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PubMedDate not supplied

The effect of in vitro androgen stimulation upon androgen metabolism and trophic parameters in cultured human epididymis.

Previous results obtained with a model system of human epididymal tubules maintained in organ culture suggested that androgenic stimulation of this tissue resulted in responses similar to those obtained in epididymides of experimental animals under physiological conditions, as well as in other human androgen-dependent tissues. In this instance we have explored the possible influence of androgens on the activity of the androgen-converting enzymes 5 alpha-reductase and 17 beta-dehydrogenase. Activity of the former enzyme increases significantly during the culture period but no differences were found among the cultured groups, regardless of the addition of androgen. On the other hand, the activity of 17 beta-dehydrogenase was unchanged in all the experimental conditions tested. The co-culture of the tissue with explants of human testis was without effect. More than 85% of the activity of both enzymes was found localized in a fraction enriched in epithelial cells. Histological observation of the cultured tissues showed a marked disorganization of the pseudostratified epithelium in the absence of androgen while the inclusion of DHT in the media partially prevented these changes. We conclude that, under the conditions employed in these experiments, the activity of the enzymes studied is not influenced by androgens.

17-Hydroxysteroid Dehydrogenases↗
PubMed1986

Androgen therapy in aplastic anaemia: a comparative study of high and low-doses and of 4 different androgens. French Cooperative Group for the Study of Aplastic and Refractory Anemias.

A prospective randomized study of androgen therapy in aplastic anaemia (AA) was performed: 2 androgens (fluoxymesterone and norethandrolone) at high (1 mg/kg/d) and low (0.2 mg/kg/d) dose were studied on 110 patients; and 4 androgens given at high doses were objectively compared in 125 other cases. When patients are matched for AA severity there is an obvious efficiency of the high-dose androgens in the survival of the less severe cases of aplastic anaemia and in their haematological improvement. The data further show that, among the 4 androgens tested, fluoxymesterone is the most efficient and stanozolol the least. We conclude that androgen therapy is truly efficient in moderately severe aplastic anaemia and that fluoxymesterone (1 mg/kg/d) for 18 months should be chosen as reference drug to any new androgen therapy assay.

Adult↗
PubMed1993

[Familial form of partial androgen insensitivity (Reifenstein syndrome): arginine-histidine mutation in position 840 in the androgen receptor].

In a large kindred with Reifenstein syndrome, we performed the molecular analysis of the androgen receptor gene. Since the biochemical characteristics of the androgen receptor, determined on the cultured genital skin fibroblasts, showed a drastic decrease of the androgen binding capacity, we assumed that a point mutation was located in exons 4-8 encoding the carboxy-terminal domain of the receptor. Enzymatic amplifications of these exons did not point out any deletions. Direct sequencing showed a G-A point mutation at position 2818 of exon 7 responsible for an arginine-histidine substitution at position 840 of the androgen receptor. The presence of the same mutation has been reported by other groups in four unrelated patients. Its association with different phenotypes of androgen insensitivity and different biochemical characteristics of the androgen receptor pointed out the complexity of the genotype-phenotype relationship in androgen insensitivity. Moreover the identification of the point mutation gave us the opportunity to perform a prenatal exclusion diagnosis of Reifenstein syndrome in this high-risk family.

Arginine↗
PubMed1994

Androgen responsiveness and androgen receptor gene expression in human kidney cells in continuous culture.

The effects of androgen and estrogen on cell growth and gene expression were investigated in KJ29 kidney epithelial cells. Incorporation of 3H leucine and 3H thymidine was increased by androgen at 10nM, but not by estrogen. Estrogen however, inhibited the effects induced by androgen. In addition, cell number and the proliferation marker Ki67 were increased by androgen, but not by estrogen. Levels of androgen receptor RNA, as detected by RT-PCR and Northern blot analysis, were not affected by either androgen or estrogen. Levels of estrogen receptor RNA could be detected only by RT-PCR, and disappeared after estrogen treatment. These studies show that sex steroid receptors are differently expressed in KJ29 cells, and suggest that androgen, via its canonic receptor, acts as a mitogenic factor in human kidney cells, whereas estrogen has an antiandrogenic action.

Antibodies, Monoclonal↗
PubMed1994

Androgen regulation of cell adhesion molecule gene expression in rat prostate during organ degeneration. C-CAM belongs to a class of androgen-repressed genes associated with enriched stem/amplifying cell population after prolonged castration.

Androgen is required for maintaining the differentiated state of prostatic epithelium, and that cell adhesion molecules play active roles in controlling the development of epithelial cells. However, little is known about the regulation of cell adhesion molecules during prostate development. In this study, we demonstrated that the expression of an epithelial cell adhesion molecule, C-CAM, in rat ventral prostatic epithelium are repressed by androgen. A similar regulatory pattern was also observed in the seminal vesicle but not in other androgen-dependent organs (the coagulating gland and the dorsolateral prostate), or other organs (the liver and kidney). These observations suggest that regulation of C-CAM expression by androgen is tissue-specific. Unlike the other androgen-repressed genes associated with apoptosis, which have transient expression patterns, the elevated level of C-CAM in the ventral prostate persisted for more than 30 days postcastration, suggesting that C-CAM belongs to a class of androgen-repressed genes which are not associated with apoptosis. Immunohistochemical study detected C-CAM on the apical surface of secretory epithelium in control rats; castration resulted in an altered localization of C-CAM expression from columnar epithelium to cuboidal basal epithelium. Taken together, the up-regulation and altered expression pattern of C-CAM in ventral prostatic epithelium by androgen deprivation may be associated with the enriched epithelial stem/amplifying cell population in degenerated ventral prostate. These observations suggest that C-CAM may play an active role in the process of prostatic epithelial differentiation.

Adenosine Triphosphatases↗
PubMed1994

Identification of a functional androgen response element in the promoter of the gene for the androgen-regulated aldose reductase-like protein specific to the mouse vas deferens.

Mouse vas deferens protein (MVDP), a member of the aldo-keto reductase superfamily, is exclusively produced in the epithelial cells of the deferent duct under androgenic regulation. To better understand androgenregulated MVDP gene expression, the location and sequences of androgen response elements (AREs) in the 5'-flanking DNA were determined. Sequence analysis revealed two putative AREs as follows: one between positions -1186 and -1171 (distal ARE) and the other between -111 and -97 (proximal ARE). To study hormonal regulation, fragments of the MVDP promoter region, extending from residue -1804 to +41, were linked to the chloramphenicol acetyltransferase (CAT) reporter gene and cotransfected with a human androgen receptor expression vector into T47D cells in a transient expression assay. A minimal region (-121 to +41) was identified as being sufficient for androgen-regulated gene expression. A mutation in proximal ARE almost completely abolished androgen induction of CAT. One copy of the sequence TGAAGT tcc TGTTCT, cloned in the opposite orientation in front of the thymidine kinase promoter, confers androgen responsiveness to the CAT reporter gene. Androgen transcriptional activity was not detected with the distal ARE. The data provide strong evidence that transcriptional regulation of the MVDP gene occurs via the sequence TGAAGT tcc TGTTCT.

Aldehyde Reductase↗
PubMed1997

Androgen receptor point mutations as the underlying molecular defect in 2 patients with androgen insensitivity syndrome.

PURPOSE: We have detected androgen receptor (AR) gene mutations as the underlying molecular defect in male pseudohermaphroditism patients. The functional properties of these mutant receptors regarding hormone binding and transactivation were characterized in 2 patients and offered a possible treatment modality for a male pseudohermaphroditism newborn. MATERIALS AND METHODS: Specific binding of dihydrotestosterone, thermostability of the receptor-hormone complex and 5alpha-reductase activity were measured in their genital skin fibroblasts. AR gene mutations were detected by direct sequencing. The ability of the mutant receptors to activate androgen responsive elements in the deoxyribonucleic acid was determined by transactivation experiments. Screening techniques that distinguish between normal and mutant ARs were developed for rapid detection of the mutation in other family members. RESULTS: The 2 patients showed a qualitative and quantitative binding defect. In both patients, point mutations in the ligand binding domain were identified as the underlying cause. Transactivation assays demonstrated that in the newborn increasing androgen concentrations can restore the mutated receptor's function completely, whereas in the patient with complete androgen insensitivity, excessive amounts of synthetic androgens were necessary. Therefore, the newborn received androgen stimulation and underwent surgical correction in the male direction. These experiments revealed that the functional difference between a mutant AR that causes a partial and one that causes a complete androgen insensitivity may be very small. CONCLUSIONS: Identification of the molecular mechanisms that cause the various forms of sex ambiguity will greatly improve both diagnosis and therapy in affected patients. Exact characterization of AR activation and function may offer a possible treatment modality in affected patients.

Child↗
PubMed2006

A naturally occurring mutation in the human androgen receptor of a subject with complete androgen insensitivity confers binding and transactivation by estradiol.

The clinical phenotype of complete androgen insensitivity (CAIS) was associated with a mutation in the human androgen receptor (hAR) gene encoding the amino acid substitution, M745I, in the hAR protein. Transcriptional activation of hAR(M745I) by the synthetic androgen, methyltrienolone (R1881), was reduced compared to wild-type (wt) hAR. The transcriptional co-activator, androgen receptor associated protein 70 (ARA70), failed to enhance transactivation of hAR(M745I) at lower concentrations of R1881 (0.01-0.1 nM), whereas the p160 co-activators, SRC-1 and TIF2, stimulated activity. Transcriptional activity of hAR(M745I) was stimulated by 1 or 10 nM R1881 and activity was further enhanced by co-expression of ARA70 similar to that of the hAR(wt). Transcriptional activity of hAR(wt) was minimally stimulated by estradiol (E2) without or with co-expression of ARA70, whereas 10 or 100 nM E2 increased transactivation by hAR(M745I) of the androgen-responsive MMTV-luciferase reporter gene by 10-fold and activity was further enhanced by ARA70. Increasing concentrations of E2 competed more effectively for binding of R1881 to hAR(M745I) than to hAR(wt), indicative of the preferential binding of E2 to the mutant hAR. Partial tryptic digestion of hAR wt and M745I revealed that activation of the mutant protein was reduced in the presence of R1881. By contrast, tryptic digestion showed that the mutant hAR was activated by the binding of E2. In conclusion, the clinical phenotype of CAIS resulted from a hAR gene mutation encoding hAR(M745I) with reduced binding and transactivation by androgens, but the novel properties of enhanced affinity for and increased transactivation by estradiol.

Amino Acid Substitution↗
PubMed1984

Androgen insensitivity syndrome: gonadal androgen receptor activity.

To determine whether abnormalities of the androgen receptor previously observed in skin fibroblasts from patients with androgen insensitivity syndrome also occur in the gonads of affected individuals, androgen receptor activity in the gonads of a patient with testicular feminization syndrome was investigated. Using conditions for optimal recovery of androgen receptor from human testes established by previous studies, we detected the presence of a high-affinity (dissociation constant = 3.2 X 10(-10) mol/L), low-capacity (4.2 X 10(-12) mol/mg DNA), androgen-binding protein when tritium-labeled R1881 was incubated at 4 degrees C with nuclear extracts from the gonads of control patients or from a patient with testicular feminization syndrome but not when incubated at 37 degrees C. Thus this patient has an androgen receptor with a temperature lability similar to that of receptors from normal persons.

Adolescent↗
PubMed2005

Inhibition of HER-2/neu kinase impairs androgen receptor recruitment to the androgen responsive enhancer.

Advanced prostate cancer invariably recurs despite androgen deprivation therapy. The androgen receptor (AR) likely plays a key role in this progression and in the continued survival and proliferation of prostate cancer cells in the low androgen environment. Cross-talk with growth factor receptors, such as epidermal growth factor receptor (EGFR) family, has been postulated as a potential mechanism to activate AR in recurrent prostate cancer. We have investigated the role of HER-2/neu (ErbB-2) tyrosine kinase in AR function by characterizing the effect of inhibiting endogenous HER-2 activity in LNCaP cells. We used two independent methods, expression of intracellular single-chain antibody against HER-2 and treatment with a novel dual EGFR/HER-2 kinase inhibitor GW572016 (lapatinib). Expression of intracellular HER-2 antibody scFv-5R and treatment with GW572016 inhibited HER-2 signaling. This HER-2 inhibition led to impairment of AR-mediated functions, such as androgen-stimulated growth and the induction of endogenous prostate-specific antigen (PSA) mRNA and protein. Androgen-stimulated recruitment of AR and histone acetylation at the androgen responsive enhancer of the PSA gene, detected by chromatin immunoprecipitation analysis, were impaired by HER-2 inhibition. GW572016 was more potent in its ability to inhibit PSA expression and AR recruitment and histone acetylation than the EGFR-selective kinase inhibitor ZD1839 (gefitinib), consistent with the HER-2 kinase playing the major role in AR regulation. These results show that HER-2 signaling is required for optimal transcriptional activity of AR in prostate cancer cells and suggest that HER-2 inhibition may provide a novel strategy to disrupt AR function in prostate cancer.

Acetylation↗
PubMed1994

[Effects of antiandrogen TZP-4238 on the prostatic androgen receptor and prostatic androgen in rat].

TZP-4238, a new steroidal antiandrogen, is an orally active drug in rats and dogs. The effects of TZP-4238 on the androgen receptor and androgen content were examined in comparison with other antiandrogens in rats. The prostate DHT levels decreased markedly within 4-8 hr after a single oral administration of TZP-4238 8mg/kg. The prostatic testosterone concentrations fell below the detection limit (5pg/g of tissue) at 4-12 hr after the initiation of treatment. The plasma testosterone level also fell to 60% of the control level after 4-8 hr and then returned to the normal range. Eight percent of DHT present in normal prostatic tissue was located in the nuclear fraction. TZP-4238 reduced the concentration of DHT in nuclei to 50% of the normal level. The concentration of the plasma drug which induced a 50% decrease in the prostatic DHT, the IC50, was about 10ng/ml, while the IC50 value for plasma testosterone was 30-50ng/ml. After oral administration of 15-OH TZP-4238, the main metabolite, the level of plasma testosterone was significantly elevated above the control level. The androgen receptor level was markedly reduced at 24 hr following castration and returned to the normal range within 5 hr of a single injection of testosterone. TZP-4238 reduced the nuclear androgen receptor level to 60% at 24 hr after a single oral dose and then, the receptor content returned to its original level. Both 15-OH TZP-4238 and cyproterone acetate also reduced the androgen receptor and DHT contents to 50%. A series of in vivo studies demonstrated that TZP-4238 inhibited the uptake of testosterone and the decrease of DHT and testosterone, and decreased the nuclear androgen receptor in the rat prostate.

Androgen Antagonists↗
PubMed2006

Selective androgen receptor modulators: in pursuit of tissue-selective androgens.

The androgen receptor mediates the androgenic and anabolic activity of the endogenous steroids testosterone and 5alpha-dihydrotestosterone. Current knowledge of the androgen receptor protein structure, and the molecular mechanisms surrounding the binding properties and activities of agonists and antagonists has led to the design and development of novel nonsteroidal ligands with selected tissue-specific androgen receptor agonist and antagonist activities. The activity of these compounds, termed selective androgen receptor modulators (SARMs), is directed toward the maintenance or enhancement of anabolic effects on bone and muscle with minimal androgenic effects on prostate growth. SARMs are of potential therapeutic value in the treatment of male hypogonadism, osteoporosis, frailty and muscle wasting, burn injury and would healing, anemia, mood and depression, benign prostatic hyperplasia and prostate cancer.

Androgen Receptor Antagonists↗
PubMed1997

Functional characterization of mutant androgen receptors from androgen-independent prostate cancer.

Mutations in the androgen receptor (AR), that alter steroid hormone specificity have been identified in a series of androgen-independent prostate cancers. To address the functional properties of these mutant ARs that may have contributed to their selection in vivo, responses to a series of steroid hormones and antiandrogens were assessed. CV-1 cells were cotransfected with wild-type or mutant ARs and a luciferase reporter plasmid regulated by an androgen-responsive element. Dose-response curves were analyzed for 5alpha-dihydrotestosterone, the most active androgen in normal prostate, and androstenedione, a major androgen derived from the adrenals. Although the mutant ARs responded to both of these steroids, the responses were equivalent to or less than the wild-type AR. In contrast, responses to flutamide, a competitive antagonist of the wild-type AR, were markedly increased by three of the mutations. Similar responses were observed with a second antiandrogen, nilutamide. Bicalutamide, another antiandrogen related to flutamide, remained an antagonist for these mutant ARs. Finally, flutamide was observed to be a weak partial agonist of the wild-type AR in this system. These results indicate that flutamide used in conjunction with androgen ablation therapy for prostate cancer may select for tumor cells with flutamide-inducible ARs.

Amino Acid Substitution↗
PubMed2001

Posttraining androgens' enhancement of cognitive performance is temporally distinct from androgens' increases in affective behavior.

Steroid hormone-induced variations in spatial learning and memory tasks have been reported. In this study, androgens' effects in various cognitive and affective tasks were investigated in order to determine whether any observed differences in cognitive performance could be due to affective changes produced by the hormones. Ovariectomized rats (N = 72) received 0.0, 3.0, or 7.5 mg/kg subcutaneously, of testosterone (T), dihydrotestosterone (DHT), or 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-Diol) suspended in 10% ethanol/sesame oil v/v. For the cognitive tasks (Y maze, inhibitory avoidance, and object recognition), subjects were injected after training trials. For the affective tasks (open field, elevated plus maze, and tailflick), subjects were injected 1 or 24 h before testing. Posttraining injections that produced physiological concentrations of androgens--T, DHT, and 3 alpha-Diol--1 h later increased the percentage of correct choices in the Y maze, the latencies to cross to the shock-associated side of the inhibitory avoidance chamber, and percentage of time exploring novel objects 24 h later, when androgen levels were no longer increased. Administration of T, DHT, and 3 alpha-Diol also increased the number of entries into the center squares of a brightly lit open field, open-arm time in the elevated plus maze, and tailflick latencies 1 but not 24 h following administration. These findings suggest that these androgens, when administered following training, can enhance cognitive performance in the tasks investigated 24 h later when androgen levels nadir, but overt changes in the affective behaviors examined occurred at the time of physiological concentrations 1 h but not 24 h following androgen administration. These findings suggest posttraining androgens can enhance consolidation and cognitive performance, independent of their anxiolytic actions.

Affect↗
PubMed2000

[Complete androgen insensitivity in an Icelandic family caused by mutation in the steroid binding region of the androgen receptor.].

INTRODUCTION: Androgen insensitivity syndrome (AIS) is a X-linked rescessive disorder characterized by impairment of the androgen-dependant male sexual differentiation. The cause of AIS is in most cases a mutation in the gene of the androgen receptor on the X chromosome. In this study we describe an Icelandic family with two girls with AIS. A search for mutations in the androgen receptor gene was performed in order to identify the genetical and molecular basis for AIS in this family. MATERIAL AND METHODS: Genomic DNA was isolated from two girls with complete AIS and their close relatives. PCR was used to amplify all eight exons of the androgen receptor gene of the two AIS girls and SSCP used to screen for mutations. DNA fragments showing abnormal SSCP pattern were subjected to nucleotide sequencing. PCR based diagnostic method was developed and used to detect the mutation causing AIS in the family. RESULTS AND CONCLUSIONS: Using SSCP and DNA sequencing a CGA to CAA missense mutation in exon 5 at codon 752 was identified. The mutation causes in an Arg to Gln amino acid substitution (R752Q mutation) in the ligand binding domain of the androgen receptor and a complete androgen insensitivity. Members of the family were genotyped using a PCR based method for identification of the mutant allele. The results strongly indicated a de novo mutation in a germ cell of the maternal grandmother, as the mutation was not found in her blood leucocytes. The diagnostic test provided a basis for genetic counselling for the family.

English Abstract↗
PubMed1997

Synergistic activation of androgen receptor by androgen and luteinizing hormone-releasing hormone in prostatic carcinoma cells.

BACKGROUND: We investigated modulation of androgen receptor (AR) activity in prostatic tumor cells by luteinizing hormone-releasing hormone (LHRH)-induced increase of the intracellular cyclic adenosine monophosphate (cAMP) level. METHODS: AR transactivation activity was assessed in transiently transfected DU-145 and in LNCaP cells. RESULTS: LHRH and cAMP derivative, respectively, induced reporter gene activity to about 15% of the maximal level in DU-145 cells transfected with an AR expression vector and an androgen-inducible reporter gene. LHRH or the cAMP analogue acted synergistically in combination with low concentrations of androgen thus lowering the androgen concentration required for maximal AR activation by a factor of 100. A similar activation of the AR by cAMP analogue was observed in LNCaP cells when enhancement of androgen-induced secretion of prostate-specific antigen was determined. The two nonsteroidal antiandrogens hydroxyflutamide and Casodex(R) inhibited reporter gene activity. CONCLUSIONS: The AR is synergistically activated by low doses of androgen and LHRH or the second messenger cAMP. This may have implications for the treatment of advanced prostate cancer.

Androgen Antagonists↗
PubMed1999

Neural androgen receptor regulation: effects of androgen and antiandrogen.

Androgens exert profound effects on the organization and function of the central nervous system. These effects are mediated by the androgen receptor (AR), a ligand-dependent transcription factor. The mechanisms of AR regulation in neural tissue, however, remain to be fully elucidated. Characterizing this process can provide important information regarding receptor function and AR gene regulation in the brain. Previously, it was shown that testosterone (T) up-regulated neural AR in a dose-dependent manner in both male and female mice. In the present study, whether AR was differentially regulated by the natural agonists T and dihydrotestosterone (DHT) or the nonsteroidal antagonist flutamide (FLU) was assessed. Males were gonadectomized and AR levels were allowed to decline to baseline 3 days after surgery. Changes in AR protein content produced by the various treatments were measured by semiquantitative Western blot of limbic system extracts. Treatment with T or DHT significantly augmented AR 3 and 7 h after hormone administration, but only DHT sustained this increase for 21 h. This difference also was observed when males were given T plus finasteride (FIN, a 5alpha reductase inhibitor). The findings demonstrate that the two endogenous ligands have differential time course effects on neural AR. The antiandrogen FLU failed to up-regulate AR at doses up to 100 times higher than T or DHT. When administered concomitantly with T or DHT, it effectively inhibited the augmentation of AR normally seen 3 h after androgen treatment. While immunohistochemical studies showed that FLU was able to promote nuclear translocation of AR, Western analysis revealed that FLU, in contrast to T and DHT, failed to maintain the integrity of AR. The results demonstrate that (a) the endogenous androgens T and DHT regulate AR differently, suggesting a potential cellular mechanism that may contribute to the difference in neural target gene sensitivity to these androgens; (b) up-regulation of AR occurs only in the presence of agonists; (c) the mechanism of action of FLU in the brain involves inhibition of AR protein up-regulation normally seen in response to androgen; and (d) FLU promotes AR nuclear translocation but not augmentation of cellular AR populations. These findings demonstrate that in vivo AR regulation in the brain basically parallels mechanisms proposed from results obtained with transfected cells and cell lines.

Androgen Antagonists↗
PubMed1998

Behavioral actions of androgens and androgen receptor expression in the electrocommunication system of an electric fish, Eigenmannia virescens.

Gymnotiform electric fish emit an electric organ discharge (EOD) that, in many species, is sexually dimorphic and used in gender recognition. The glass knife fish Eigenmannia has been a major neuroethological model system, and there have been reports that its EOD is sexually dimorphic. However, no study has examined the role of steroids in establishing this dimorphism. We tested the effect of three androgens, testosterone, dihydrotestosterone, and 11-ketotestosterone (11kT), on the EOD of Eigenmannia virescens. Implants of any of these three androgens induced a decrease in EOD frequency, consistent with several studies showing that males have a lower EOD frequency than females. In a separate experiment, we found that 11kT treatment also increases EOD pulse duration, but has no effect on the duty cycle, the relative duration of the positive and negative phases of the wave, or the harmonic content of the EOD. Using immunocytochemistry, we found that the cells of the electric organ (the electrocytes) that produce the EOD and control its pulse duration label positively with an antibody to the androgen receptor. These experiments indicate that androgens decrease the firing frequency of the medullary pacemaker and alter the ion current kinetics in the electrocytes. Moreover, the presence of nuclear androgen receptors in electrocytes suggests that androgens act directly on the electric organ to modify EOD pulse duration.

Androgens↗