Influence of cyproterone acetate on the concentration of dihydrotestosterone, androgen receptor and glandular weight in the rat ventral prostate
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Journal Article Influence of cyproterone acetate on the concentration of dihydrotestosterone, androgen receptor and glandular weight in the rat ventral prostate Get access J K Huang, J K Huang Abteilung Klinische Chemie, II. Medizinische Universitätsklinik, Hamburg Search for other works by this author on: Oxford Academic Google Scholar W Bartsch, W Bartsch Abteilung Klinische Chemie, II. Medizinische Universitätsklinik, Hamburg Search for other works by this author on: Oxford Academic Google Scholar K D Voigt K D Voigt Abteilung Klinische Chemie, II. Medizinische Universitätsklinik, Hamburg Search for other works by this author on: Oxford Academic Google Scholar Acta Endocrinologica (Norway), Volume 110, Issue 1_Supplement_a, Apr 1979, Pages S95–S96, https://doi.org/10.1530/acta.0.109S095 Published: 01 April 1985Keywords:
Cyproterone
Dihydrotestosterone
Dihydrotestosterone
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Cyproterone acetate の投与による睾丸の造精機能および内分泌機能の変化を雄ラットで検討する目的で, 成熟雄ラットに cyproterone acetate を10mg/kg/day連日2週間又は4週間投与し, 投与終了時に血漿中LH, FSH, testosterone 値を測定し, 電気刺激射精法によつて得られた精液中精子数を算定した. さらに摘出睾丸潅流法により睾丸の progesterone, 17α-hydroxyprogesterone および testosterone 分泌能を測定し, 睾丸間質の組織学的所見と併せて対照群と cyproterone acetate 投与群と比較検討した. Cyproterone acetate 投与後の睾丸重量は, 対照群と比べ有意差はなく, 組織学的には, 精細管精子細胞の変性が認められたが, 睾丸間質細胞数には対照群と差はなかつた. 射精液中の精子数は対照群で742±200×104 (mean±SEM) に対し, cyproterone acetate 投与群で399±89×104と減少したが両者間に有意差はなかつた. 血中LH, FSH値は本剤投与により有意に上昇し (p<0.001), 逆に testosterone 値は有意に減少した (p<0.05). 睾丸潅流法による testosterone 分泌能は, 対照群の3.39±0.67ng/minに対し, 投与2週後で1.55±0.67ng/minと減少し, 投与4週後には0.91±0.21ng/minと有意に抑制された (p<0.001). また cyproterone acetate 投与により, 睾丸の progesterone 分泌能は対照群と比べ有意差はなかつたが, 17α-hydroxyprogesterone 分泌能は有意に増加した (p<0.05). この事実から cyproterone acetate が睾丸の17, 20 desmolase もしくは 17ketosteroid reductase 活性を抑制する可能性が示唆された.
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Androgens secreted by the testes bind the androgen receptor in developing target tissues to induce the expression of genes required for male sexual differentiation and development. Androgen concentration and androgen receptor levels vary in male reproductive target tissues during development. Exposure to environmental androgen antagonists during critical windows of fetal and postnatal development can inhibit male sexual development by blocking transcription of androgen-dependent genes. As the sensitivity to androgen antagonists under conditions of varying androgen concentrations and varying androgen receptor levels is unknown, we used a luciferase reporter assay to investigate the transcriptional effects of a known androgen antagonist (the vinclozolin metabolite M2) at different androgen concentrations and different androgen receptor levels. The ability of M2 to inhibit transcription was greater at lower concentrations of androgen (5α-dihydrotestosterone) and androgen receptor. The data were modeled to determine the dose-response surface of M2 and androgen receptor concentrations at different 5α-dihydrotestosterone levels and the relationship of the 3 components to the response. The model and hypothesis testing results suggest that, at 0.01 and 0.1 nM 5α-dihydrotestosterone concentrations within the expected in vivo range of free androgen levels during development, the response-surface shapes were similar and the interaction of the androgen receptor and M2 concentrations to the response were similarly antagonistic. Thus, two components of the developmental stage, androgen and androgen receptor concentrations, are critical for sensitivity to the inhibitory effects of an androgen antagonist.
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Male Wistar rats were treated for three weeks with cyproterone (1·7 or 5·1 mg/day) or cyproterone acetate (2 or 6 mg/day). The adrenal weights of animals treated with either dose of cyproterone acetate were significantly less ( P < 0·001) than those of untreated animals. In contrast, the adrenal weights of animals treated with cyproterone did not differ from those of the controls. The concentrations of corticosterone in the plasma were significantly less ( P < 0·001) in both groups treated with cyproterone acetate compared with those of the controls; only the higher dose of cyproterone reduced the plasma concentration of corticosterone ( P < 0·001). Cyproterone acetate inhibited the rat adrenal 3β-hydroxysteroid dehydrogenase–5-ene,4-ene-isomerase complex in vitro , with both pregnenolone and dehydroepiandrosterone as substrates. Analysis of the reaction rates suggested an uncompetitive mode of inhibition. These results suggest that in rats the antiandrogens cyproterone and cyproterone acetate may provoke adrenal insufficiency by inhibition of steroid biosynthesis. Furthermore, indirect evidence from the mass and morphology of the adrenal suggests that cyproterone acetate may also suppress production or secretion of ACTH by the pituitary gland.
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Slices from canine prostate were superfused with [17alpha-3H] testosterone and 5alpha-dihydro[1,2-3H]testosterone at 'physiological' concentrations; to some wuperfusions, either [3H]cyproterone or [3H]cyproterone acetate was also added. The following parameters were measured: 'uptake' of anti-androgen by the tissue, rate of entry of testosterone and 5alpha-dihydrotestosterone into the tissue, rate of efflux from the tissue of 5alpha-dihydrotestosterone and concentration of 'diffusible' 5alpha-dihydrotestosterone in the slices. The adsorption of steroids on to the surface of the slices and the bulk flow of tritiated water into the slices were also investigated. It was concluded that these two factors did not interfere with the measurement of entry and efflux of the androgens. Cyproterone and cyproterone acetate were not metabolized, but were concentrated in the slices to many times the level in the medium. With rate of supply of anti-androgens up to 43 pmol/min, their uptake increased together with the rate of entry of the two androgens and the rate of efflux of 5alpha-dihydrotestosterone. At a higher rate of supply of anti-androgens, their uptake and the rates of entry and efflux of the androgens decreased sharply. In most cases, the inward movement of 5alpha-dihydrotestosterone into the slices took place against a negative concentration gradient, while that of testosterone always occurred down a positive concentration gradient. These results confirmed the hypothesis already put forward that 'carriers' involved in the transport of androgens are present in the membrane of prostatic cells (Giorgi, Moses, Grant, Scott & Sinclair, 1974). Non-specific and specific intracellular binding, exhibiting greater affinity for 5alpha-dihydrotestosterone than for testosterone, was demonstrated in canine prostate by means of 'washing-out' experiments. On the basis of its affinity for androgens and the presence of inhibition by low concentrations of anti-androgen, intracellular binding seemed to be due to components distinct from the postulated membrane 'carriers'.
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Cyproterone (1,2α-methylene-6-chloro-Δ4,6-pregnadien-17α-ol-3,20-dione) 17α-acetate, a potent anti-androgen, suppressed the uptake of radioactive androgens in vivo by the ventral prostate of rats. This was accompanied by a decrease in the retention of 5α-dihydrotestosterone (17β-hydroxy-5α-androstan-3-one) by prostate cell nuclei . Cyproterone and its 17α-acetate (less than 0.5 µg/ml) also inhibited the formation of a specific dihydrotestosterone-protein complex in prostate cell nuclei when minced prostate was incubated with radioactive testosterone or dihydrotestosterone. Estradiol-17β, diethylstilbestrol, and progesterone, but not hydrocortisone succinate, also suppressed the retention of dihydrotestosterone by prostatic cell nuclei in vitro, but to a much lesser extent than cyproterone.
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Testosterone-induced DNA synthesis in cultured rat ventral prostate was evaluated as an in vitro model for screening the direct effects of anticancer agents on prostatic growth. Optimal conditions for this bioassay, particularly the concentration of testosterone, were established using the inhibitory effects of cyproterone acetate on testosterone-induced 125iododeoxyuridine (I-UdR) uptake as an index of DNA synthesis inhibition. Using 4 X 10(-7) M testosterone, only the highest concentration (X 10(-5) M) of cyproterone acetate inhibited I-UdR uptake and histological observations indicated that this was due to a non-specific cytotoxic effect. In contrast, cyproterone acetate had a dose-dependent inhibitory effect on the proliferative response to 4 X 10(-9) M testosterone. Cyproterone acetate (4 X 10(-7) M) combined with 4 X 10(-9) M testosterone exerted an inhibitory effect on I-UdR uptake and caused epithelial atrophy indicative of androgen deprivation. The results are consistent with similar in vivo studies and confirm the hypothesis that cyproterone acetate acts by directly antagonising testosterone action at the target tissue level. Thus, this in vitro method provides a useful model for screening the direct effects of antiprostatic drugs.
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