Androgen Receptor Defects: Historical, Clinical, and Molecular Perspectives*

Quigley, Charmian A.; Bellis, Alessandra De; Marschke, Keith B.; El-Awady, Mostafa K.; Wilson, Elizabeth M.; French, Frank S.

doi:10.1210/edrv-16-3-271

Cited by 866 publications

(892 citation statements)

References 262 publications

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“…After ligand binding, heat-shock proteins dissociate from the receptor, and then the AR translocates to the nucleus [3], where it regulates transcription by binding to specific androgen response elements in promoters of target genes. Together with co-regulatory proteins and general transcription factors, a stable transcription initiation complex is formed [4][5][6]. An important feature of ligand binding is that it induces a conformational change in the AR LBD (ligand-binding domain), providing a surface for interactions with co-regulatory proteins.…”

Section: Introductionmentioning

confidence: 99%

Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)

Berrevoets

Umar

Trapman

et al. 2004

Biochemical Journal

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Antiandrogens are widely used agents in the treatment of prostate cancer, as inhibitors of AR (androgen receptor) action. Although the precise mechanism of antiandrogen action is not yet elucidated, recent studies indicate the involvement of nuclear receptor co-repressors. In the present study, the regulation of AR transcriptional activity by N-CoR (nuclear receptor co-repressor), in the presence of different ligands, has been investigated. Increasing levels of N-CoR differentially affected the transcriptional activity of AR occupied with either agonistic or antagonistic ligands. Small amounts of co-transfected N-CoR repressed CPA (cyproterone acetate)-and mifepristone (RU486)-mediated AR activity, but did not affect agonist (R1881)-induced AR activity. Larger amounts of co-transfected N-CoR repressed AR activity for all ligands, and converted the partial agonists CPA and RU486 into strong AR antagonists. In the presence of the agonist R1881, co-expression of the p160 co-activator TIF2 (transcriptional intermediary factor 2) relieved N-CoR repression up to control levels. However, in the presence of RU486 and CPA, TIF2 did not functionally compete with N-CoR, suggesting that antagonistbound AR has a preference for N-CoR. The AR mutation T877A (Thr 877 → Ala), which is frequently found in prostate cancer and affects the ligand-induced conformational change of the AR, considerably reduced the repressive action of NCoR. The agonistic activities of CPA-and hydroxyflutamideoccupied T877A-AR were hardly affected by N-CoR, whereas TIF2 strongly enhanced their activities. These results indicate that lack of N-CoR action allows these antiandrogens to act as strong agonists on the mutant AR.

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Section: Introductionmentioning

confidence: 99%

Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)

Berrevoets

Umar

Trapman

et al. 2004

Biochemical Journal

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“…It has a major influence on the wellbeing and psychological status of patients, therefore improved diagnosis and development of treatment strategies is essential [6,16,23]. In the past years, research interest has been focused on the association studies between different genetic polymorphisms and recurrent spontaneous abortion.Androgens are lipophilic hormones with several physiological effects in both sexes [17]. Androgen signaling in female is very important for the differentiation of human endometrial stromal cells into decidual cell; a process is called decidualization that critically controls embryo implantation and placentation [11].…”

mentioning

confidence: 99%

“…Androgens are lipophilic hormones with several physiological effects in both sexes [17]. Androgen signaling in female is very important for the differentiation of human endometrial stromal cells into decidual cell; a process is called decidualization that critically controls embryo implantation and placentation [11].…”

mentioning

confidence: 99%

StuI polymorphism on the androgen receptor gene is associated with recurrent spontaneous abortion

Jahaninejad

Ghasemi

Kalantar

et al. 2013

J Assist Reprod Genet

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Purpose This is a case-control study to determine whether G1733A polymorphism of androgen receptor gene is associated with an increased risk for recurrent spontaneous abortion (RSA). Method A total of 85 women with at least two recurrent spontaneous abortion before 20th week of gestation composed the study group. Subjects were genotyped by the polymerase chain reaction restriction fragment length polymorphism method. Results The observed frequencies of GG, GA and AA genotypes of the G1733A polymorphism were 5.89 %, 82.35 % and 11.76 %, respectively, for the patient group and 71.76 %, 23.51 % and 4.71 %, respectively, for the control group. Allele frequencies of the G1733A polymorphism among patients and controls were 0.47 and 0.84, respectively, for the dominant allele (G) (wild type) and 0.53 and 0.16, respectively, for the A allele (mutant type). Conclusions These results indicated that the androgen receptor G1733A polymorphism is strongly associated with increased risk for RSA.Keywords Recurrent spontaneous abortion . Androgen receptor . Polymorphism . RFLP PCR Recurrent spontaneous abortion (RSA) is a reproductive problem that occurs in women in reproductive age with a frequency of 1 %-3 % [20]. It is defined as two or more repeated pregnancy losses before the 20th week of gestation [14]. The risk of miscarriage is enhanced by a variety of factors including chromosomal abnormalities, uterine abnormalities, hereditary thrombophilia, endocrinologic disorders,-immunologic factors, infections, and nutritional and environmental factors [18,19]. In women with a history of recurrent miscarriage, the risk of miscarriage in a subsequent pregnancy is about 40 % to 50 %. It has a major influence on the wellbeing and psychological status of patients, therefore improved diagnosis and development of treatment strategies is essential [6,16,23]. In the past years, research interest has been focused on the association studies between different genetic polymorphisms and recurrent spontaneous abortion.Androgens are lipophilic hormones with several physiological effects in both sexes [17]. Androgen signaling in female is very important for the differentiation of human endometrial stromal cells into decidual cell; a process is called decidualization that critically controls embryo implantation and placentation [11]. The effect of androgens such as testosterone and dihydrotestosterone mediated by androgen receptor (AR) that is a nuclear receptor [3]. Androgen receptor is widely expressed in female reproductive tissue such as endometrium [1] and binds to a steroid ligand and then is transferred into the nucleus, where it regulates the transcription of androgen-responsive genes [5]. The AR gene is located on the X chromosome between q11 and q12 loci and is composed of eight exons [2] that encode a 110-kd protein that contains an N-terminal transactivation domain, Capsule Our results indicated that the androgen receptor G1733A polymorphism is strongly associated with increased risk for RSA.T. Jahaninejad (*) :

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“…During fetal life, the failure of testicular development, problems of secretion of androgens or their detection by defective androgen receptors can lead to a variety of abnormalities of the male external genitalia. In some genetic males, androgen insensitivity resulting from mutations of the androgen receptor gene can result in external genitalia that cannot be distinguished from normal females [31].…”

Section: Andrological Disordersmentioning

confidence: 99%

Determinants of male health: the interaction of biological and social factors

Kretser¹

2010

Asian J Androl

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This review discusses the social and biological factors that may influence male development from conception to adulthood and also underlie the development of health disorders. It will provide assistance to those who may be considering the formulation of a male health policy. It aims to emphasize that social determinants function on a biological background that is profoundly influenced by a male's genome, inherited from his parents. The importance of the male-specific reproductive disorders is emphasized, but these also affect somatic structures through the secretion of androgens secreted from the testes. In turn, the function of the cardiovascular and nervous systems can significantly influence reproductive processes such as erectile dysfunction.

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Androgen Receptor Defects: Historical, Clinical, and Molecular Perspectives*

Cited by 866 publications

References 262 publications

Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)

Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR)

StuI polymorphism on the androgen receptor gene is associated with recurrent spontaneous abortion

Determinants of male health: the interaction of biological and social factors

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