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The effects of both androsterone and hemisuccinate of androsterone on the perfusion pressure and vascular resistance in isolated rat hearts (Langendorff model) were evaluated.
Several studies have suggested that testosterone has a role in nociception. Recently, we have shown that castration and flutamide, a testosterone antagonist, induce analgesia in the late phase of formalin test, which is related to increase of 5-HT levels in the dorsal horn of the lumbar spinal cord. The aim of the present study was to investigate the effect of fluoxetine, a selective serotonin reuptake inhibitor, on castration and flutamide-induced analgesia in order to further explore the role of 5-HT systems in such analgesia. Four weeks after castration, there was an analgesia in the late phase of formalin test, and this was potentiated by acute (0.32 mg kg(-1) ip) treatment of fluoxetine. Furthermore, coadministration of fluoxetine (0.32 mg kg(-1) ip) and flutamide (10 mg kg(-1) ip) produced more antinociceptive effect than those animals receiving fluoxetine and flutamide alone. The analgesic effect of fluoxetine (0.32 mg kg(-1) ip) and flutamide (10 mg kg(-1) ip) was abolished by pretreatment with 5,7-DHT (100 microg/rat it) and naloxone (2 mg kg(-1) ip). In summary, our data suggest that fluoxetine and flutamide have antinociceptive effects in tonic inflammatory pain through functional alteration of serotonergic systems, and their effects are potentiated by coadministration. The possible role of opioidergic system in their antinociceptive effect cannot be neglected.
Recently, others and we have demonstrated that prenatal exposure to an extremely low dose of diethylstilbestrol (DES) and other estrogenic compounds produces a significant effect on mouse prostate development in vivo and in vitro in the presence and absence of androgen. In this study, we investigated the mechanism by which DES produces this effect and determined the role of its estrogenic activity on the growth and branching, induced by DES in the 17-day-old fetal prostate in culture. Additionally, we investigated whether the androgen receptor (AR) plays a role and whether any of the growth factors, namely, EGF and IGF-1 which are known to modulate the estrogen receptor (ER) and androgen receptor (AR)-dependent process, mediate the DES-induced effects. Using the organ culture bioassay of prostate development, we demonstrate that DES enhanced the growth and branching of the prostate at both 0.1 and 0.5 pg/ml dosages, thus, confirming a previous report of ours. An anti-estrogen, ICI164,387 blocked both of the effect of DES, suggesting that both of these two effects are ER dependent. Anti-androgen, flutamide also blocked both branching and prostatic growth induced by DES, while cyproterone acetate blocked only the branching effect, suggesting a role for AR in the DES-induced effects. Depletion of EGF by anti-EGF antibody blocked the DES-induced effects and this was reversed following EGF replacement in the organ culture system. Anti-IGF-1 antibody, on the other hand, only blocked the branching effect, but produced no effect on the prostatic growth, induced by DES. Estrogenic chemicals, bisphenol A and DES enhanced EGF-mRNA level of the cultured prostates. Taken together, it appears that DES-induced prostatic enlargement involves enhancement of ER-dependent EGF and IGF-1 synthesis, mediating prostatic enlargement and androgen action.
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A functional model of adult human prostate epithelium is described. This model shows that stromal cells, but not an androgenic stimuli, are required for architectural organisation of prostate epithelium. Within an organised structure, androgenic stimulation is required for the establishment of secretory epithelial cell morphology and associated function. In the absence of stromal cells but in the presence of androgens architectural organisation and secretory function are lost. Epithelial parenchymal units (organoids) from human prostate tissue were isolated, cultured within a three-dimensional collagen matrix, and xenografted subcutaneously into athymic mouse hosts. The grafted gels were rapidly invaded by host fibroblasts. Epithelial organisation initially disappeared but was re-established concurrently with the stromal cell invasion. In intact male hosts, cuboidal and columnar cells that expressed human prostate-specific secretory markers were found. In castrated male and in female hosts epithelial structures were lined with flattened epithelium with no secretory function. This phenomenon could be reversibly replicated by treating intact male hosts with the anti-androgen Flutamide. Gels containing organoids grafted within 0.45 microns Millipore chambers were not invaded by stromal cells and rapidly lost all epithelial organisation and secretory function. When organoids cocultured with human foreskin fibroblasts were grafted within chambers, structural organisation of the epithelium was supported. These results indicate that both heterologous human fibroblasts and mouse stromal cells are capable of permissively supporting adult human prostate epithelial function.
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We carried out a prospective study to determine and compare the prostate-specific antigen (PSA) response and survival in patients with hormone relapsed prostate cancer (HRPC), all of whom had previously shown a good response to medical or surgical castration. The patients were randomised to treatment with diethylstilboestrol (DES) and aspirin, or the antiandrogen flutamide. In addition, quality of life was determined by interview and questionnaire.
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Cognitive dysfunction is known to be influenced by circulating sex steroidal hormones. The aim of this study was to examine the protective effect and possible protective mechanism of testosterone (T) on cognitive performance in male rats induced by intrahippocampal injections of beta amyloid 1-42 oligomers (Aβ1-42). Treatment with T as evidenced by the Morris water maze (MWM) test significantly shortened escape latency and reduced path length to reach the platform compared to the control (C). During probe trials, the T group displayed a significantly greater percent of time in the target quadrant and improved the number of platform crossings compared with C, flutamide (F), an antiandrogen, and a combined F and T group. Flutamide markedly inhibited the influence of T on cognitive performance. Following Nissl staining, the number of intact pyramidal cells was significantly elevated in the T group, and the effect of T was blocked by F. Immunohistochemisty and Western blot analysis showed that the protein expression level of Aβ 1-42 was markedly decreased and expression levels of synaptophysin (SYN) significantly increased with T, while F inhibited all T-mediated effects. Our data suggest that the influence of T on cognitive performance was mediated via androgen receptors (AR) to remove beta amyloid, which leads to enhanced synaptic plasticity.
While there are many suggested reasons for the marked gender bias in cardiovascular events, much of the available data indicate that circulating estrogens are cardioprotective. The possibility that endogenous androgens may be detrimental to the cardiovascular system has received relatively less attention. We investigated the short-term modulatory effects of various concentrations of testosterone on vascular function in isolated porcine coronary artery rings.
The 26S proteasome is a ubiquitin-dependent proteolytic system that has been implicated in the regulation of cell cycle progression and apoptosis. We investigated the effects of the proteasome inhibitors MG115 and PSI alone or in combination with different concentrations of the antiandrogen hydroxyflutamide on the cellular proliferation, apoptosis and viability of 10 prostatic adenocarcinoma cell cultures. Treatment with both proteasome inhibitors resulted in apoptosis induction, whereas the combinations with hydroxyflutamide generally did not, with the exception of MG115 combined with 10(-7) M hydroxyflutamide. MG115 caused a significant decrease in cellular proliferation, as did the combinations of both proteasome inhibitors with hydroxyflutamide, whereas hydroxyflutamide alone was only effective at a concentration of 10(-5) M. Cellular viability was significantly reduced when both proteasome inhibitors were combined with 10(-5) M hydroxyflutamide. Although the results varied among different cell lines, we conclude that proteasome inhibitors are able to induce apoptosis and reduce cellular proliferation. They might prove effective as antineoplastic substances in prostatic adenocarcinoma alone or in combination with antiandrogens.
Doppler flow measurement of the uterine artery and serum hormone concentration determination during the early follicular phase of the menstrual cycle before treatment and during the third month of treatment.
A recombinant human androgen receptor yeast assay was applied to investigate the occurrence of antiandrogens as well as the mechanism for their removal during gray wastewater and coking wastewater treatment. The membrane reactor (MBR) system for gray wastewater treatment could remove 88.0% of antiandrogenic activity exerted by weakly polar extracts and 97.3% of that by moderately strong polar extracts, but only 32.5% of that contributed by strong polar extracts. Biodegradation by microorganisms in the MBR contributed to 95.9% of the total removal. After the treatment, the concentration of antiandrogenic activity in the effluent was still 1.05 μg flutamide equivalence (FEQ)/L, 36.2% of which was due to strong polar extracts. In the anaerobic reactor, anoxic reactor, and membrane reactor system for coking wastewater treatment, the antiandrogenic activity of raw coking wastewater was 78.6 mg FEQ/L, and the effluent of the treatment system had only 0.34 mg FEQ/L. The antiandrogenic activity mainly existed in the medium strong polar and strong polar extracts. Biodegradation by microorganisms contributed to at least 89.2% of the total antiandrogenic activity removal in the system. Biodegradation was the main removal mechanism of antiandrogenic activity in both the wastewater treatment systems.
We have investigated the role of autocrine/paracrine TGF-beta secretion in the regulation of cell growth by androgens as demonstrated by its inhibition by two androgen response modifiers; the nonsteroidal antiandrogen hydroxyflutamide (OHF), believed to act by inhibiting androgen binding to androgen receptors, or finasteride, an inhibitor of 5alpha-reductase, the enzyme necessary for the conversion of testosterone to 5alpha-dihydrotestosterone (DHT), using the nontumorigenic rat prostatic epithelial cell line NRP-152. Growth of these cells was stimulated three- to sixfold over control by either testosterone or DHT under serum-free culture conditions. This was accompanied by a two- to threefold decrease in the secretion rate of TGF-beta1, -beta2, and -beta3. Finasteride reversed the ability of testosterone but not DHT to stimulate growth and downregulate expression of TGF-beta1, -beta2, and -beta3 in a dose-dependent fashion, suggesting that this activity of testosterone required its conversion to DHT. OHF antagonized the stimulatory effects of DHT on NRP-152 cell growth but could reverse the inhibitory effects of DHT only on TGF-beta2 and TGF-beta3 and not TGF-beta1 secretion. This suggests that either TGF-beta1 regulation by DHT or the androgen antagonism of OHF occurs independent of androgen receptor binding. Neutralizing antibodies to TGF-beta (pantropic and isoform-specific) were able to block the ability of finasteride to antagonize the effects of testosterone nearly completely while only partially inhibiting the antiandrogenic effects of OHF. Thus, the ability of androgens to stimulate growth of NRP-152 cells involves the downregulation of the production of TGF-beta1, -beta2, and -beta3 in addition to other growth-stimulatory mechanisms.
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A rapid phosphorylation expression of ERK1/2 was observed by treatment of the HUVECs with 3 x 10(-8) mol/L testosterone, especially at 30 minutes. This phosphorylation was greatly inhibited by incubation with androgen receptor antagonist flutamide for 3 hours previously.
These promising preliminary findings, a number of issues remain to be determined before non-steroidal antiandrogen monotherapy can be considered to be routine clinical practice. These include optimum indication and dosage, long-term clinical efficacy and tolerability, and response to second-line therapy.
Experiments on intact mature male Wistar rats showed the ability of hydroxyniftolide (4'-nitro-3'-trifluoromethyl-2-hydroxy-2-methylpropionylanilide), a hydroxylated antiandrogen derivative of niftolide, to inhibit the effects of male sex hormones in androgen target organs. At doses of 10 mg/kg and upwards administered intravenously or intramuscularly for 10 days, it stimulated the hypothalamohypophy-seogonadal system expressed in an increase in the activity of delta 5-steroid-3 beta-ol-dehydrogenase in the testicles and blood plasma testosterone concentration. Comparative studies on antiandrogenic properties of niftolide and hydroxyniftolide made it possible to show that the effect of the first agent was more noticeable with relation to the hypothalamic centers of gonadotropin secretion regulation whereas the effect of the second one was more noticeable in the accessory sex glands.
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Rat hearts from age-matched adult males, females, castrated males, males with androgen receptor blocker-flutamide, castrated males with chronic 5α-dihydrotestosterone (DHT) implantation, or acute testosterone infusion (ATI) (n = 9/group) were subjected to I/R (Langendorff). Castration or flutamide treatment significantly up-regulated myocardial Akt activation, increased downstream apoptosis-regulatory molecules p-Bad, Bcl-2, p-FOXO3a, but reduced Fas-L, consistent with decreased myocardial injury in male hearts following I/R. ATI administration, but not chronic DHT, reversed these effects on Akt signaling associated with further exacerbated cardiac dysfunction in castrated males. Notably, lower levels of MnSOD were observed in male hearts, and castration or flutamide treatment restored myocardial MnSOD expression to the levels of females in male hearts after I/R.
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Primary CAB treatment brought initial disease control without relapse in the majority of our selected cases. The %PBC may help predict time to relapse in the pretreatment setting. The results implicate that CAB can be an option as a primary treatment for clinically localized prostate cancer unsuitable for local definitive treatment. To confirm the exact efficacy of primary CAB, these findings should be reviewed in a large cohort of patients with long-term follow-up from various viewpoints, including disease control, toxicities, quality-of-life and medical cost.
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These findings suggest that treatment with a balanced formulation including all ovarian hormones may prevent or reduce estrogenic cancer risk in the treatment of girls and women with ovarian failure.
The involvement of androgens in the control of ovulation has been assessed by administration of the androgen antagonist, hydroxyflutamide, to prepubertal rats treated with pregnant mare's serum gonadotropin (PMSG) to induce first estrus and ovulation. Without human chorionic gonadotropin (hCG) injection, only 46% of rats that received six 5-mg, s.c. injections of hydroxyflutamide at 12-h intervals, beginning an hour before s.c. injection of 4 IU PMSG on Day-2 (Day 0 = the day of proestrus), had ovulated a mean of 1.3 +/- 0.4 oocytes per rat when killed on the morning of Day 1, whereas 92% of sesame oil-treated controls had ovulated a mean of 6.9 +/- 0.6 oocytes. After i.p. injection of hCG at 1600 h on Day 0, 92% of hydroxyflutamide-treated rats ovulated a mean of 8.3 +/- 1.2 oocytes compared to 100% of controls, which ovulated 7.3 +/- 0.4 oocytes per rat: these groups were not significantly different from each other, nor from control rats that received no hCG. Thus, exogenous hCG completely overcame the inhibitory effect of hydroxyflutamide on ovulation. Rats treated with PMSG and hydroxyflutamide without hCG were killed either on the morning of Day 0 to determine serum and ovarian steroid levels or on the afternoon of Day 0 to determine serum LH levels. Serum levels of estradiol-17 beta and testosterone in hydroxyflutamide-treated rats were significantly higher (178% and 75%, respectively; p less than 0.01) than levels observed in controls on the morning of Day 0. Ovarian concentrations of the steroids were also elevated in hydroxyflutamide-treated rats (p less than 0.01 for testosterone only).(ABSTRACT TRUNCATED AT 250 WORDS)
No marked effect of race on clinical outcome was observed regardless of antiandrogen, suggesting that similar treatment benefits are to be expected in either race.
Increasing evidence suggests that AR (androgen receptor) acetylation is critical for prostate cancer cell growth. In the present study, we identified Pro-B3 (procyanidin B3) as a specific HAT (histone acetyltransferase) inhibitor. Pro-B3 selectively inhibited the activity of HATs, but not other epigenetic enzymes. Pro-B3 substantially inhibited the p300-mediated AR acetylation, both in vitro and in vivo. Pro-B3 inhibited both p300-dependent and agonist-induced AR transcription. We demonstrate that the p300-mediated AR acetylation is critical for the hormone responsiveness of AR. Interestingly, B3 treatment efficiently enhanced the antagonist activity of flutamide through suppression of p300 HAT activity, demonstrating that relative p300 activity is critical for the antagonist action. Finally, Pro-B3 treatment inhibited acetylation-dependent prostate cell proliferation and expression of cell-cycle control genes, subsequently increasing cell death, indicating the functional importance of AR acetylation for prostate cancer cell growth.
Histrelin, a potent luteinizing hormone releasing hormone (LHRH) agonist, and flutamide, an antiandrogen, were administered to intact and adrenalectomized rats to determine the role of adrenal androgens in the additive effects of the two drugs on prostate regression. Each compound, given separately, was effective in decreasing prostate weights in intact rats. When given together, additive effects were demonstrated by even greater atrophy of the prostates. It has previously been proposed that this additive effect may be primarily attributed to the ability of the antiandrogen to block the action of adrenal androgens. However, in adrenalectomized rats, the combination of histrelin and flutamide still produced a greater reduction in prostate weights than did either drug alone, indicating that the role of adrenal androgens in this effect is negligible. This experiment also was repeated with castrate, androgen-supplemented rats, and the additive effects previously described were not observed. In a final experiment, prostatic atrophy in castrate rats was not enhanced by either adrenalectomy or flutamide treatment. Thus, the additive effects of histrelin and flutamide appear to focus on testicular rather than adrenal androgens.
Macrophage migration inhibitory factor (MIF) is a ubiquitary cytokine whose expression has been investigated in tumors, showing a correlation between tumor aggressiveness and production of this protein by neoplastic cells. The aim of our study was to correlate MIF expression with tumor grade (Gleason scoring system) and histopathological changes after combined endocrine treatment (CET) of prostate adenocarcinoma.
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Classic congenital adrenal hyperplasia (CAH) requires lifetime steroid replacement and supraphysiologic glucocorticoid dose is often required for adequate adrenal androgen suppression. Patients often suffer from long-term co-morbidities and female infertility is common.