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[Action of androgens and one anti-androgen on the genital ducts of young discoglosses. Early development of seminal vesicles and inhibition of mullerian ducts (author's transl)].

Young Discoglossus pictus Otth (Amphibian, Anura) received either male hormone (testosterone or testosterone propionate) or the anti-steroid anti-androgen cyproterone acetate. The male hormone had a masculinizing effect on the genital tract when observed four months later and, paradoxically, the anti-androgen had the same effect: -- Hypertrophy of the posterior segment of the Wolffian ducts yields seminal vesicles, whose wall is covered with a flat epithelium after androgen treatment. Cyproterone acetate treatment, however, results in the cytological differentiation of this epithelium. -- Müllerian ducts persist in a vestigial form. In this respect, the inhibitory action of cyproterone acetate is stronger than that of the male hormone.

Amphibians↗
PubMed2001

Expression of androgen receptor mRNA in the brain of Gekko gecko: implications for understanding the role of androgens in controlling auditory and vocal processes.

The neuroanatomical distribution of androgen receptor (AR) mRNA-containing cells in the brain of a vocal lizard, Gekko gecko, was mapped using in situ hybridization. Particular attention was given to auditory and vocal nuclei. Within the auditory system, the cochlear nuclei, the central nucleus of the torus semicircularis, the nucleus medialis, and the medial region of the dorsal ventricular ridge contained moderate numbers of labeled neurons. Neurons labeled with the AR probe were located in many nuclei related to vocalization. Within the hindbrain, the mesencephalic nucleus of the trigeminal nerve, the vagal part of the nucleus ambiguus, and the dosal motor nucleus of the vagus nerve contained many neurons that exhibited strong expression of AR mRNA. Neurons located in the peripheral nucleus of the torus in the mesencephalon exhibited moderate levels of hybridization. Intense AR mRNA expression was also observed in neurons within two other areas that may be involved in vocalization, the medial preoptic area and the hypoglossal nucleus. The strongest mRNA signals identified in this study were found in cells of the pallium, hypothalamus, and inferior nucleus of the raphe. The expression patterns of AR mRNA in the auditory and vocal control nuclei of G. gecko suggest that neurons involved in acoustic communication in this species, and perhaps related species, are susceptible to regulation by androgens during the breeding season. The significance of these results for understanding the evolution of reptilian vocal communication is discussed.

Androgens↗
PubMed2007

Differential effects of naturally occurring and synthetic organoselenium compounds on biomarkers in androgen responsive and androgen independent human prostate carcinoma cells.

Epidemiological studies and clinical trials show that selenium supplementation results in reduction of prostate cancer incidence; however, the form of selenium and mechanisms underlying protection remain largely unknown. Toward this end, we compared the effects of naturally occurring selenomethionine (SM) and Se-methylselenocysteine (MSC) and synthetic 1,4-phenylenebis(methylene)selenocyanate (p-XSC) and p-xylylbis(methylselenide) p-XMS) organoselenium compounds in androgen responsive (AR) LNCaP and its androgen independent clone (AI) LNCaP C4-2 human prostate carcinoma cells on cell growth, secretion of prostate specific antigen (PSA), intracellular redox status and genomic profiles with emphasis on identifying redox sensitive genes. Both p-XSC and p-XMS reduced cell number and total protein concentration compared to control-treated AR and AI cells, while SM and MSC exhibited no effect on growth of AR and AI cells. SM, p-XSC and p-XMS but not MSC inhibited levels of secreted PSA in AR cells. SM, MSC and p-XMS increased glutathione (GSH) levels in AI LNCaP cells. By contrast, in both cell types, only p-XSC significantly decreased GSH concentrations to <50% of control suggesting either an increase in intracellular oxidative stress or a change in GSH/GSSG ratio. On the basis of RT-PCR analysis, SM and p-XSC increased p53 gene expression by 2-fold in AR cells but not in AI cells and only SM enhanced epidermal growth factor receptor in AR cells. Depending on the structure, organoselenium compounds exhibit differential effects on growth, PSA secretion, oxidative stress and selective gene responses in human prostate cancer cells and suggest the potential of developing novel organoselenium compounds as chemopreventive agents in models of human prostate cancer.

Androgens↗
PubMed2006

An androgen-independent androgen receptor function protects from inositol hexakisphosphate toxicity in the PC3/PC3(AR) prostate cancer cell lines.

BACKGROUND: Inositol hexakisphosphate (IP6) is a phytochemical exhibiting anticancer activity. Because few prostate cancer (PCa) cell lines have been used to study IP6, we assessed its efficacy in a panel of PCa cell lines. METHODS AND RESULTS: Using WST-1 assays we observed that, although androgens did not modulate its efficacy, IP6 was more active in androgen receptor (AR) negative cells than in AR-positive cells. Stable expression of the AR in PC3 cells (PC3(AR)) decreased the response to IP6, which was reversed by an AR-targeting siRNA. Furthermore, AR expression in PC3 cells resulted in significantly reduced caspase-3 activation (P < 0.001) and DNA fragmentation (P < 0.05) in response to IP6. Similarly, although treatment with IP6 caused the upregulation of NF-kappaB-responsive (IkappaB-alpha, IRF-2) and p53/E2F-responsive genes (Puma, Noxa) in PC3 cells, this increase was reduced in PC3AR cells (P < 0.01). CONCLUSION: We conclude that resistance to IP6 can be linked to a ligand-independent AR function.

Androgens↗
PubMed1996

Regulation of growth, PSA/PAP and androgen receptor expression by 1 alpha,25-dihydroxyvitamin D3 in the androgen-dependent LNCaP cells.

The involvement of vitamin D in prostate carcinogenesis was investigated using the human prostatic LNCaP cells. Incubation of the LNCaP with 100 nM 1 alpha,25-dihydroxyvitamin D3 for 2 days resulted in a 30-40% suppression of cell growth, which was accompanied by a greater than 70% down-regulated expression of the proliferating cell nuclear antigen (PCNA). The intracellular and secreted forms of PSA showed a 2-fold increase following a 48 h culture in the presence of vitamin D3. The vitamin D3-elicited PSA increases were preceded by an induction of androgen receptor (AR) expression, as measured by Western blot analysis and by binding assays using [3H]R1881 as the ligand. These results are consistent with the hypothesis that the growth inhibitory effects of vitamin D3 is partially mediated through its ability to modulate PCNA expression. Moreover, vitamin D3 may effect increases in PSA expression indirectly by up-regulating androgen receptors.

Acid Phosphatase↗
PubMed1999

Inhibition of histone deacetylation augments dihydrotestosterone induction of androgen receptor levels: an explanation for trichostatin A effects on androgen-induced chromatin remodeling and transcription of the mouse mammary tumor virus promoter.

The integrated mouse mammary tumor virus (MMTV) promoter has provided an excellent model system with which to study the impact of steroid hormones on transcriptional activation in the context of a defined chromatin structure. The hormone response element (HRE) of this promoter is positioned on a phased nucleosome which becomes remodeled in response to steroids. One possible mechanism of chromatin remodeling by steroid receptors could involve recruitment of coactivators which alter the histone acetylation status of the HRE nucleosome. To examine how the androgen receptor (AR) influences transcription and chromatin remodeling and to assess whether changes in histone acetylation are involved in these effects, we determined whether the specific histone deacetylase inhibitor trichostatin A (TSA) influenced basal- and androgen-mediated transcriptional activation of the integrated MMTV promoter in the mouse L-cell fibroblast cell line 29+. These cells harbor the MMTV promoter integrated in the genome and express only one steroid hormone receptor subtype, i.e., the AR. Surprisingly, we found that treatment of the cells with TSA alone had virtually no effect on transcription and chromatin remodeling of the MMTV promoter nor on AR levels. However, pretreatment with TSA augmented the DHT effects on all three parameters. These results suggest that histone acetylation changes at the MMTV B nucleosome per se are not alone sufficient to induce chromatin remodeling and subsequent induction of MMTV transcription. Rather, the histone deacetylase inhibitor TSA exerts a portion of its effect on MMTV chromatin remodeling and transcriptional activation indirectly through increases in AR levels.

Acetylation↗
PubMed1992

Point mutation in the steroid-binding domain of the androgen receptor gene in a family with complete androgen insensitivity syndrome (CAIS).

An exonic single nucleotide substitution in the human androgen receptor gene (hAR) could be detected in an Italian family with two children affected by complete androgen insensitivity syndrome (CAIS), also called testicular feminization. This mutation leads to a guanine to adenine transition in exon 5, changing the sense of the codon from methionine (ATG) to valine (GTG). As this mutation abolishes a NcoI restriction site, a rapid test for the mutation can be performed by digestion of the polymerase chain reaction products with this enzyme. Previous results of indirect gene diagnosis in this family could be confirmed by this method.

Amino Acid Sequence↗
PubMed2004

Mutation of the androgen receptor (R840S) in an Egyptian patient with partial androgen insensitivity syndrome: review of the literature on the clinical expression of different R840 substitutions.

The X-linked androgen insensitivity syndrome (AIS) encompasses a heterogeneous group of defects in the androgen receptor (AR) that result in varying degrees of undermasculinization. In the current study, we characterize the R840S mutation on exon 7 of the AR ligand-binding domain. The Egyptian patient, who had been reared as female, presented ambiguous genitalia at 6.5 yr. Diagnosis of partial AIS (PAIS) was based on clinical phenotype and laboratory evidence of good testosterone response and normal testosterone/dihydrotestosterone (T/DHT) ratio. The therapeutic response to testosterone depot injections justified reassignment to male sex. To our knowledge, this mutation has been reported only once in two Brazilian brothers with PAIS. Three other mutations of this residue (R840C; R840G, nonconservative; and R840H, conservative) have been reported in patients with PAIS and, when expressed in vitro, they led to subnormal transactivation of a reporter gene. Each of these mutations was associated with a very diverse spectrum of phenotypes. These data highlight the role of the AR ligand-binding pocket (LBP) in the expression of transcriptional activity during prenatal sex differentiation.

Amino Acid Substitution↗
PubMed2003

Identification of a mutant allele of the androgen receptor gene in a family with androgen insensitivity syndrome: detection of carriers and prenatal diagnosis.

We report the results of a molecular study of a large family segregating the complete form of the Androgen Insensitivity Syndrome (CAIS) in several members from three generations. We identified the mutant allele by Polymerase Chain Reaction (PCR) amplification of the short tandem repeat (CAG)n, highly polymorphic in the population, present in the first exon of the androgen receptor (AR) gene. In this family four different alleles were detected and one of these showed a perfect segregation with the disease. This study enabled us to identify the heterozygous females in this family. We think that this simple, indirect test, is also suitable for prenatal diagnosis of Morris' syndrome when the mother is heterozygous for the size of the short tandem repeat and one affected subject in the family may be studied.

Adolescent↗
PubMed2003

Identification of a mutant allele of the androgen receptor gene in a family with androgen insensitivity syndrome: detection of carriers and prenatal diagnosis.

We report the results of a molecular study of a large family segregating the complete form of the Androgen Insensitivity Syndrome (CAIS) in several family members from three generations. We identified the mutant allele by polymerase chain reaction (PCR) amplification of the short tandem repeat (CAG)n, highly polymorphic in the population, present in the first exon of the androgen receptor (AR) gene. In this family four different alleles were detected and one of these showed a perfect segregation with the disease. This study enabled us to identify the heterozygous females in this family. We think that this simple, indirect test, is also suitable for prenatal diagnosis of Morris' syndrome when the mother is heterozygous for the size of the short tandem repeat and one affected subject in the family may be studied.

Adolescent↗
PubMed2000

Androgen receptor gene mutation identified by PCR-SSCP and sequencing in 4 patients with complete androgen insensitivity syndrome.

To study the genetic defect of the human androgen receptor (hAR) gene in the complete androgen insensitivity syndrome (CAIS), we amplified each of the eight exons by PCR in genomic DNA extracted from the paraffin blocks of the resected gonads. We analyzed using SSCP, and directly sequenced the abnormally shifted bands. Mutations were found in 4 cases of CAIS. Patient 1 carried a point mutation; a G to A transition in exon 7 resulted in a change from arginine to glutamine at codon 831. Patient 2 carried a point mutation; a C to T transition in exon 7 resulted in a change from arginine to stop at codon 831. Patient 3 carried a point mutation and deletion in exon 7. A point mutation was an A to G transition that caused a glutamine to be substituted for the asparagine present at codon 819. A deletion of a G at codon 820 resulted in a frameshift and consequently in the introduction of a premature stop at codon 821. Patient 4 carried a mutation in 5' splice donor site of intron 7; a G to T transition might have caused an abnormal splicing of the exon 7. All of the mutations were found in exon 7. These mutations of hAR gene might be related to the pathogenesis of CAIS.

Adolescent↗
PubMed1997

Functional assessment and clinical classification of androgen sensitivity in patients with mutations of the androgen receptor gene. German Collaborative Intersex Study Group.

UNLABELLED: In the genetic male, mutations of the androgen receptor (AR) gene cause phenotypes ranging from female to subfertile male. Binding assays on genital skin fibroblasts and DNA analysis alone provide incomplete information about receptor function. We used the sex hormone-binding globulin (SHBG) response to stanozolol as a measure of AR function and correlated the results with phenotypes which were classified according to the degree of defective masculinization. Of the 34 patients investigated, 9 had complete, and 14 had partial androgen insensitivity syndrome (AIS) with predominantly female, ambiguous, or predominantly male phenotype. Eleven subjects served as controls. Mutations were characterized using polymerase chain reaction-single strand conformation polymorphism analysis and direct DNA sequencing. DNA analysis revealed two major deletions, two minor defects leading to premature stop codons in exon 1, and 19 point mutations in the DNA- and hormone-binding domains of the AR gene. After stanozolol, SHBG remained unchanged in patients with complete AIS (102.0 +/- 3.8 [SE]%; range 92.4%-129% of the initial value). The SHBG decrease was diminished in partial AIS with predominantly female (83.8% +/- 1.7%; range 81.3%-87.0%), ambiguous (80.4% +/- 4.4%, range 68.4%-89.1%), and predominantly male (mean 65.9% +/- 4.9%, range 48.6%-80.8%) phenotypes, and normal in controls (51.4% +/- 2.1%, range 35.6%-62.1%). Differences between controls and each AIS group were statistically significant (P < 0.05 - < 0.0001). A close correlation was found between the degree of undermasculinization (AIS phenotype) and the SHBG response. CONCLUSIONS: The SHBG test provides functional information about the severity of the receptor defect in vivo and hence adds to the structural information provided by DNA analysis. It detects receptor defects due to mutations within the entire gene, including the DNA-binding domain, and is a rapid, simple, and cost effective procedure. It may provide useful information for the diagnosis and management of affected children.

Adolescent↗
PubMed2001

Eight novel mutations of the androgen receptor gene in patients with androgen insensitivity syndrome.

Androgen insensitivity syndrome (AIS) is an X-linked genetic disorder of male sexual differentiation caused by mutations in the androgen receptor (AR) gene. A reliable genotype-phenotype correlation in these patients does not exist as yet. Here we report the molecular studies performed on eight individuals with AIS. Exon-specific polymerase chain reaction (PCR), single-strand conformation polymorphism, and sequencing analyses, were performed in exons 2 to 8 of the AR gene. In one case, total cellular RNA was extracted from genital skin fibroblasts and reverse transcriptase-PCR was performed. Six different point mutations leading to amino acid substitutions (P682T, Q711E, G743E, F827V, H874R, D879Y), one splice-junction mutation (g-->c at +5, exon 6/intron 6), and a missense mutation without amino acid substitution (S888S) were identified. All mutations, including a de novo mutation, were previously undescribed on the steroid binding domain. Of the eight mutations identified, four led to a complete female phenotype (codons 743, 827, 874 and the donor splice site +5), two were detected in phenotypic females with partial virilization (codons 682 and 711), and two were present in phenotypic male subjects with undervirilized external genitalia, thus indicating that all of these sites determine AR functional activity.

Adolescent↗
PubMed1982

The effects of histamine H2 receptor antagonists on androgen action in vivo and dihydrotestosterone binding to the rat prostate androgen receptor in vitro.

Several histamine H2 receptor antagonists have been tested for antiandrogenic activity by determining their effects on accessory sex organ weights in castrate testosterone propionate (TP) treated rats and on [3H] dihydrotestosterone (DHT) binding to the androgen receptor of the rat ventral prostate in vitro. When given in high doses cimetidine and metiamide possessed antiandrogenic activity whereas the other H2 receptor antagonists SK&F 92456, SK&F 92994, SK&F 92629 amd SK&F 93479 did not Cimetidine, metiamide and SK&F 92456 inhibited (3H] DHT binding to rat ventral prostate androgen receptor in vitro whereas SK&F 92629 and SK&F 93479 did not. SK&F 92994 affects DHT binding only slightly. Of the compounds that are similar to cimetidine in their potency as H2 receptor antagonists only metiamide was antiandrogenic. However SK&F 92994 and SK&F 93479 are not antiandrogenic despite being more potent than cimetidine as H2 antagonists. It is concluded that the antiandrogenicity of cimetidine and metiamide was not related to their activity as histamine H2 receptor antagonists.

Androgen Antagonists↗
PubMed1982

Defective activation of androgen-receptor complexes: a marker of androgen insensitivity.

Partially-purified 5 alpha-dihydrotestosterone-receptor (DHT-R) complexes, extracted from normal genital skin fibrolasts (GSF) previously labelled with [3H]DHT, dissociate with monophasic kinetics and dissociation rate constants (k-2) of 10, 6, 3 and 2 x 10(-3) min-1 at 40, 37, 32 and 29 degrees C, respectively. An Arrhenius plot yields an activation energy of 28 kcal/mole. We studied 2 subjects who have constitutional androgen insensitivity (AI) despite a normal level of specific DHT-R activity in their GSF. Subject 1 has complete AI and unambiguous female external genitalia; subject 2 has partial AI and had ambiguous external genitalia at birth. In contrast to normal, the DHT-R complexes extracted from the GSF of these 2 subjects dissociate with biphasic kinetics. At 37 degrees C the k-1 of their early ('fast') component is 21 +/- 0.4(+/-SEM) x 10(-3) min-1(n = 7), while that of their late ('slow') component (k-2) is 7.8 +/- 0.3 x 10(-3) min-1 (n = 7). The latter value is very similar to the single k-2 (6.1 +/- 0.1 x 10(-3) min-1, n = 9) of the DHT-R complexes extracted from normal fibroblasts. When dissociation of DHT-R complexes is studied with intact fibroblasts, monophasic kinetics are observed for both the normal and mutant subjects. A k-1 of 18 x 10(-3) min-1 was previously observed for both mutant subjects at 37 degrees C (normal: K-2, 5.9 +/- 0.3 x 10(-3) min-1, n = 15). At 40 degrees C subject 1 has a rate constant of 25 while that of subject 2 is 50 x 10(-3) min-1(normal: 10 x 10(-3) min-1). An Arrhenius plot of the results from subject 1 yields an activation energy of 18 kcal/mole. The 2 sets of data suggest that inability of DHT-R complexes to transform from a rapidly dissociating to a slowly-dissociating form within intact target cells is a marker of genetic mutations that alter the androgen receptor and thereby cause certain types of partial of complete AI.

Androgen-Insensitivity Syndrome↗
PubMed1982

The role of androgen metabolism in the control of androgen action in the rat prostate.

Recent results from a number of laboratories have led us to re-examine the role of 3 beta-androstanediol in the rat ventral prostate. Whereas previously 5 alpha-dihydrotestosterone and 3-beta androstanediol were thought to have distinctly separate effects on the prostate, we suggest that 3 beta-androstanediol serves only as an intermediate in the metabolism and removal of 5 alpha-dihydrotestosterone from the organ. In our view the action of androgens on the prostate are exerted exclusively through the binding of 5 alpha-dihydrotestosterone to the androgen receptor and its subsequent translocation to the nucleus. Differences in effects are related to the amount of 5 alpha-dihydrotestosterone available to the gland. 3 alpha-Hydroxysteroid dehydrogenase may play a critical role in modulating the level of 5 alpha-dihydrotestosterone available to the translocatable receptor.

3-Hydroxysteroid Dehydrogenases↗
PubMed1987

Androgen receptor-binding regions of an androgen-responsive gene.

The interaction of 5 alpha-dihydrotestosterone-receptor complexes with purified DNA fragments representing upstream, coding and intervening sequences of the prostate binding protein C3(1) gene was investigated using a DNA-cellulose competition binding assay. The partially purified androgen-receptor complexes which were used in the assay had proven DNA-binding capabilities. Two fragments were identified with relatively high affinity for androgen-receptor complexes. A 300 bp fragment extending from -220 to +80 and a 500 bp fragment derived entirely from the first intron consistently competed most effectively in the system. The presence of a high affinity site or sites in or near the promoter region of the gene is consistent with current models of transcriptional activation of hormone-responsive genes by steroid receptors. High affinity sites for steroid receptors within introns may indicate a role for receptors in regulation of transcription at other stages, or in post-transcriptional modification.

Androgens↗
PubMed1994

Nuclear extracts enhance the interaction of fusion proteins containing the DNA-binding domain of the androgen and glucocorticoid receptor with androgen and glucocorticoid response elements.

Comparable fragments of the androgen receptor (AR) (amino acids 540-607) and of the glucocorticoid receptor (GR) (amino acids 412-515) were expressed in E. coli as fusion proteins with protein A. Both fusion proteins, denoted ARF1 and GRF1, contain the DNA-binding domain and some flanking amino acids. In vitro binding assays have shown that both fusion proteins interact with androgen/glucocorticoid response elements (ARE/GREs) in an intron fragment of the C3(1) gene of the androgen-regulated rat prostatic binding protein and in the typically glucocorticoid-responsive long terminal repeat (LTR) promoter of mouse mammary tumour virus. Present results indicate that the interaction of both ARF1 and GRF1 with the C3(1) as well as the LTR fragments is enhanced in the presence of nuclear extract. The factor that gives rise to this enhancement appears to be ubiquitous and sensitive to trypsin and temperature treatment. In the C3(1) fragment, the enhancing effect requires the presence of an intact functional ARE/GRE (Core II) as well as a region spanning the ARE/GRE half-site Core I.

Androgens↗