K, von Eckardstein S, Simoni M, Gromoll J, Nieschlag E. CAG repeat length in the androgen receptor gene affects the risk of male infertility. Int J Androl 2003; 26: 255_61.

272 Tse JY, Liu VW, Yeung WS, Lau EY, Ng EH, Ho PC. Molecular analysis of the androgen receptor gene in Hong Kong Chinese infertile men. J Assist Reprod Genet 2003; 20: 227_33.

273 Erasmuson T, Sin IL, Sin FY. Absence of association of androgen receptor trinucleotide expansion and poor semen quality. Int J Androl 2003; 26: 46_51.

274 Hadjkacem L, Hadj-Kacem H, Boulila A, Bahloul A, Ayadi H, Ammar-Keskes L. Androgen receptor gene CAG repeats length in fertile and infertile Tunisian men. Ann Genet 2004; 47: 217_24.

275 Milatiner D, Halle D, Huerta M, Margalioth EJ, Cohen Y, Ben-Chetrit A, et al. Associations between androgen receptor CAG repeat length and sperm morphology. Hum Reprod 2004; 19: 1426_30.

276 Canale D, Caglieresi C, Moschini C, Liberati CD, Macchia E, Pinchera A, et al. Androgen receptor polymorphism (CAG repeats) and androgenicity. Clin Endocrinol 2005; 63: 356_61. Erratum in: Clin Endocrinol 2005; 63: 482.

277 Lavery R, Houghton JA, Nolan A, Glennon M, Egan D, Maher M. CAG repeat length in an infertile male population of Irish origin. Genetica 2005; 123: 295_302.

278 Li ZX, Tang WH, Wang ZH, Wang L, Wang YY, Ma LL, et al. (CAG)n polymorphism of androgen receptor gene in idiopathic azoospermic and oligospermic Chinese men. Zhonghua Nan Ke Xue 2005; 11: 335_8.

279 Tufan AC, Satiroglu-Tufan NL, Aydinuraz B, Satiroglu MH, Aydos K, Bagci H. No association of the CAG repeat length in exon 1 of the androgen receptor gene with idiopathic infertility in Turkish men: implications and literature review. Tohoku J Exp Med 2005; 206: 105_15.

280 Hakimi JM, Schoenberg MP, Rondinelli RH, Piantadosi S, Barrack ER. Androgen receptor variants with short glutamine or glycine repeats may identify unique subpopulations of men with prostate cancer. Clin Cancer Res 1997; 3: 1599_608.

281 Giovannucci E, Stampfer MJ, Chan A, Krithivas K, Gann PH, Hennekens CH, et al. CAG repeat within the androgen receptor gene and incidence of surgery for benign prostatic hyperplasia in U.S. physicians. Prostate 1999; 39: 130_4.

282 Giovannucci E, Platz EA, Stampfer MJ, Chan A, Krithivas K, Kawachi I, et al. The CAG repeat within the androgen receptor gene and benign prostatic hyperplasia. Urology 1999; 53: 121_5.

283 Nam RK, Elhaji Y, Krahn MD, Hakimi J, Ho M, Chu W, et al. Significance of the CAG repeat polymorphism of the androgen receptor gene in prostate cancer progression. J Urol 2000; 164: 567_72.

284 Panz VR, Joffe BI, Spitz I, Lindenberg T, Farkas A, Haffejee M. Tandem CAG repeats of the androgen receptor gene and prostate cancer risk in black and white men. Endocrine 2001; 15: 213_6.

285 Beilin J, Harewood L, Frydenberg M, Mameghan H, Martyres RF, Farish SJ, et al. A case-control study of the androgen receptor gene CAG repeat polymorphism in Australian prostate carcinoma subjects. Cancer 2001; 92: 941_9.

286 Latil AG, Azzouzi R, Cancel GS, Guillaume EC, Cochan-Priollet B, Berthon PL, et al. Prostate carcinoma risk and allelic variants of genes involved in androgen biosynthesis and metabolism pathways. Cancer 2001; 92: 1130_7.

287 Shibata A, Garcia MI, Cheng I, Stamey TA, McNeal JE, Brooks JD, et al. Polymorphisms in the androgen receptor and type II 5 alpha reductase genes and prostate cancer prognosis. Prostate 2002; 52: 269_78.

288 Gsur A, Preyer M, Haidinger G, Zidek T, Madersbacher S, Schatzl G, et al. Polymorphic CAG repeats in the androgen receptor gene, prostate-specific antigen polymorphism and prostate cancer risk. Carcinogenesis 2002; 23: 1647_51.

289 Gilligan T, Manola J, Sartor O, Weinrich SP, Moul JW, Kantoff PW. Absence of a correlation of androgen receptor gene CAG repeat length and prostate cancer risk in an African-American population. Clin Prostate Cancer 2004; 3: 98_103.

290 Platz EA, Leitzmann MF, Rifai N, Kantoff PW, Chen YC, Stampfer MJ, et al. Sex steroid hormones and the androgen receptor gene CAG repeat and subsequent risk of prostate cancer in the prostate-specific antigen era. Cancer Epidemiol Biomarkers Prev 2005; 14: 1262_9.

291 Li AJ, Karlan BY. Androgen mediation of thrombocytosis in epithelial ovarian cancer biology. Clin Cancer Res 2005; 11: 8015_8.

292 Yu H, Bharaj B, Vassilikos EJ, Giai M, Diamandis EP. Shorter CAG repeat length in the androgen receptor gene is associated with more aggressive forms of breast cancer. Breast Cancer Res Treat 2000; 59: 153_61.

293 Elhaji YA, Gottlieb B, Lumbroso R, Beitel LK, Foulkes WD, Pinsky L, et al. The polymorphic CAG repeat of the androgen receptor gene: a potential role in breast cancer in women over 40. Breast Cancer Res Treat 2001; 70: 109_16.

294 Giguere Y, Dewailly E, Brisson J, Ayotte P, Laflamme N, Demers A, et al. Short polyglutamine tracts in the androgen receptor are protective against breast cancer in the general population. Cancer Res 2001; 61: 5869_74.

295 Haiman CA, Brown M, Hankinson SE, Spiegelman D, Colditz GA, Willett WC, et al. The androgen receptor CAG repeat polymorphism and risk of breast cancer in the Nurses' Health Study. Cancer Res 2002; 62: 1045_9.

296 Haiman CA, Hankinson SE, De Vivo I, Guillemette C, Ishibe N, Hunter DJ, et al. Polymorphisms in steroid hormone pathway genes and mammographic density. Breast Cancer Res Treat 2003; 77: 27_36.

297 Liede A, Zhang W, De Leon Matsuda ML, Tan A, Narod SA. Androgen receptor gene polymorphism and breast cancer susceptibility in the Philippines. Cancer Epidemiol Biomarkers Prev 2003; 12: 848_52.

298 Lillie EO, Bernstein L, Ingles SA, Gauderman WJ, Rivas GE, Gagalang V, et al. Polymorphism in the androgen receptor and mammographic density in women taking and not taking estrogen and progestin therapy. Cancer Res 2004; 64: 1237_41.

299 Wang W, John EM, Ingles SA. An

drogen receptor and prostate-specific antigen gene polymorphisms and breast cancer in African-American women. Cancer Epidemiol Biomarkers Prev 2005; 14: 2990_4.