The ErbB3-binding protein Ebp1 suppresses androgen receptor-mediated gene transcription and tumorigenesis of prostate cancer cells.
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Down-regulation of the androgen receptor (AR) is being evaluated as an effective therapy for the advanced stages of prostate cancer. We report that Ebp1, a protein identified by its interactions with the ErbB3 receptor, down-regulates expression of AR and AR-regulated genes in the LNCaP prostate cancer cell line. Using microarray analysis, we identified six endogenous AR target genes, including the AR itself, that are down-regulated by ebp1 overexpression. Chromatin immunoprecipitation assays revealed that Ebp1 was recruited to the prostate-specific antigen gene promoter in response to the androgen antagonist bicalutamide, suggesting that Ebp1 directly affected the expression of AR-regulated genes in response to androgen antagonists. Ebp1 expression was reduced in cells that had become androgen-independent. Androgens failed to stimulate either the growth of ebp1 transfectants or transcription of AR-regulated reporter genes in these cells. The agonist activity of the antiandrogen cyproterone acetate was abolished in ebp1 transfectants. In severe combined immunodeficient mice, Ebp1 overexpression resulted in a reduced incidence of LNCaP tumors and slower tumor growth. These findings suggest that Ebp1 is a previously unrecognized therapeutic target for treatment of hormone refractory prostate cancer. (+info)
Influence of exogenous oestrogen or (anti-) androgen administration on soluble transferrin receptor in human plasma.
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The objective of this investigation was to study the effects of sex steroids on levels of haemoglobin (Hb) and haematocrit (Hct) and to analyse whether these effects can be related to levels of the soluble transferrin receptor (sTfR), a marker of erythropoietic activity. Nineteen male-to-female transsexuals were randomly assigned to either oral ethinyl oestradiol (EE) (n=12) or transdermal 17beta-oestradiol (E2) (n=7); both treatments included the anti-androgen cyproterone acetate (CA). Six male-to-female transsexuals were treated with CA only. Fifteen female-to-male transsexuals were treated with i.m. testosterone esters. The Hct, and levels of Hb, IGF-I, GH and sTfR were measured before and after 4 months of hormone administration. Androgen administration significantly increased the sTfR concentration by 31.5% (P=0.008) and increased levels of Hct, Hb and IGF-I. Both regimens of CA with oral EE and transdermal E2 reduced plasma testosterone similarly to castrate values and decreased Hb and Hct. The CA+oral EE combination induced a decrease in sTfR of 19.0% (P=0.002) which was not the case with CA+transdermal E2 (P=0.27). This cannot be explained by the profound decline in plasma testosterone which was similar with both regimens, but this difference could be related to the different effects of the two regimens on plasma IGF-I. This assumption is supported by the positive correlation that was found to exist between plasma sTfR and IGF-I after the interventions (P<0.05). (+info)
Simultaneous determination of cyproterone acetate and ethinylestradiol in tablets by derivative spectrophotometry.
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Derivative spectrophotometry offers a useful approach for the analysis of drugs in multi-component mixtures. In this study a third-derivative spectrophotometric method was used for simultaneous determination of cyproterone acetate and ethinylestradiol using the zero-crossing technique. The measurements were carried out at wavelengths of 316 and 226 nm for cyproterone acetate and ethinylestradiol respectively. The method was found to be linear (r2>0.999) in the range of 0.5-6 mg/100 ml for cyproterone acetate in the presence of 35 microg/100 ml ethinylestsradiol at 316 nm. The same linear correlation (r2>0.999) was obtained in the range of 10-80 microg/100 ml of ethinylestradiol in the presence of 2 mg/100 ml of cyproterone acetate at 226 nm. The limit of determination was 0.5 mg/100 ml and 10 microg/100 ml for cyproterone acetate and ethinylestradiol respectively. The method was successfully applied for simultaneous determination of cyproterone acetate and ethinylestradiol in pharmaceutical preparations without any interferences from excipients. (+info)
Rosiglitazone and ethinyl estradiol/cyproterone acetate as single and combined treatment of overweight women with polycystic ovary syndrome and insulin resistance.
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BACKGROUND: Few studies have evaluated insulin sensitizers in comparison/association with oral contraceptives (OC) in women with polycystic ovary syndrome (PCOS) with insulin resistance (IR). This study assessed the effects of a thiazolidinedione versus an anti-androgenic estrogen-progestin followed by their sequential combinations in overweight PCOS women. METHODS AND RESULTS: Twenty-eight candidates in whom elevated insulin was not normalized after 4 months of diet were randomly assigned to 6 months of rosiglitazone 4 mg/day or to ethinyl estradiol 35 mg/cyproterone acetate 2 mg (EE/CPA: 21/28 days cycle). Each group then received both medications for another 6 months. Rosiglitazone reduced insulin, IR indices [homeostasis model assessment (HOMA) and quantitative sensitivity check index (QUICKI)] and the insulin area under the curve in response to an oral glucose tolerance test (OGTT), but had limited effect on lipids, androgens and hirsutism. EE/CPA did not modify insulin and OGTT response but increased high-density lipoprotein cholesterol and triglycerides and decreased androgens and hirsutism. Similar changes occurred during combined treatments. End results were highly significant in combined groups without noticeable side-effects or changes in safety parameters. CONCLUSIONS: In obese PCOS women with high insulin not corrected by diet, the combination of rosiglitazone and EE/CPA may be used to achieve complementary beneficial effects on endocrine-metabolic anomalies and clinical symptoms. (+info)
Disappearance of a virilizing adrenal tumor following therapy with cyproterone acetate.
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A 57-year-old woman presented with an apparently obvious diagnosis of iatrogenic virilization. At the age of 51, she began a 4-year treatment with prednisone or cyclosporine, which are known to promote hair growth, for Behcet disease. At the age of 56, osteoporosis was overtreated with the anabolic steroid nandrolone. Insignificant inhibition by dexamethasone of the extremely high serum concentrations of testosterone and less high concentrations of weak androgens prompted us to search for a virilizing tumor. Computed tomography showed a 2.3 x 1.5 cm nodule in the right adrenal gland. As the patient refused surgery, virilization was treated with the antiandrogen cyproterone acetate (CPA), but for only 4 months because clinical and hormone abnormalities reversed and the tumor was no longer visible. The patient remains symptom-free. This first report of a curative effect of CPA on a purely virilizing adrenal tumor opens new avenues in the management of such tumors. (+info)
Atmospheric pressure photoionization applied to quantitation of cyproterone acetate in human plasma.
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Cyproterone acetate [6-chloro-1beta,2beta-dihydro-17alpha-hydroxy- 3'H-cyclopropa(1,2)-pregna-1,4,6-triene-3,20-dione acetate] is a powerful antiandrogen used in the treatment of women suffering from disorders associated with androgenization such as hirsutism and acne. A fast, sensitive, and robustness method is developed for the determination and quantitation of cyproterone acetate in human blood plasma by liquid chromatography coupled with tandem mass spectrometry. Cyproterone acetate is extracted from 0.2 mL human plasma by liquid-liquid extraction. The method has a chromatographic run of 4.5 min, using a C18 analytical column (100- yen 2.1-mm i.d.), and the linear calibration curve over the range is linear from 1 to 500 ng/mL (r2 > 0.994). The between-run precision, based on the relative standard deviation replicate quality controls, is 96.2% (3 ng/mL), 97.5% (120 ng/mL), and 99.1% (400 ng/mL). The between-run accuracy was +/- 2.7%, 3.1%, and 4.8% for the previously mentioned concentrations, respectively. The method is employed in a bioequivalence study of two tablet formulations of cyproterone acetate (100 mg). (+info)
The efficacy of topical cyproterone acetate alcohol lotion versus placebo in the treatment of the mild to moderate acne vulgaris: a double blind study.
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Acne is an inflammatory condition of the pilosebaceous unit. One of the essential factors for development of acne lesions is increased sebum excretion that is promoted by androgen. It is shown that oral cyproterone acetate significantly reduces the sebum excretion. In this study we evaluated the efficacy of cyproterone acetate alcohol lotion (CAAL) in the treatment of the mild to moderate acne vulgaris. This was a randomized double-blind clinical trial performed on 86 female patients with mild to moderate acne. They were randomly divided into 3 groups and were treated with 0.5 percent CAAL (n = 30), 1 percent CAAL (n = 13) and placebo (n = 43). They were followed every 15 days for a period of 45 days. Response to treatment was evaluated by the total acne lesions counting (TLC) and acne severity index (ASI) and was analyzed statistically by SPSS program. The efficacy of treatment on TLC was maximum for 1 percent CAAL (90 % reduction in TLC)(P value = 0.000). CAAL at 0.5 percent was able to reduce TLC as high as 80.8 percent during 6 weeks followup. The efficacy of placebo was determined to be 38.5 percent. Regarding TLC, 1 percent CAAL was 2.33 times more effective than placebo. CAAL at 0.5 percent was 2.09 times more effective than placebo in this respect. The efficacy of treatment on ASI was maximum for 1 percent CAAL (88 % reduction in ASI)(P value = 0.000). CAAL at 0.5 percent reduced ASI as much as 79.5 percent during 6 weeks of followup. The efficacy of placebo was calculated to be 9.8 percent in reduction of ASI . Regarding ASI, 1 percent CAAL was 8.97 times more effective than placebo. CAAL at 0.5 percent was 8.06 times more effective than placebo. Regarding the results of this study, we suggest the use of cyproterone acetate alcohol lotion as one of the main treatments for mild-moderate acne in female patients and as an adjuvant treatment for moderate to severe acne vulgaris. (+info)
Serum and urine tissue kallikrein concentrations in male-to-female transsexuals treated with antiandrogens and estrogens.
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BACKGROUND: The expression of human tissue kallikrein genes is regulated by steroid hormones, but most studies have been conducted with cancer cell lines. Our purpose was to examine serum and urinary tissue kallikrein concentration changes in male-to-female transsexuals before and after treatment with antiandrogens and estrogens. METHODS: Thirty-five male-to-female transsexuals receiving cyproterone acetate and estrogens (orally or transdermally) were included in this study. Serum and urine samples were collected before initiation of therapy and 4 and 12 months post therapy. ELISAs were used to measure multiple kallikreins in serum and urine. RESULTS: After antiandrogen and estrogen therapy, serum testosterone concentrations decreased dramatically, as did serum and urinary concentrations of human glandular kallikrein (hK2) and prostate-specific antigen (PSA; hK3). Statistically significant but relatively small changes in serum and urinary concentrations of many other kallikreins were also seen. Kallikreins in serum and urine were correlated before and after treatment. CONCLUSIONS: The concentrations of hK2 and hK3, but not of any other kallikreins, decrease dramatically after combined antiandrogen and estrogen treatment in male-to-female transsexuals. The smaller responses of the other kallikreins presumably reflect their expression in multiple tissues. (+info)