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PubMed1984

Androgen-binding proteins in sheep epididymis: characterization of a cytoplasmic androgen receptor in the ram epididymis.

An androgen receptor (Rc) was demonstrated in caput, corpus and cauda epididymal cytosols of the ram. This receptor had a high affinity for 5 alpha-dihydrotestosterone (Kd = 5.2 X 10(-9) mol/l) and could be distinguished from the androgen-binding protein (ABP) by several characteristics. On polyacrylamide-gel electrophoresis, Rc had a mobility of 0.37 and ABP 0.61; Rc sedimented in the 9S region of a linear sucrose gradient whereas ABP migrated in the 4.3S region; the molecular weights were 192 000 and 90 000 for Rc and ABP; their isoelectric points were 5.7 and 4.8-5.0; they were proteinaceous components since they were destroyed by proteolytic enzymes and heating (50 degrees C for Rc and 60 degrees C for ABP); they exhibited different half-times of dissociation:20 h at 0 degree C for Rc and 6 min for ABP, which is in agreement with their respective physiological roles, intra- and extracellular transport of androgens. The content of Rc-binding sites in caput epididymis was 18, in corpus 4 and in cauda 22 fmol/mg protein.

Androgen-Binding Protein↗
PubMed2002

Transition C2718T in the AR gene, resulting in generation of a termination codon and truncated form of the androgen receptor, causes complete androgen insensitivity syndrome.

The action of testosterone and 5 alpha-dihydrotestosterone are essential to the development of the male phenotype. Patients with karyotype 46,XY, resistant to these hormones, exhibit a wide spectrum of phenotypes: from phenotypic female, through a range of incomplete masculinization, to under-virilized, infertile man. These disturbances are caused by mutations in the androgen receptor gene (AR). We studied a 46,XY fenotypic female with typical symptoms of Complete Androgen Insensitivity Syndrome (CAIS). Multiple temperature single-stranded conformation polymorphism (MSSCP) and sequence analysis of exon 6 of the AR gene in a patient revealed a C2718T transition causing R786X mutation in the loop between helices VII and VIII of the LBD of the androgen receptor. The R786X mutation has been described in a patient with CAIS only once and no such mutations have been described in Eastern Europe.

Androgens↗
PubMed2003

Interruption of nuclear factor kappaB signaling by the androgen receptor facilitates 12-O-tetradecanoylphorbolacetate-induced apoptosis in androgen-sensitive prostate cancer LNCaP cells.

12-O-tetradecanoylphorbolacetate (TPA) influences proliferation, differentiation, and apoptosis in a variety of cells including prostate cancer cells. Here, we show that androgen treatment potentiates TPA-induced apoptosis in androgen-sensitive prostate cancer LNCaP cells but not in androgen-independent prostate cancer cell lines DU145 and PC-3. The use of the antiandrogen bicalutamide (Casodex) rescued LNCaP cells from 5-alpha-dihydrotestosterone (DHT)/TPA-induced apoptosis, suggesting that DHT/TPA-induced apoptosis is mediated by androgen/androgen receptor (AR). In addition, a caspase-3 inhibitor (Ac-DEVD-CHO) reduced the level of apoptosis, suggesting that DHT/TPA-mediated apoptosis occurs through a caspase-3-dependent pathway. A functional reporter assay using nuclear factor (NF) kappaB-luciferase and an electromobility gel shift assay showed that DHT suppressed NFkappaB activity. In addition, apoptosis mediated by combined DHT/TPA treatment was abrogated by overexpression of the NFkappaB subunit p65 in LNCaP-p65 cells, suggesting that NFkappaB may play an important role in regulating the effects of androgen/AR and TPA on apoptosis. Furthermore, use of the c-Jun N-terminal kinase (JNK) inhibitor SB202190 showed that the combination of DHT/TPA increased JNK activation in LNCaP cells but not in LNCaP-p65 cells, demonstrating that NFkappaB may be able to suppress JNK activity. These results indicate that androgen/AR facilitates TPA-induced apoptosis by interruption of the NFkappaB signaling pathway, leading to activation of JNK in LNCaP cells. These data describe a signaling pathway that could potentially be useful in proposed therapeutic treatment strategies exploiting combinations of different agents that control apoptosis in prostate tumors.

Androgens↗
PubMedDate not supplied

Partial androgen insensitivity syndrome with R840H mutation in androgen receptor: report of one case.

Androgen insensitivity syndrome (AIS) is the major cause of male pseudohermaphroditism. The severity of the disorders varies widely, ranging from the phenotypic women with female external genitalia in cases of complete AIS to the phenotype of ambiguous genitalia in partial androgen insensitivity syndrome (PAIS) and a rare group of phenotypic normal males with azoospermia. Here, we report an infant of PAIS with a missense mutation at position 2881 (G-->A) in exon 7, encoding substitution of histidine for arginine at codon 840 of the androgen receptor (AR) gene. Both the biochemical and molecular studies are presented. Establishing the diagnosis of PAIS is very important for gender assignment to an infant of ambiguous genitalia. The molecular analysis will facilitate genetic counselling to the maternal side relatives for carrier detection and prenatal diagnosis.

Androgen-Insensitivity Syndrome↗
PubMed1991

[Expression of androgen receptor gene in normal subjects and patients with complete androgen insensitivity].

The Androgen Receptor (AR) mRNA was studied in cultured cells from normal subjects and 10 patients with Complete (CAI, 9 patients, 5: R-, 4: R+) or Partial (PAI, 1 patient) Androgen Insensitivity. The probe was a 3,4 cDNA coding for the entire AR. AR mRNA appears as a 10 kb band. It is strongly expressed in genital skin fibroblasts, 50 to 100 times less in non genital skin. In genital skin fibroblasts, a 3 to 5 fold increase is observed after 1 h of treatment of the cultures with dihydrotestosterone (DHT, 5 nM) whereas a 22 fold decrease is observed after 24 h. A 3 fold increase is also observed after 1 h of treatment with progesterone (50 nM) or cyproterone acetate (500 nM) which does not seem to act as an antiandrogen in this model. The 10 kb band was present in all 10 A1 patients studied, though expressed at a much lower level. It is therefore possible that an abnormal regulation of the AR gene expression is involved in the mechanism of Androgen Insensitivity.

Androgens↗
PubMed1990

An exonic point mutation of the androgen receptor gene in a family with complete androgen insensitivity.

We have discovered in the X-linked androgen receptor gene a single exonic nucleotide substitution that causes complete androgen insensitivity (resistance) in a sibship with three affected individuals. The mutation, a guanine-to-adenine transition, occurs at nucleotide number 2682 and changes the sense of codon 717 from tryptophan to a translation stop signal. Codon 717 is in exon 4, so the mutation predicts the synthesis of a truncated receptor that lacks most of its androgen-binding domain. The substitution abolishes a recognition sequence for the restriction endonuclease HaeIII. Amplification of exon 4 by the polymerase chain reaction followed by double digestion with HinfI and HaeIII permits facile recognition of hemizygotes and heterozygous carriers of the mutation.

Amino Acid Sequence↗
PubMed1989

[Increased androgen-binding capacity and decreased free androgen index in male alcoholics with liver disease].

Androgen binding capacity in the serum of 30 male patients under 51 years of age suffering from chronic alcoholic liver disease was investigated with tritiated 5 alpha-dihydrotestosterone. The result received by saturation analysis is regarded as an indicator of the SHBG (sex hormone binding globulin) content of the blood. Testosterone was measured simultaneously and the free androgen index (FAI) was calculated. The diagnosis of liver disease was based on case histories, physical symptoms and laboratory abnormalities, in some cases on liver biopsy too. Age-matched control group consisted of 18 healthy males. The results showed markedly elevated androgen binding capacities (SHBG contents), testosterone values in the normal range and significantly decreased FAI, indicating insufficient amounts of biologically active testosterone.

Androgen-Binding Protein↗
PubMed1993

Estrogen and androgen receptors in aorta of the rabbit and regulation by estrogen and androgen.

This study was designed to investigate the sexual and/or regional dimorphism of the effects of estrogens and androgens on the aorta. Estrogen, estradiol-17 beta (E2) and estriol (E3), or androgen, dihydrotestosterone (DHT) and testosterone (T), binding levels, and of effects of E2 and T on their levels were determined in aortas of the male and female rabbits. Priming with E2 affected estrogen binding levels of the male aorta, but the physiological condition with E2 plus T induced the levels of E2 and E3 receptors in the female aorta. DHT receptor level in the male was increased with E2 alone or with T, while a rise in T binding level was seen in the male and female primed with E2 and T. These findings suggest that there is a sexual and/or regional dimorphism in the actions of estrogen and androgen on their receptor synthesis in the aorta.

Androgens↗
PubMed2004

Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen-independent status.

BACKGROUND: Coactivator-associated arginine methyltransferase 1 (CARM1) is a transcriptional coactivator of the androgen receptor (AR). It is involved in the regulation of the biologic functions of the AR. It remains to be determined whether CARM1 is involved in prostatic carcinogenesis. METHODS: The expression of CARM1 in normal prostate epithelium, high-grade prostatic intraepithelial neoplasia (PIN), and prostate carcinoma tissue was examined in 66 previously untreated patients with prostate carcinomas, as well as 12 patients with hormone-independent prostate carcinoma, using immunohistochemical methods. RESULTS: Cell staining was observed in the cytoplasm and the nucleus. In 66 patients without previous hormonal treatment, the percentage of cells that stained positively for CARM1 in benign prostate tissue specimens (mean values: cytoplasm, 23%; nucleus, 16%) was statistically significantly less than the percentage of positively stained cells in PIN (mean values: cytoplasm, 56%; nucleus, 30%; P < 0.001) and in prostatic adenocarcinoma specimens (mean values: cytoplasm, 79%; nucleus, 53%; P < 0.001). The difference between adenocarcinoma and PIN also was statistically significant (P < 0.001). The staining intensity for CARM1 was significantly lower in benign prostate tissue specimens compared with PIN and prostatic adenocarcinoma specimens (P < 0.001). In the 12 patients with androgen-independent prostatic adenocarcinoma, the expression of CARM1 was significantly increased when compared with patients without previous hormonal treatment. Expression of CARM1 was not correlated with age, Gleason score sum, pathologic stage, lymph node metastasis, extraprostatic extension, surgical margin status, vascular invasion, or perineural invasion. CONCLUSIONS: The authors found that overexpression of CARM1 was involved in the development of prostate carcinoma as well as androgen-independent prostate carcinoma. Since CARM1 is functionally different from most other transcriptional coactivators of the AR, it may serve as a new target for the treatment of hormone-independent prostate carcinoma.

Adenocarcinoma↗
PubMed1998

Autoregulation of estrogen and androgen receptor mRNAs and downregulation of androgen receptor mRNA by estrogen in primary cultures of lizard testis cells.

Steroid hormones regulate many developmental and physiological processes via specific receptors whose number can be up- or downregulated. The regulation of estrogen (ER) and androgen (AR) receptor mRNAs in primary cultures of lizard testis is described. The high degree of homology between the probes used and the receptor mRNAs in lizard testis was consistent with the high-stringency hybridisation conditions and the molecular size of ER mRNAs (7.4 and 4.5 kb) and AR mRNA (9.5 kb). Primary cultures of testis cells revealed a time- and drug-dependent relationship between ER and AR mRNAs. 17beta-oestradiol (E) autoregulated ER mRNA and downregulated AR mRNA. The antiestrogen ICI 164,384 reversed the latter effect. Cycloheximide (Cy), to inhibit protein synthesis, in combination with E, impaired the AR mRNA expression. Testosterone (T) autoregulated the expression of its own receptor mRNA whereas this effect was reversed by both flutamide (F) and Cy. Dose-response experiments showed that low concentrations of steroids (E or T 10(-12) M) increased ER or AR mRNA levels, respectively. These results suggest that both estrogen and androgen may autoregulate the expression of their own receptor mRNAs. Since in lizard testis androgens are significantly involved in meiosis and spermiogenesis and E dramatically impairs the AR mRNA expression, the latter effect may be key in regulating certain phases of reproduction.

Animals↗
PubMed2000

The expression of androgen receptors in human neck and limb muscles: effects of training and self-administration of androgenic-anabolic steroids.

The purpose of this study was to investigate the immunohistochemical expression of androgen receptors (AR) in human vastus lateralis and trapezius muscles and to determine whether long-term strength training and self-administration of androgenic-anabolic steroids are accompanied by changes in AR content. Biopsy samples were taken from eight high-level power-lifters (P), nine high-level power-lifters who used anabolic steroids (PAS) and six untrained subjects (U). Myonuclei and AR were visualised in cross-sections stained with the monoclonal antibody against AR and 4',6-diamidino-2-phenylindole. The proportion of AR-containing myonuclei per fibre cross-section was higher in the trapezius than in the vastus lateralis (P<0.05). In the trapezius, the proportion of AR-containing myonuclei was higher in P compared to U and in PAS compared to both P and U (P<0. 05). On the contrary, in the vastus lateralis, there were no differences in AR content between the three groups. Myonuclear number in both muscles was higher in P compared to U and in PAS compared to both P and U (P<0.05). In conclusion, AR content differs greatly between human neck and limb muscles. Moreover, the regulation of AR-containing myonuclei following training and self-administration of androgenic-anabolic steroids is muscle dependent.

Adult↗
PubMed1986

Testosterone regulation of androgen receptor levels in the uropygial gland of quails (Coturnix coturnix): a further proof for the androgen dependency of the uropygial gland.

In castrated quails supplemented with testosterone by a chronically implanted silastic capsule, removal of the implant resulted in the gradual disappearance of the androgen receptors in both cloacal and uropygial glands. However, after a 7-day time span, the receptors reappeared in both glands but did not reach the original level of implanted birds. On the other hand, the photostimulation of intact birds induced an increase of the receptor content of their uropygial and cloacal glands when compared to sexually quiescent birds. These results show that, the concentration of the androgen receptors of the uropygial and cloacal glands of adult male quails is partly controlled by testosterone. By comparison with the mechanism of the action of testosterone in mammal target organs, our results add weight to the androgen dependency of quails uropygial glands (a sebaceous like organ).

Animals↗
PubMed1990

The binding of 3H-labelled androgen-receptor complexes to hypothalamic chromatin of neonatal mice: effect of sex and androgenization.

The binding of 3H-labelled androgen-receptor complexes, prepared by (NH4)2SO4 precipitation from the 105,000 g supernatant of hypothalamic cytosol, to hypothalamic chromatin of neonatal mice covalently coupled to cellulose was measured in vitro. Saturation binding was also determined after extraction of histones and the masking of acidic proteins with high molarities of guanidine hydrochloride. This investigation showed the presence of high-affinity, low-capacity acceptor sites for [3H]-testosterone-receptor complexes in male hypothalamic chromatin (Kd value = 0.39 x 10(-10) M and binding sites of 41 fmol per mg of DNA). Acceptor activity seems to be associated with the acidic protein fraction of chromatin. No specific acceptor sites of similar nature were found in chromatin taken from the hypothalami of female mice. On the basis of these results, it is suggested that the androgen-unresponsiveness of female mice is related to the absence of acceptors for the androgen-receptor in female mice hypothalami.

Animals↗
PubMed1979

Reversible interaction between androgen binding protein and testicular macromolecules causing inhibition of androgen binding activity.

Sertoli cells in culture isolated from immature rat testes secrete androgen binding protein (ABP) in the culture medium. Binding activity of ABP in concentrated medium was estimated with equilibrium dialysis against 1 nM dihydrotestosterone at 4 degrees C. The ABP protein activity was inhibited approximately 50% through addition of cytosol preparations from testis or liver, but not from brain tissue, to the concentrated culture medium; this inhibition remained constant for at least two days. The inhibitor is probably a macromolecule, because the activity could not be removed by charcoal treatment and dialysis. The percent inhibition of ABP binding activity was increased when increasing amounts of cytosol were added, it decreased in the presence of increased concentrations of androgens, but it was not influenced by variations of the concentration of ABP. Inhibition of androgen binding to ABP by cytosols in the presence of 1 nM testosterone could be reversed after dialysis in the presence of 10 nM testosterone. These results suggest a reversible competition between testosterone and the testicular macromolecule for ABP. The occurrence of this interaction between ABP and a testicular macromolecule can explain the variable results of estimated ABP binding activity in testis cytosol preparations.

Androgens↗
PubMed1996

A simple, differential extraction method for the simultaneous direct radioimmunoassay of androgens and androgen glucuronides in human serum.

A method is described for the differential extraction of unconjugated androgens (testosterone and dihydrotestosterone) and glucuronidated androgens (androstane-3 alpha,17 beta-diol glucuronide and androsterone glucuronide) from human serum using solid-phase, gravity-flow extraction columns. In this method, 100-microL aliquots of serum are loaded onto the normal-phase columns, unconjugated androgens are eluted with ethyl ether, and glucuronides are eluted with ethyl ether containing 2% acetic acid. Glucuronide eluates are washed with 1% aqueous acetic acid to remove cross-reacting steroid sulfates. Assays of sera for the four steroids were performed using standard radioimmunoassay methodology, except for androsterone glucuronide. This steroid was assayed with a novel radioimmunoassay method that employees a tritiated, unconjugated androsterone tracer and an anti-dehydroepiandrosterone sulfate antiserum. The new method is well suited for the assay of conjugated and unconjugated steroids in large numbers of specimens, particularly where the sample volume is limited.

Adult↗
PubMed1977

Studies on the synergistic effect of androgen on the stimulation of progestin secretion by FSH in cultured rat granulosa cells: progesterone metabolism and the effect of androgens.

Metabolic transformations of progesterone in cultures of granulosa cells from immature hypophysectomized rats treated with diethylstilbestrol were studied in relation to the synergistic action of exogenous androgen and FSH on progestin (progesterone and 20alpha-dihydroprogesterone) accumulation. Androstenedione (Ad; 10 ng/ml) enhanced the sensitivity of rat granulosa cells to this steroidogenic action of FSH, lowering the threshold of the response from greater than 4 ng/ml (FSH alone) to 0.8 ng/ml in the presence of Ad. A synergistic effect with FSH was also shown by various 5alpha-androstane derivatives. They were, however, less effective than the parent delta4-3 keto androstenes. Progesterone underwent extensive 5alpha-reduction during culture, leading to accumulation of endogenous 5alpha-pregnane compounds, and to transformation of labelled progesterone into 5 alpha-reduced radiometabolites. These compounds corresponded in gas-liquid and thin-layer chromatographic behaviour to 3alpha-hydroxy-5alpha-pregnan-20-one, 20alpha-hydroxy-5alpha-pregnan-3-one and 5alpha-pregnane-3alpha,20alpha-diol. The rate of 5alpha-reduction of progestins was not affected by the presence of exogenous Ad (1 microgram/ml), ruling out the possibility that the effect of androgen on progestin accumulation depends on competitive inhibition of 5alpha-reductase. An involvement of androgen of thecal origin in the enhancement of the sensitivity of the FSH-responsive mechanism in granulosa cells is suggested.

20-alpha-Dihydroprogesterone↗
PubMed1987

Flow cytometric and karyotypic analyses of androgen-responsive and androgen-independent Shionogi mouse mammary tumours.

The androgen-responsive (AR) Shionogi mouse mammary carcinoma is a heterogeneous tumour composed of AR and androgen-independent (AI) cells. We characterized the cells of the AR tumour and those of its AI derivative by flow cytometric analysis of DNA content and karyotypic analysis of metaphase spreads. Both tumours had diploid and near tetraploid populations of cells. However, the AR and AI malignant cells of these tumours both appeared to be polyploid. A decrease in the polyploid population of the AR tumour accompanied tumour regression following castration, but this population was restored when tumour growth resumed. Although karyotypic analysis of metaphase spreads showed wide variations in chromosome numbers among the polyploid population, the range, 55-88 chromosomes, was found in both AR and AI tumours. In addition, the same chromosome anomalies, including a marker chromosome, were identified in both tumours. Since the AR and AI malignant cells could not be distinguished on the basis of their DNA content or karyotype, the cell types may not represent genetically distinct populations of cells. The AR cells may undergo alterations in gene expression in adapting to their androgen-free environment.

Androgens↗
PubMed2006

Androgen receptor immunostaining and androgen receptor messenger ribonucleic acid expression are increased in cremaster muscles associated with undescended testis.

OBJECTIVES: To determine and compare androgen receptor (AR) immunostaining and AR messenger ribonucleic acid (mRNA) expression in cremaster muscles associated with descended or undescended testis. METHODS: Eight boys with descended testis but with inguinal hernia and 8 boys with undescended testis were evaluated. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and free testosterone levels were determined, and samples of cremaster muscles were immunostained for AR. Groups were compared by unpaired t tests and Fisher's exact tests; P values of <0.05 were considered significant. Samples of cremaster muscles were obtained from another 5 boys with descended testis but with inguinal hernia and 5 boys with undescended testis. The expression of AR mRNA in those samples was determined by semiquantitative reverse transcriptase polymerase chain reaction. RESULTS: Serum FSH, LH, testosterone, and free testosterone levels were similar among groups. None of the samples from boys with descended testis showed positive staining, but 4 of 8 samples from boys with undescended testis stained positive for AR. Androgen receptor mRNA transcript levels were approximately 10 times lower in cremaster muscles of boys with descended testis compared with those in boys with undescended testis. CONCLUSIONS: Despite similar serum hormone levels, more AR expression in cremaster muscles associated with undescended testis might represent evidence of being subjected to a lesser degree of androgenic effects.

Child, Preschool↗