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

Abstract

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.

The effects of chlormadinone acetate (CMA), antiandrogen, on the pituitary, testis, prostate and adrenal gland of the dog with spontaneous benign prostatic hyperplasia.

“…In fact, immunostaining of nuclear AR in both epithelial and fibro-muscular stromal cells was markedly decreased after treatment with CMA. It is further well-documented that prostatic nuclear AR contents were decreased after treatment with gonadotropin-releasing hormone (GnRH) agonist (Forti et al, 1989) as well as CPA (Huang et al, 1985), an antiandrogenic agent. Based on our present data and these facts, decreased immunostaining of AR after treatment with CMA may be explained by a decrease in the number of AR.…”

Immunohistochemical Studies of the Effect of Chlormadinone Acetate (CMA) on Prostatic Hyperplasia.

“…1B). It is well documented that prostatic nuclear AR contents are decreased after treatment with gonadotropin-releasing hormone (GnRH) agonist [5] as well as cyproterone acetate [8], an antiandrogenic agent. Based on our data and these facts, decreased immunostaining of AR after treatment with CMA may be explained by a decrease in the number of AR.…”

Immunohistochemistry of the Canine Prostate.

“…In fact, the intensity of the immunostaining of nuclear AR in both epithelia and fibro-muscular stromal cells is dose-dependently weakened by treatment with CMA (Table 2). It is a well documented fact that prostatic nuclear AR contents are decreased after treatment with gonadotropin-releasing hormone (GnRH) agonist [5] as well as cyproterone acetate [10], an antiandrogenic agent.…”