Cyproterone acetate prevents translocation of the androgen receptor in the rat prostate

Brinkmann, Albert O.; Lindh, Liselott; Breedveld, D.I.; Mulder, E.; Molen, H. J. van der

doi:10.1016/0303-7207(83)90076-x

Cited by 41 publications

(17 citation statements)

References 15 publications

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“…The growth impairment in sex organs of CA-treated males may be due, in part, to some degree of insensitivity related to an alteration of their androgen receptor content since androgens themselves may regulate the number of their own receptors (Boesel, Klipper & Shain, 1980;Blondeau, Baulieu & Robel, 1982). On the other hand, CA, which prevents translocation of the androgen receptor into the nucleus (Brinkmann et al 1983), may also alter the synthesis of androgen-dependent proteins since steroid hormones exert their effects at the level of gene transcription (Chan, Means & O' Malley, 1978). Thus the imprinting process reported here is perhaps related to the effect of neonatal exposure of the genome to high endogenous levels of androgens.…”

Section: Discussionmentioning

confidence: 97%

Permanent changes in the functional development of accessory sex organs and in fertility in male mice after neonatal exposure to cyproterone acetate

Jean‐Faucher¹,

Berger²,

Turckheim³

et al. 1985

Journal of Endocrinology

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Male mice were injected daily with cyproterone acetate for 10 consecutive days during one of the four following periods: 1-10 days, 11-20 days, 21-30 days or 31-40 days. At all stages studied cyproterone acetate caused a significant reduction in the relative weights of epididymis, vas deferens, preputial gland and seminal vesicle in males killed 24 h after the last injection; the androgen content (testosterone + dihydrotestosterone) of the accessory sex organs was also reduced but the differences were not always significant. Cyproterone acetate treatment from 1 to 10 days resulted in a definitive reduction in the relative weights of all accessory sex organs studied and when injected from 11 to 20 days in epididymis and vas deferens. When cyproterone acetate was injected after 20 days of age, the inhibition of sexual organ weights was reversible and at adulthood organs were normally developed. Cyproterone acetate treatment induced a high percentage of infertile males only when injected from 1 to 10 days. Spermatogenesis, androgen levels in plasma and accessory sex organs, and sexual behaviour were not affected in sterile males. These results suggest that the functional development of accessory sex organs can be permanently affected by short-term neonatal exposure to endogenous androgens.

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Section: Discussionmentioning

confidence: 97%

Permanent changes in the functional development of accessory sex organs and in fertility in male mice after neonatal exposure to cyproterone acetate

Jean‐Faucher¹,

Berger²,

Turckheim³

et al. 1985

Journal of Endocrinology

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“…The steroid specificity of this process is reflected by the finding of similar 3a-diol values in the cytosol of the CyAc treated and control groups, since this metabolite is known not to bind to the androgen receptor (Krieg & Voigt 1977). 2) The CyAc-androgen receptor complex is either not translocated to or not retained in the nuclei (Callaway et al 1982;Brinkmann et al 1983), as substantiated by the accumulation of the androgen receptor in the cytosol and the decreased values of this protein as well as of CR-DHT, DHT and testosterone in the nuclear extract or nuclei, respectively. The specific transport function of the androgen receptor for DHT and testosterone transfer from the cytoplasm to the nucleus can be furthermore seen from the absence of 3a-diol in the nuclei, since this metabolite is, as mentioned above, not bound by the androgen receptor.…”

Section: Cyacmentioning

confidence: 97%

“…Cyproterone acetate (CyAc) is a synthetic progestogen which possesses, in addition to anti-gonadotrophic, anti-androgenic properties (Neumann & Steinbeck 1974). The latter are based on competi¬ tive inhibition of the formation of androgen re¬ ceptor complexes in the androgen target tissue (Fang & Liao 1971;Liao et al 1975;Krieg et al 1974), resulting in decreased nuclear retention of DHT-receptor complexes (Callaway et al 1982;Brinkmann et al 1983;Bartsch et al 1984) and finally in reduced target organ weights (Neumann & Steinbeck 1974).…”

mentioning

confidence: 97%

Interactions of an anti-androgen (cyproterone acetate) with the androgen receptor system and its biological action in the rat ventral prostate

Huang¹,

Bartsch²,

Voigt³

1985

Acta Endocrinologica

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Male Wistar rats were castrated and implantated with testosterone-filled silastic depots (in vitro release rate: 60 \g=m\g/24h) prior to treatment with 10 mg cyproterone acetate (CyAc) on day 1, and 5 mg on days 4, 7, 10 and 13. Animals were sacrificed on day 14. Control animals were treated identically, with the exception of CyAc administration. Blood was collected and the ventral prostates of 6\p=n-\8 animals were pooled, homogenized and processed into cytosol and purified nuclei. Steroid determinations (CyAc, testosterone, 5\g=a\-dihydrotestosterone (DHT), 5\g=a\-androstane-3\g=a\,17\g=b\-diol(3\g=a\-diol))were performed by RIA. Specifically bound DHT (charcoal resistant DHT = CR-DHT) represents DHT values (RIA) following treatment of cytosol or nuclear extract with dextran coated charcoal. The androgen receptor was determined in cytosol and nuclear extract by 'exchange assay' using [3H]methyltrienolone (MT) (18 h, 15\ s=deg\ C).The main results were: 1) The steroid levels in plasma (testosterone, DHT, 3\g=a\-diol) were in the range of untreated adult animals and not significantly influenced by the CyAc treatment. Final CyAc levels were 305 \m=+-\58 nmol/l (mean \ m=+-\SD, n = 5). 2) Significantly lower DHT, CR-DHT and testosterone levels (P at least < 0.01) were found in cytosol and in nuclei in the CyAc-treated group (cytosol (fmol/mg protein): DHT 305 \ m=+-\ 61 (n = 5), CR-DHT 54 \ m=+-\ 37 (n = 8), testosterone \ m=l e\ 8 (n = 5); nuclei (pmol/mg DNA): DHT 0.4 \ m=+-\0.2 (n = 5), CR\ x=req-\ DHT 0.7 \ m=+-\0.2 (n = 3), testosterone \m=l e\ 0.2 (n = 5)) when compared to controls (cytosol: DHT 645 \ m=+-\ 232 (n = 15), CR-DHT 204 \ m=+-\49 (n = 8), testosterone 24 \m=+-\12 (n = 10); nuclei: DHT 5.0 \ m=+-\2.5 (n = 12), CR-DHT 3.1 \m=+-\0.7 (n = 5), testosterone 0.9 \m=+-\0.6 (n = 7)). 3\g=a\-diol was similar in the cytosol of both groups and could not be detected in the nuclei. 3) The androgen receptor concentration was increased in the cytosol of the CyAc-treated group (216 \ m=+-\17 (n = 4), control group 98 \ m=+-\ 10 (n = 5) fmol/mg protein, P < 0.001)) and decreased in the nuclear extract (0.61 \m=+-\0.25 (n = 4), control 1.75 \ m=+-\0.25 (n = 5) pmol/mg DNA, P < 0.001). 4) The weight and DNA content of the prostate were reduced following CyAc treatment (weight 191 \m=+-\11 mg (n = 9), DNA 622 \m=+-\61 \g=m\g/organ(n = 8), controls 312 \m=+-\9 (n = 8) and 838 \m=+-\103 (n = 8), respectively). The data demonstrate that an approximate 40-fold excess of CyAc over testosterone in plasma led to a distinct but partial reduction of nuclear DHT and androgen receptor values coinciding with partial effects on prostate weight and DNA content. These results reflect the ability of the prostate to maintain significant androgen stimulation in the presence of low nuclear DHT and androgen receptor values.

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“…Cyproterone acetate prevents translocation of the androgen receptor in different organs and is also endowed with progestational activity (Mulder, Peters, de Vries & Van der Molen, 1975;Brinkmann, Lindh, Breedveld et al 1983). Since progestin receptors have not been reported in the testis (Tähkä, 1986) the observed effect of the antiandrogen supports the possibility that DHT interacts with specific androgen receptors.…”

Section: Discussionmentioning

confidence: 98%

Testicular 3β-hydroxysteroid dehydrogenase/Δ5–4 isomerase in the hypophysectomized rat: effect of treatment with 5α-dihydrotestosterone

Fanjul¹,

Quintana²,

Gonzalez³

et al. 1992

Journal of Endocrinology

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The in-vivo regulatory effect of androgens on steroidogenesis was investigated. Adult (2 to 3 months old) hypophysectomized rats were treated intratesticularly with increasing doses of 5 alpha-dihydrotestosterone (DHT; 10-200 micrograms/100 g body weight) or vehicle (50 microliters dimethyl sulphoxide; DMSO) in the contralateral testis. Intratesticular testosterone concentrations were extremely low in hypophysectomized rats 15-20 days after surgery. Treatment with DHT caused a dose-dependent inhibition of testicular 3 beta-hydroxysteroid dehydrogenase/delta 5-4 isomerase (3 beta-HSD) 2 h later, and this effect was apparent at the dose of 20 micrograms/100 g body weight (P less than 0.01). The inhibitory effect of 3 beta-HSD was not due to a possible interference of DHT in the enzyme assay, since various concentrations of the androgen (0.1-100 mumol/l) were ineffective as inhibitors of 3 beta-HSD. The highest dose of DHT used in this study (200 micrograms/100 g body weight) resulted in a rapid (1-2 h) and transient (4-6 h) inhibition (approximately 80%) of 3 beta-HSD activity. Pretreatment of rats with the antiandrogen cyproterone acetate (5 mg/rat) or the protein synthesis inhibitor cycloheximide (10 mg/rat) did not affect the enzyme activity of testes injected with DMSO, but counteracted the inhibitory effect of DHT on 3 beta-HSD activity in the contralateral testis. The results presented suggest that the inhibitory effect of the non-aromatizable androgen DHT is receptor-mediated and involves the synthesis of a factor(s) that modulates 3 beta-HSD activity.

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Cyproterone acetate prevents translocation of the androgen receptor in the rat prostate

Cited by 41 publications

References 15 publications

Permanent changes in the functional development of accessory sex organs and in fertility in male mice after neonatal exposure to cyproterone acetate

Permanent changes in the functional development of accessory sex organs and in fertility in male mice after neonatal exposure to cyproterone acetate

Interactions of an anti-androgen (cyproterone acetate) with the androgen receptor system and its biological action in the rat ventral prostate

Testicular 3β-hydroxysteroid dehydrogenase/Δ5–4 isomerase in the hypophysectomized rat: effect of treatment with 5α-dihydrotestosterone

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