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PubMed1999

Effects of castration and androgen treatment on androgen-receptor levels in rat skeletal muscles.

The effects of castration and dihydrotestosterone (DHT) treatment on levels of skeletal muscle androgen receptor (AR) were examined in three groups of adult male rats: 1) intact normal rats, 2) rats castrated at 16 wk of age, and 3) rats castrated at 16 wk of age and given DHT for 1 wk starting at week 17. All animals were killed at 18 wk of age. Castration caused a decrease (P < 0.05) in the weights of the levator ani and bulbocavernosus muscles. The administration of DHT to the castrated rats increased (P < 0.05) the weights of the levator ani and bulbocavernosus muscles. Castration caused a significant downregulation of AR levels in the bulbocavernosus (P < 0.05) but had no significant effect on AR levels in the levator ani muscle. DHT administration to the castrated group upregulated AR levels in the bulbocavernosus and levator ani muscles. The plantaris muscle did not significantly (P > 0.05) change for any of the treatments. These findings suggest that the effects of castration and androgen replacement differentially affect skeletal muscle mass and AR levels.

Animals↗
PubMed2006

Germ-line genetic variation in the key androgen-regulating genes androgen receptor, cytochrome P450, and steroid-5-alpha-reductase type 2 is important for prostate cancer development.

Prostate cancer risk may be influenced by single genetic variants in the hormone-regulating genes androgen receptor (AR), cytochrome P450 (CYP17), and steroid-5-alpha-reductase type 2 (SRD5A2). In this study, we comprehensively investigated polymorphisms in these three loci and their joint effect in a large population-based study. We selected 23 haplotype-tagging single-nucleotide polymorphisms (htSNP) that could uniquely describe >95% of the haplotypes (6 in AR, 6 in CYP17, and 11 in SRD5A2). These htSNPs were then genotyped in the Cancer Prostate in Sweden population (2,826 case subjects and 1,705 controls). We observed significant association for several SNPs in the AR gene (P = 0.004-0.02) and CYP17 (P = 0.009-0.05) and one SNP in SRD5A2 (P = 0.02). Carriers of the most common AR haplotype had a significant excess risk to develop prostate cancer [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.1-1.5; P = 0.002], yielding an estimated population attributable risk of 16% (95% CI, 0.06-0.25). Combining risk alleles from these genes yielded a 12% risk increase for each additional high-risk allele carried (95% CI, 1.1-1.2; P for trend = 9.2 x 10(-5)), with an overall OR of 1.87 (95% CI, 1.0-3.4) for carriers of all five included risk alleles, an OR of 2.13 (P for trend = 8 x 10(-4)) for advanced disease, and an OR of 4.35 (P for trend = 7 x 10(-5)) for disease onset before age 65 years. Genetic variation in key genes in the androgen pathway is important for development of prostate cancer and may account for a considerable proportion of all prostate cancers. Carriers of five high-risk alleles in the AR, CYP17, and SRD5A2 genes are at approximately 2-fold excess risk to develop prostate cancer.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1992

Transient down-regulation of androgen receptor messenger ribonucleic acid (mRNA) expression in Sertoli cells by follicle-stimulating hormone is followed by up-regulation of androgen receptor mRNA and protein.

Cooperative actions of FSH and androgens on initiation, maintenance, and restoration of spermatogenesis have been described. In the present experiments the regulatory effects of FSH on androgen receptor (AR) gene expression in Sertoli cells were studied. In immature rats injection of FSH (1 microgram/g BW, ip) resulted in a rapid down-regulation of testicular AR mRNA expression (4 h), followed by recovery to the control level (10 h). Using cultured immature Sertoli cells, a similar transient effect on AR mRNA expression was observed after the addition of FSH (500 ng/ml) or (Bu)2cAMP (0.5 mM). Cycloheximide treatment of the cells did not prevent the rapid FSH-induced down-regulation of AR mRNA expression, indicating that de novo protein synthesis is not required for this effect. Furthermore, using a transcriptional run-on assay, no marked decrease in the rate of AR gene transcription was found upon treatment of the cultured Sertoli cells with FSH for 2 or 4 h. This demonstrates that the short term effect of FSH or AR mRNA expression reflects a change in mRNA stability. The AR protein level was not markedly affected by the transient decrease in AR mRNA expression. When immature Sertoli cells were incubated with FSH for longer time periods (24-72 h), both AR mRNA and protein expression were increased. In Sertoli cells isolated from 15-day-old rats, this increase was higher (mRNA, 2- to 3-fold; protein, 2-fold) than in Sertoli cells isolated from 25-day-old animals. The results indicate that FSH plays a complex role in the regulation of AR expression in immature rat Sertoli cells.

Aging↗
PubMed1979

Anti-androgen TSAA-291. II. Manifestation of the anti-androgenic action of a steroid ester TSAA-330 (16 beta-ethyl-17 beta-hydroxy-4-oestren-3-one caproate) and elucidation of its long-lasting mechanism using a simple steroid determination technique.

Using a simple steroid determination technique, in situ steroid absorption from a subcutaneously injected sesame oil solution in rats was pursued following the time-course changes in the steroid concentration. Based on the knowledge thus obtained, the anti-androgenic effect of a steroidal compound, TSAA-330, could be manifested in the subcutaneous route. (1) Anti-androgenic steroid TSAA-291 and its esters in the subcutaneously injected sesame oil solution were selectively absorbed into the general circulation at different rates according to their chemical nature and structures, while the oil itself remained at the injected site for a considerably long period. At the injected site where subcutaneous doses of steroids molar equivalent to 50 mg of TSAA-291 were administered in 5 ml/rat of sesame oil, TSAA-291 decreased to the level of 10% of the initial concentration on the 4th day. TSAA-328 decreased slowly to the 50% and 20% levels on the 7th and 21st day, respectively. TSAA-335 decreased more slowly to the 50% level on the 14th day. TSAA-330 decreased most slowly only to the 70% level on the 49th day. (2) A single subcutaneous administration of 200 mg of TSAA-330 suppressed the weight increase of the accessory sex organs caused by a single subcutaneous injection of testosterone caproate (10 mg) in the immature orchiectomized rat. The suppressive effect was obvious from 2 weeks after the administration, and seemed to last for more than two weeks. The levator ani weight was not affected by the administration of TSAA-330. (3) Dose-dependent inhibitions of the accessory sex organs were obtained three weeks after a single subcutaneous administration of 50 to 400 mg of TSAA-330 in the adult male rat. (4) Daily oral administrations of 50 mg of TSAA-291 or TSAA-330 to the adult male rat for 8 days resulted in depression of the accessory sex organs to almost the same extent obtained with either agent. One week after the last administration, however, the weight of the accessory sex organs of the TSAA-291-administered animals recovered to almost the comparable level with the control, whereas a significant after-effect of the inhibition was still evident in the TSAA-330-administered animals.

Absorption↗
PubMed1982

Specific interaction of radioactive anti-androgen TSAA-291 with androgen receptor in rat prostates.

A steroidal anti-androgen ISSA-291 (16 beta-ethyl-17 beta-hydroxy-4-oestren-3-one) bound to a macromolecular component in the cytosol of rat ventral prostates with high affinity (kd = 5.0 X 10-9 M) and in a saturable manner. The number of binding sites was comparable to that for 5 alpha-dihydrotestosterone (5 alpha-DHT). [3H]TSAA-291 binding was effectively displaced by unlabelled 5-alpha-DHT, 19-nortestosterone and cyproterone acetate but to a lesser degree by corticosterone. Glycerol density-gradient centrifugation analysis revealed that the sedimentation coefficient of the [3H]-TSAA-291-macromolecule complex was 3-4.5 S. However, when the unlabelled cytosol was fractionated by glycerol density-gradient centrifugation before the binding of [3H]TSAA-291 was examined, specific binding of [3H]TSAA-291 was observed in fractions corresponding to 8-10 S. Binding of the [3H]TSAA-291-macromolecules complex to prostatic nuclei and DNA-cellulose was considerably less than binding by the [3H]5 alpha-DHT-macromolecule complex. Instability of the TSAA-291 binding component on heat treatment before and after complex formation was also revealed and the results are discussed in terms of the anti-androgenic activity of TSAA-291.

Animals↗
PubMed2005

Adequacy of androgen replacement influences bone density response to testosterone in androgen-deficient men.

OBJECTIVE: Androgen deficiency (AD) leads to bone loss and contributes to osteoporotic fractures in men. Although low bone mineral density (BMD) in AD men is improved by testosterone replacement, the responses vary between individuals but the determinants of this variability are not well defined. DESIGN AND METHODS: Retrospective review of dual energy X-ray absorptiometry (DEXA) of the lumbar spine and proximal femur in men with established AD requiring regular androgen replacement therapy (ART). After a DEXA scan all men were treated with testosterone implants (800 mg, approximately 6 month intervals). Patients were classified as having a congenital, childhood, or post-pubertal onset, as well as according to the adequacy of treatment prior to their first DEXA scan as untreated, partially treated or well treated. RESULTS: Men with AD requiring regular ART (n = 169, aged 46.3+/-1.1 years, range 22-84 years) underwent a DEXA scan prior to being treated with testosterone implants (800 mg, approximately 6 month intervals). In cross-sectional analysis at the time of the first DEXA scan untreated men (n = 24) had significantly reduced age-adjusted BMD at all four sites (L1-L4, femoral neck, Ward's triangle and trochanter). Well-treated men (n = 77) had significantly better age-adjusted BMD at all four sites compared with those who were partially treated (n = 66) or untreated (n = 24) with their age-adjusted BMD being normalized. In a longitudinal assessment of men (n = 60) who had two or more serial DEXA scans, at the second DEXA scan after a median of 3 years, men who were previously partially treated (n = 19) or untreated (n = 11) had proportionately greater improvements in BMD, significantly for Ward's triangle (P = 0.025) and the trochanter (P = 0.044) compared with men (n = 30) previously well treated. CONCLUSIONS: The present study demonstrates a positive relationship between adequacy of testosterone replacement and BMD in men with overt organic AD. Additionally, the BMD of well-treated AD men approximates that of age-matched non-AD controls. The greatest BMD gains are made by those who have been either untreated or partially treated, and optimal treatment over time (median 3 years) normalizes BMD to the level expected for healthy men of the same age.

Absorptiometry, Photon↗
PubMed1983

In-vitro metabolism of unconjugated androgens, oestrogens and the sulphate conjugates of androgens and oestrone by accessory sex organs of the mature domestic boar.

Minces of the prostate and seminal vesicles of the mature boar were incubated with the following major testicular steroids of the pig: [3H]dehydroepiandrosterone, [3H]5-androstene-3 beta, 17 beta-diol, [3H]oestrone, [3H]oestradiol-17 beta and their respective sulphate conjugates (excluding oestradiol-17 beta). Incubations were also carried out with [3H]testosterone, [3H]5 alpha-dihydrotestosterone and [3H]5 alpha-androstanediols. Minces of the epididymides were incubated with [3H]dehydroepiandrosterone and [3H]oestrone sulphates. The prostate and seminal vesicles converted dehydroepiandrosterone predominantly to weak androgens, whereas 5-androstene-3 beta, 17 beta-diol was primarily converted to testosterone; testosterone and its 5 alpha-reduced metabolites were metabolized in a manner typical of androgen end target organs. Unconjugated oestrone and oestradiol-17 beta were interconverted by the prostate and seminal vesicles. The metabolism of C19 steroid sulphates was less than 1% in all incubations; some oestrone sulphate, however, was converted to unconjugated oestrone and oestradiol, particularly by the caput epididymidis. The significance of these results is discussed in relation to recent studies in vivo.

Androgens↗
PubMed2002

Androgen receptors in human synoviocytes and androgen regulation of interleukin 1beta (IL-1beta) induced IL-6 production: a link between hypoandrogenicity and rheumatoid arthritis?

OBJECTIVE: To investigate the hypothesis that synoviocytes possess androgen receptors (AR) that could be modulated by the non-aromatizable androgen, dihydrotestosterone (DHT), resulting in altered levels of inflammatory cytokines. METHODS: Using molecular analyses of AR in combination with the multiprobe ribonuclease protection assay and ELISA, we investigated the presence of AR and the effect of DHT on interleukin 1beta (IL-1beta) induced expression of the IL-6 superfamily of cytokines in synoviocytes. RESULTS: Our studies corroborate the presence of AR in synoviocytes. DHT exerts a suppressive effect on IL-1beta induced IL-6, macrophage-colony stimulating factor (CSF), and granulocyte-CSF production by synoviocytes. This modulatory effect is exerted at both the transcriptional and translational level; 17beta-estradiol, at high concentrations, had a stimulatory effect. CONCLUSION: The identification of functional AR in synoviocytes and the modulatory effect of DHT on the inflammatory process in the joint suggest a direct link between hypoandrogenicity and rheumatoid arthritis (RA) disease status. Understanding the complex regulation of inflammatory cytokines by hormones may contribute to the development of new therapeutic targets for clinical intervention in RA.

Adolescent↗
PubMed2003

[Maximal androgen blockade and maximal androgen blockade combined with 125I brachytherapy for prostatic cancer].

OBJECTIVE: To assess the effect of the maximal androgen blockade(MAB) and MAB combined with 125I brachytherapy on prostatic cancer. METHODS: Forty-four patients with prostatic cancer (from 1993 to 2002), 28 at pathologic stage C and 16 at stage D, were analyzed retrospectively. Thirty-five of them were treated by bilateral orchidectomy and anti-androgen drugs, i.e. MAB, and 9 treated by MAB combined with 125I brachytherapy. The survival rates and the variation of serum prostate-specific antigen (PSA) levels between pre- and post-treatment were compared. RESULTS: The level of PSA decreased from 60.3 micrograms/L to 12.1 micrograms/L in 35 patients treated by MAB, and from 72.1 micrograms/L to 3.6 micrograms/L in 9 patients treated by MAB combined with 125I brachytherapy after 6 months. The post-treatment survival rates were 81.3% (26/32, excluding 3 deaths by other diseases) for patients treated by MAB after a mean follow-up of 39.2 (9-84) months and 100% for patients by MAB combined with 125I brachytherapy after a mean follow-up of 13(7-24) months. CONCLUSION: MAB and MAB combined with 125I brachytherapy are effective for patients with prostatic cancer.

Aged↗
PubMed1987

Development of cartilage-like tissue from androgen-dependent Shionogi carcinoma 115 in androgen-depleted hosts.

Androgen-dependent Shionogi carcinoma 115 (SC115) is an undifferentiated medullary carcinoma showing a compact cell pattern. When SC115 was inoculated into castrated DS mice, slowly growing tumors containing cartilage-like tissue developed. The cartilage-like tissue showed close similarities in electron microscopical and histochemical features to normal cartilage tissue. The origin of the cartilage-like cells was investigated by using the electrophoretic pattern of 3-phosphoglycerate kinase (PGK, EC 2.7.2.3) as a marker. The original DS strain had B-type PGK, but we developed a congenic strain with A-type PGK. The SC115 tumor, which had B-type PGK, was grafted into castrated congenic mice with A-type PGK. The cartilage-like tissue that developed was divided into two parts; one part was used for PGK analysis and the other for histological examination. All histologically confirmed cartilage-like tissues had only B-type PGK, suggesting that SC115 cells may change into cartilage-like cells in androgen-depleted conditions.

Androgens↗
PubMed1979

Effect of chronic combined glucocorticoid and estrogen on serum androgens and androgen binding in hirsutism.

Forth-six patients with hirsutism are presented herein. Twenty-four of these patients had menstrual irregularities. Treatment with 5 mg prednisone at bedtime, and 0.625 to 1.25 mg conjugated estrogens daily except during menses resulted in a signficant decrease in serum 17 beta-ol androgens, and an even more statistically significant increase in serum androgen binding. Thus the biochemical abnormalities associated with hirsutism were improved and no apparent side effects were observed.

Adolescent↗
PubMed1982

Mechanisms of action of androgens and antiandrogens: effects of antiandrogens on translocation of cytoplasmic androgen receptor and nuclear abundance of dihydrotestosterone.

The effects of antiandrogens on the translocation of androgen receptor and the accumulation of nuclear dihydrotestosterone in rat ventral prostate were investigated. Using an isotope-exchange assay and radioimmunoassay it was found that 1 hr after the injection of 70 nmol of dihydrotestosterone into 1-day castrated rats, 19,000 +/- 2.350 (mean +/- SE) receptor molecules and 99,300 +/- 8,200 molecules of dihydrotestosterone were recovered per nucleus. When equivalent doses of antiandrogens were substituted for dihydrotestosterone only 0-1,500 receptor molecules were translocated. After injection of antiandrogens followed 1 hr later by injection of dihydrotestosterone, the inhibition of translocation given by the reduction in the mean numbers of molecules of receptor and dihydrotestosterone, respectively, was as follows: 17 beta-estradiol (0, 0); megestrol acetate (2000, 0); diethylstilbestrol (6000, 4000); cyproterone acetate (5500, 27000); flutamide (10000, 29000); R2956 (10000, 28000). With the exception of the effect of cyproterone acetate on receptor translocation, the reductions produced by the latter three antiandrogens were all statistically significant (P less than 0.5). Since less than 20% of the dihydrotestosterone in the nucleus is bound to receptor in dihydrotestosterone-treated rats, and since the concentrations of receptor and dihydrotestosterone are unequally affected by some antiandrogens, we infer that the nuclear abundance of dihydrotestosterone may be regulated in part through nonreceptor-mediated processes.

Androgen Antagonists↗
PubMed2003

Inactivation of androgen receptor coregulator ARA55 inhibits androgen receptor activity and agonist effect of antiandrogens in prostate cancer cells.

Antiandrogens given to antagonize androgen receptor (AR) activity gradually lose their efficacy as antagonists and eventually function as agonists to promote (instead of block) AR-mediated growth of prostate cancer cells. The mechanisms of how antiandrogens acquire this agonist activity during hormonal therapy are largely unknown. Here, we report that expression of a dominant-negative AR-associated protein 55 (dARA55) coregulator, inhibits AR transcriptional activity and reduces the agonist activity of antiandrogens. Inducibly expressed dARA55 inhibits prostate-specific antigen and cell growth in prostate cancer cells. Further dissection of the molecular mechanism shows dARA55 can selectively suppress endogenous AR-associated protein 55 (ARA55) enhanced AR transactivation by means of interruption of dimerization between ARA55 and ARA55. These results were confirmed by using RNA interference-mediated silencing of the ARA55 gene. These results therefore provide evidence that AR function could be suppressed without mutation or change in AR itself. Taken together, these findings not only demonstrate the important roles of the ARA55 coregulator in the AR-mediated growth of prostate cancer, they also may provide a critical target for developing therapeutic agents for the antiandrogen therapy that almost always fails in the treatment of hormone-refractory prostate cancer.

Androgen Antagonists↗
PubMed1998

Androgen-independent basal cell re-epithelialization, c-erbB-2 mRNA expression and androgen-dependent EGFr mRNA expression in benign prostatic hyperplasia explant cultures treated with finasteride.

We have analyzed the effects of the 5alpha-reductase inhibitor, finasteride (MK906), on the mRNA expression of the epidermal growth factor receptor and c-erbB-2 genes, in benign prostatic hyperplasia explant cultures treated with testosterone and with testosterone plus finasteride. A decrease of the epithelial cell content and an androgen-independent basal cell re-epithelialization was observed during the first 10 days of culture, suggesting a role of basal cells as stem cells involved in androgen-independent epithelial regeneration. Using a semi-quantitative reverse transcription polymerase chain reaction technique, we observed a significant decrease in expression of the epidermal growth factor receptor in the cultures treated with finasteride whereas no effect of finasteride on c-erbB-2 transcription was detected, although the expression of both genes was increased by dihydrotestosterone.

Cholestenone 5 alpha-Reductase↗
PubMed1993

Effects of pretreatment with androgen or thyroid hormone on androgen-induced proliferation of granular convoluted tubular cells in mouse submandibular glands.

The effects of pretreatment with androgen or thyroid hormone on androgen-induced proliferation of granular convoluted tubular cells (GCT cells) in the submandibular glands of ovariectomized female BALB/c or C57BL/6 mice were investigated. The proliferation of GCT cells was estimated by their labeling index. Daily injections of 5 alpha-dihydrotestosterone (DHT) (100 micrograms/mouse/day) caused a transient increase in the labeling index of GCT cells of ovariectomized 60-day-old BALB/c mice during the first four injections, but injections of thyroxine (T4) (15 micrograms/mouse/day) did not. On the other hand, both DHT and T4 increased the esteroprotease activity, a marker of the differentiation of GCT cells, time dependently. Injections of DHT into ovariectomized 102-day-old BALB/c mice also caused a transient increase in the labeling index of GCT cells. However, pretreatment of ovariectomized 60-day-old BALB/c mice with DHT for 4 or 14 days completely abolished the DHT-induced increase in the labeling index of 102-day-old mice, and pretreatment with T4 for 14 days reduced this increase. Pretreatment with DHT or T4 for 14 days did not affect the DHT-induced increase in esteroprotease activity. Pretreatment of ovariectomized 60-day-old C57BL/6 mice with DHT for 14 days also completely abolished the DHT-induced increase in the labeling index of GCT cells at the age of 102 days, but pretreatment with T4 for 14 days did not affect the increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1976

Density regulation of amino acid transport in cultured, androgen-responsive tumour cells.

In androgen-responsive cells, activity of a sodium-dependent transport system for neutral amino acids is shown to be density-dependent, whereas activity of a sodium-independent system is not. Transport of the non-metabolizable amino acid, alpha-aminoisobutyric acid (alpha-aib) was largely sodium-dependent, whereas transport of cycloleucine (cyleu) was by both sodium-dependent and sodium-independent systems. The Km for cyleu transport changed with density because only the sodium-dependent portion of this transport was density-dependent. By contrast, the Vmax for alpha-aib transport changed with density, indicating that either the amount of functional membrane carrier or the activity of the sodium pump was affected.

Amino Acids↗
PubMed1994

Synergistic effects of estrogen with androgen on the prostate--effects of estrogen on the prostate of androgen-administered rats and 5-alpha-reductase activity.

To clarify the effects of estrogen on the prostate of androgen-treated rats, we administered estradiol (E2; 0.01 mg/day) to testosterone (T; 1 mg/day)-treated Wistar rats under various conditions. There were three variable factors: the age of the rat, the untreated period after castration, and the presence of testes. Under all conditions, E2 stimulated the growth of the prostate in T-treated rats compared with growth in rats in treated with T only. To analyze the mechanism underlying this enhancement of prostate growth by estrogen, we measured 5-alpha-reductase activity and calculated its kinetic parameters, i.e., both Vmax and Km. The Vmax of the nuclear fraction was higher in E2-administered T-treated rats than in T only-treated rats. In contrast, the Vmax of the microsomal fraction was lower in E2-administered rats. Km values in the two groups showed no significant differences. Elevation of the nuclear fraction of 5-alpha-reductase activity could explain the synergistic effects of estrogen on the prostate growth of androgen-treated rats.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗