Activity Of Cyproterone Acetate Research Articles

Dose-Dependent Protective Effect of Hygrophila auriculata Seeds on Cyproterone Acetate-Induced Testicular Dysfunction.

Infertility affects 15% of global population. This study was designed to search out the most effective dose of chloroform fraction of hydro-ethanolic extract of Hygrophila auriculata seed to ameliorate cyproterone acetate (CPA)-treated male subfertility. The rats were made subfertile by CPA at the dose of 2.5 mg/100gm body weight for 45 days. The male subfertility represented by low sperm concentration, less motile, less viable, and less hypo osmotic tail swelled spermatozoa in CPA-treated group. Serum LH, FSH, and testosterone levels were significantly decreased in CPA-treated group in respect to control. Androgenic key enzyme Δ5,3β-HSD, 17β-HSD activities and gene expression pattern were also decreased significantly in respect to control. These antispermatogenic and antiandrogenic activities of CPA were significantly recovered after the treatment of Hygrophila auriculata at the dose of 2.5 mg, 5mg, and 10 mg/100gm body weight. CPA also generate oxidative free radical that indicated by altered catalase, superoxide dismutase, and peroxidase activities and protein expression pattern along with conjugated diene and thiobarbituric acid reactive substance levels in testis. Expression pattern of Bax and Bcl2 genes were deviated from control after CPA treatment. Significant diminution of body weight, organo-somatic indices, and SGOT, SGPT activities were observed in CPA-treated group. All these biomarkers significantly recovered towards control after the treatment of Hygrophila auriculata at different doses. More significant recovery was observed in 5 mg and 10 mg of chloroform fraction-treated group and 5 mg dose, i.e., the minimum therapeutic dose to recover the CPA-induced subfertility.

Effects of antiandrogenic progestins, chlormadinone and cyproterone acetate, and the estrogen 17α-ethinylestradiol (EE2), and their mixtures: Transactivation with human and rainbowfish hormone receptors and transcriptional effects in zebrafish (Danio rerio) eleuthero-embryos

Synthetic progestins act as endocrine disrupters in fish but their risk to the environment is not sufficiently known. Here, we focused on an unexplored antiandrogenic progestin, chlormadinone acetate (CMA), and the antiandrogenic progestin cyproterone acetate (CPA). The aim was to evaluate whether their in vitro interaction with human and rainbowfish (Melanotaenia fluviatilis) sex hormone receptors is similar. Furthermore, we investigated their activity in zebrafish (Danio rerio) eleuthero-embryos.First, we studied agonistic and antagonistic activities of CMA, CPA, and 17α-ethinylestradiol (EE2), in recombinant yeast expressing either the human progesterone (PGR), androgen (AR), or estrogen receptor. The same compounds were also investigated in vitro in a stable transfection cell system expressing rainbowfish nuclear steroid receptors. For human receptors, both progestins exhibited progestogenic, androgenic and antiestrogenic activity with no antiandrogenic or estrogenic activity. In contrast, interactions with rainbowfish receptors showed no progestogenic, but antiandrogenic, antiglucocorticoid, and some antiestrogenic activity. Thus, interaction with and transactivation of human and rainbowfish PGR and AR were distinctly different.Second, we analyzed transcriptional alterations in zebrafish eleuthero‐embryos at 96 and 144h post fertilization after exposure to CPA, CMA, EE2, and binary mixtures of CMA and CPA with EE2, mimicking the use in oral contraceptives. CMA led to slight down-regulation of the ar transcript, while CPA down-regulated ar and pgr transcripts. EE2 exposure resulted in significant transcriptional alterations of several genes, including esr1, pgr, vtg1, cyp19b, and gonadotropins (fshb, lhb). The mixture activity of CMA and EE2 followed the independent action model, while CPA and EE2 mixtures showed additive action in transcriptional alterations.Third, we analyzed the interactions of binary mixtures of CMA and CPA, and of CMA and EE2 for their joint activity in vitro and in eleuthero-embryos. Both mixtures behaved according to the concentration addition model in their in vitro interaction with human and rainbowfish receptors, often showing antagonism. In zebrafish eleuthero-embryos, binary mixtures of CMA and EE2 showed the same expression patterns as EE2 alone, indicating an independent action in vivo.Our study demonstrates that CMA and CPA interact distinctly with human and rainbowfish receptors, suggesting that activities of these and possibly additional environmental steroids determined with yeast expressing human receptors cannot simply be translated to fish. The lack of agonistic activities of both progestins to rainbowfish PGR and AR is the probable reason for the low activity found in zebrafish eleuthero-embryos.

Antiandrogen therapy in metastatic male breast cancer: results from an updated analysis in an expanded case series.

Male breast cancer is a rare disease treated as hormone receptor-positive female breast cancer. The characterization of breast cancer at the molecular level has lately revealed gender-related differences. As the androgen receptor is emerging as a potential oncogenic driver in male breast cancer, we analyzed efficacy data from metastatic patients treated with antiandrogens. We evaluated the activity of cyproterone acetate, either as a monotherapy or combined with a GnRH analog, in 36 metastatic male breast cancer patients. Fourteen patients were treated with cyproterone acetate as monotherapy and 22 patients with complete androgen blockade. We recorded 4 complete responses and 15 partial responses, for an overall response rate of 52.8% (95% CI, 36.5-69.4). Stable disease was reported in 11 patients. Median PFS was 8.9months (95%CI, 6.1-11.7), and median OS was 24.3months (95%CI, 22.5-26.1). Data on androgen receptor expression were available for 7 patients. All the 4 patients with androgen receptor-expressing tumors had a clinical benefit, including a patient with an estrogen receptor-negative disease. Conversely, none of the 3 patients with androgen receptor-negative tumors had a tumor response. Antiandrogen-based therapy showed efficacy in metastatic male breast cancer patients. Our results encourage considering antiandrogens in the therapeutic continuum, especially if supported by androgen receptor expression.

Crystal Structure of the T877A Human Androgen Receptor Ligand-binding Domain Complexed to Cyproterone Acetate Provides Insight for Ligand-induced Conformational Changes and Structure-based Drug Design

Cyproterone acetate (CPA) is a steroidal antiandrogen used clinically in the treatment of prostate cancer. Compared with steroidal agonists for the androgen receptor (AR) (e.g. dihydrotestosterone, R1881), CPA is bulkier in structure and therefore seemingly incompatible with the binding pockets observed in currently available x-ray crystal structures of the AR ligand-binding domain (LBD). We solved the x-ray crystal structure of the human AR LBD bound to CPA at 1.8A in the T877A variant, a mutation known to increase the agonist activity of CPA and therefore facilitate purification and crystal formation of the receptor.drug complex. The structure demonstrates that bulk from the 17alpha-acetate group of CPA induces movement of the Leu-701 side chain, which results in partial unfolding of the C-terminal end of helix 11 and displacement of the loop between helices 11 and 12 in comparison to all other AR LBD crystal structures published to date. This structural alteration leads to an expansion of the AR binding cavity to include an additional pocket bordered by Leu-701, Leu-704, Ser-778, Met-780, Phe-876, and Leu-880. Further, we found that CPA invokes transcriptional activation in the L701A AR at low nanomolar concentrations similar to the T877A mutant. Analogous mutations in the glucocorticoid receptor (GR) and progesterone receptor were constructed, and we found that CPA was also converted into a potent agonist in the M560A GR. Altogether, these data offer information for structure-based drug design, elucidate flexible regions of the AR LBD, and provide insight as to how CPA antagonizes the AR and GR.

Antiandrogenic activity of norgestimate in a human androgen-dependent stable-transfected cell line

Background. Acne occurs from an overstimulation of the sebaceous glands by high levels of androgens or because sebaceous glands are hypersensitive to normal levels of testosterone. In women with moderate acne, norgestimate (NG) in association with ethinyl estradiol (EE) is acknowledged as an effective treatment; this is related to the effect of oral contraceptives on androgen production and transport. However, the antiandrogenic properties of NG itself have been poorly studied.Design. The present work was undertaken to find out whether NG and its derivative, 17-deacetylnorgestimate (dNG), present antiandrogen activity. First, we studied the effect of NG and dNG on the intracellular localization of green fluorescent protein (GFP)-labeled androgen receptor (AR). Then, we compared the AR activity of NG and dNG with that of cyproterone acetate (CPA), a gold-standard antiandrogenic compound, by investigating competitive binding, antagonist activity and transactivation level of AR.Results. NG and dNG decreased GFP-AR nuclear translocation, revealing their antiandrogenic property, as for CPA. In the whole cell competition assay performed in a human cell line stably expressing an AR-responsive luminescent reporter gene (PALM cells) with 3H-labeled R1881 as tracer, NG and dNG were slightly stronger competitors than the antiandrogen CPA. Half-maximal inhibition (Ki) of 3H-labeled R1881 (10−9 M) binding occurred at 4.2 ± 0.5×10−8 M of NG, 3.4 ± 0.4×10−8 M of dNG and 6.6 ± 0.8×10−8 M of CPA. Comparison of antagonist activities of NG, dNG and CPA on AR transactivation levels showed that NG, dNG and CPA inhibited androgen-induced luciferase activity in PALM cells. We observed slight and similar inhibition with 6×10−8 M respectively of NG, dNG and CPA. For the three compounds, the best inhibitory effect was found at 3×10−7 M: 24% for NG and dNG vs. 47% for CPA. The antiandrogenic activity of NG and dNG was found to be 50% that of CPA.Conclusion. In a human androgen-dependent stable-transfected cell line, a useful tool for studying AR transcriptional activity and its subnuclear localization in the presence of androgens and antiandrogens, we demonstrated that NG and dNG have antiandrogenic properties that could partly explain the efficacy of NG in association with EE for the treatment of moderate acne in women.

Co-activator and co-repressor interplay on the human androgen receptor

The human androgen receptor (hAR) is a member of the nuclear hormone receptor (NHR) superfamily. Because the activated hAR positively stimulates the growth of prostate cancer (PC), its inactivation remains the central goal of current PC therapies. Androgen antagonists (antihormones) bind to and inactivate the hAR. One underlying mechanism that we have identified is that the hAR-mediated transactivation is inhibited through recruitment of co-repressors that bind to hAR in the presence of androgen antagonists (Dotzlaw et al., 2002). Co-repressors are cofactors required for target gene repression originally identified for those transcription factors having a silencing function (Burke & Baniahmad, 2000). Interestingly, the recruitment of co-repressors to the hAR is dependent on the response element of the target genes, suggesting a structural influence of the DNA that might impose conformational changes on the hAR, and also implies that not all hAR target genes will be repressed to a similar extent by treatment with androgen antagonists. The known androgen antagonists act either as the complete antagonists hydroxyflutamide and casodex (Cas, bicalutamide) or as the partial antagonists cyproterone acetate (CPA) on hAR. Testing for binding of co-repressors in the presence of these different types of androgen antagonists revealed that the binding of co-repressors to hAR on a given response element is dependent on the type of antagonist used. For example, the SMRT co-repressor is recruited to the prostate specific antigen promoter but not to mouse mammary tumour virus (MMTV) promoter in the presence of CAS, whereas SMRT is recruited to the MMTV promoter in the presence of CPA (Dotzlaw et al., 2002; Shang et al., 2002; Kang et al., 2004). This indicates that in addition to the response element specificity, the type of ligand induces a specific AR-structure that dictates the binding specificity of co-repressors to hAR as well. Unlike to other members of the NHR, it is the amino(N-) terminus of hAR that harbours the major transactivation function. The previously known interaction domain of co-repressors with other NHR was identified to be the receptor carboxy(C-) terminus that includes the ligand binding domain. In contrast to other nuclear hormone receptors, we found that co-repressors such as SMRT, NCoR and Alien interact with the hAR N-terminus (Dotzlaw et al., 2002, 2003; Hodgson et al., 2005, and unpublished). Thus, both the co-repressors and the co-activators bind to the same AR-domain. At the functional level, the efficacy of inhibition of hAR by partial antagonists, such as CPA, was shown to be dependent on the level of co-repressors in the cell; the higher the level of co-repressors, the more potent the CPA-mediated inhibition of hAR (Dotzlaw et al., 2002). This strongly suggests that co-repressors mediate the inhibition of hAR by androgen antagonists. Insights into the interplay of co-repressors with co-activators have been gained by comparing pure agonists with the partial agonistic activity of CPA, which when employed in the absence of any agonist, is able to induce AR transactivation. However, the extent of AR-mediated transactivation is weaker than that induced by pure agonists. This suggests that in addition to co-repressors, co-activators bind AR in the presence of CPA as well. Surprisingly, we found that co-repressors also bind hAR in the presence of pure androgen agonists, as assayed by mammalian one hybrid and chromatin immuno-precipitation techniques. Furthermore, co-repressor binding in the presence of agonist did not lead to a significant repression of hAR (Dotzlaw et al., 2002 and unpublished). This suggests that the interplay of co-activators and co-repressors is also dependent on the type of ligand. But two central questions arose that yet remain unanswered. One is how the binding of co-repressors to agonist-bound hAR does not result in significant gene repression. The other question is how the interplay between co-repressors and co-activators act together to regulate the activity of hAR. Interestingly, using the partial antagonist CPA, a competition between co-activators and co-repressors binding was observed. Consistently with this, increasing the

Differential modulation of androgen receptor transcriptional activity by the nuclear receptor co-repressor (N-CoR).

Antiandrogens are widely used agents in the treatment of prostate cancer, as inhibitors of AR (androgen receptor) action. Although the precise mechanism of antiandrogen action is not yet elucidated, recent studies indicate the involvement of nuclear receptor co-repressors. In the present study, the regulation of AR transcriptional activity by N-CoR (nuclear receptor co-repressor), in the presence of different ligands, has been investigated. Increasing levels of N-CoR differentially affected the transcriptional activity of AR occupied with either agonistic or antagonistic ligands. Small amounts of co-transfected N-CoR repressed CPA (cyproterone acetate)- and mifepristone (RU486)-mediated AR activity, but did not affect agonist (R1881)-induced AR activity. Larger amounts of co-transfected N-CoR repressed AR activity for all ligands, and converted the partial agonists CPA and RU486 into strong AR antagonists. In the presence of the agonist R1881, co-expression of the p160 co-activator TIF2 (transcriptional intermediary factor 2) relieved N-CoR repression up to control levels. However, in the presence of RU486 and CPA, TIF2 did not functionally compete with N-CoR, suggesting that antagonist-bound AR has a preference for N-CoR. The AR mutation T877A (Thr877-->Ala), which is frequently found in prostate cancer and affects the ligand-induced conformational change of the AR, considerably reduced the repressive action of N-CoR. The agonistic activities of CPA- and hydroxyflutamide-occupied T877A-AR were hardly affected by N-CoR, whereas TIF2 strongly enhanced their activities. These results indicate that lack of N-CoR action allows these antiandrogens to act as strong agonists on the mutant AR.

Bioassay of steroid hormone agonist and antagonist activities of anti-androgens on mammary gland, seminal vesicles and spleen of male mice.

Young intact and adult castrated outbred C3H/Di male mice were used to characterize steroid hormone agonist and antagonist activities of anti-androgens by bioassay. Animals were injected subcutaneously with flutamide (Flut), chlormadinone acetate (CMA), cyproterone acetate (CA) or Casodex (Cas) alone or simultaneously with oestradiol (E), E plus progesterone (Prog) or norethindrone acetate (NA; a steroid exhibiting progestational and oestrogenic activities) and testosterone (T) for 15 days. Mammary gland growth was not affected with anti-androgen alone. However, all anti-androgens decreased seminal vesicle weights in intact males. In E (0.01 microg day(-1))-treated intact males, mammary growth was stimulated by CMA (progestational activity) and inhibited by CA. The inhibitory effect of CA on mammary growth (glucocorticoid activity) was overcome with high dose of E (0.1 microg day(-1)). When seminal vesicles weights were decreased with a moderate dose of E (0.01 microg day(-1)) anti-androgens injected simultaneously acted synergistically with E and decreased seminal vesicles weights more than E alone. However, in animals overloaded with E (0.1 microg day(-1)), anti-androgen CA was unable to decrease seminal vesicles weights. E (0.01 or 0.05 microg day(-1)) or E + Prog (500 or 1000 microg day(-1)) or NA (12.5 to 50 microg day(-1)) stimulated mammary growth was inhibited by T at doses 20-200 microg day(-1) and these effects were decreased or abolished by simultaneous application of Flut, CMA or Cas in both young intact and adult castrated males. In the same animals, the seminal vesicles weights were increased by T and decreased by anti-androgens. The effects of higher doses of T (300 microg day(-1)) were not inhibited by anti-androgens both in the mammary gland and seminal vesicles. Spleen weights were not consistently affected with Flut, CMA or Cas, but decreased with CA by dose dependent manner. These results demonstrated that anti-androgenic activities could be detected not only on seminal vesicle but also on the mammary gland. Our model system also detected a glucocorticoid activity of CA and progestational activity of CMA.

In vivo cell lineage analysis in cyproterone acetate–treated rat liver using genetic labeling of hepatocytes

Genetic labeling using recombinant retroviruses is a powerful strategy for the study of cell lineage in the liver. However, this type of vector is only able to infect dividing cells. The synthetic steroid cyproterone acetate (CPA) is mitogenic and carcinogenic in the adult rat liver. In this study, we used retroviral vectors carrying the nuclear targeted β-galactosidase gene to selectively label and follow the fate of hepatocytes dividing on administration of CPA. Labeled cells as well as those in mitosis were preferentially located around the portal tract, whereas apoptotic bodies were predominant in the pericentral area. Labeled hepatocytes did not disappear after apoptosis, suggesting a preferential elimination of nontransduced cells. The presence of labeled binucleated hepatocytes showed the persistence of a binucleation process. Finally, we performed long-term analysis of labeled cells in transgenic animals tolerant for β-galactosidase and treated with 2-acetylaminofluorene (2-AAF) to promote the growth of CPA-initiated hepatocytes. The presence of β-galactosidase–positive hepatocyte clones showed that hepatocytes divided during treatment with 2-AAF. Only 3% of β-galactosidase clones were positive for the placental form of glutathione S-transferase (GSTp), indicating the absence of a preferential appearance of preneoplastic foci in the population of β-galactosidase–labeled hepatocytes. In conclusion, our results show that the mitogenic and tumor-initiating activities of CPA are directed toward different hepatocyte populations. (HEPATOLOGY .)

Cyproterone Acetate: A Genotoxic Carcinogen?

Cyproterone acetate, a widely used synthetic progestagen with antiandrogenic activity, is known for years to produce liver tumours in rats, with a higher incidence in females. This effect was attributed to a rodent-specific tumour promoting mode of action based on the detection of a strong hepato-mitogenic activity of cyproterone acetate. However, more recent studies have demonstrated that cyproterone acetate is sex-specifically activated to (a) DNA-damaging intermediate(s) in the liver of female rats which result in the formation of DNA adducts, induction of DNA repair, and increased levels of micronuclei and gene mutations. Consistent with a sex-specific genotoxicity, cyproterone acetate showed a tumour-initiating potential in a liver foci assay with female rats but not with male rats. Most important, cyproterone acetate was found to induce formation of DNA adducts in primary cultures of human hepatocytes indicating that human liver cells have the capacity to activate cyproterone acetate to genotoxic intermediates. However, the overall assessment of the preclinical data presented in this review suggests that induction of liver tumours in female rats most probably depends on both, genotoxic and mitogenic effects which would suggest a non-linear mode of action with regard to tumour formation. With the exception of DNA adduct formation all other adverse effects induced by cyproterone acetate in rat liver, including gene mutations and liver tumours, can be detected at very high dose levels only. Hence, a cancer risk estimate based on a simple linear extrapolation from high dose to low exposure conditions of recommended clinical use would be questionable. Human data from pharmacoepidemiological studies that specifically addressed the question of possible liver cancer risk in patients treated with cyproterone acetate do in principle support this interpretation. In agreement with these considerations the regulatory authorities of the European Union came to the common conclusion that a possible cancer risk associated with the clinical use of cyproterone acetate, if any, appears to be low and the risk-benefit ratios for the currently authorised indications remain favourable.

The DNA damaging drug cyproterone acetate causes gene mutations and induces glutathione-S-transferase P in the liver of female Big Blue transgenic F344 rats.

The gestagenic and antiandrogenic drug cyproterone acetate (CPA) is mitogenic, tumorigenic and induces DNA-adducts and DNA-repair synthesis in rat liver. Thus CPA is expected to be mutagenic. However in vitro mutagenicity test systems were negative. To examine whether CPA induces mutations in rat liver, the in vivo mutation assay based on Big Blue transgenic F344 rats was employed. Single oral doses of 25, 50, 75, 100 and 200 mg CPA/kg b.w. respectively were administered to female Big Blue rats. Six weeks after treatment, liver DNA was assayed for mutations. At the highest dose, 200 mg CPA/kg b.w., the frequency of (17 +/- 4) x 10(-6) spontaneous mutations was increased to a maximum of (80 +/- 8) x 10(-6) mutations. One-hundred and 75 mg CPA/kg b.w. resulted in mutation frequencies of (35 +/- 5) and (27 +/- 5) x 10(-6), respectively. The mutation frequency at doses of 50 and 25 mg CPA/kg b.w. was similar to that of vehicle treated controls. Statistical analysis of the dose-effect relationship revealed that it was not possible to decide whether a threshold dose exists or not. DNA adducts were analyzed by the 32P-postlabelling technique. The total level of the major and the two minor adducts observed in the autoradiograms increased between doses of 25 to 75 mg CPA/kg b.w. to a maximum of approximately 12,000 +/- 3000 adducts per 10(9) nucleotides. The level did not further increase significantly with 100 and 200 mg CPA/kg b.w. After CPA treatment no preneoplastic liver foci were observed. However, single glutathione-S-transferase placental form (GST-P) positive hepatocytes were observed and the frequency was dependent on the dose. These cells are not supposed to represent initiated cells, since they occurred only transiently after 6 weeks and disappeared thereafter completely. In conclusion, our results demonstrate that CPA is mutagenic in vivo. The mutation frequency increased at high CPA doses, when the increase of the DNA adduct formation had already ceased. This suggests that the mitogenic activity of CPA is required to express the mutations.

Initiation of enzyme-altered foci by the synthetic steroid cyproterone acetate in rat liver foci bioassay.

Cyproterone acetate (CPA) is a synthetic steroid which is used in oral contraceptive and anti-androgen formulations. It has previously been classified as a tumor promoter in rat liver. Recent studies have shown that CPA induces DNA repair synthesis in isolated hepatocytes, and this implies that CPA is genotoxic. We studied the initiating activity of CPA in vivo by means of a rat liver foci bioassay, using weanling female Sprague-Dawley rats. The results show that CPA induces adenosine-triphosphatase-deficient and gamma-glutamyltranspeptidase-positive putative preneoplastic foci in a dose-dependent manner. This indicates that CPA has not only promoting but also initiating activity and may therefore act as a complete carcinogen in rat liver.

Effects of Castration, Depo-Testosterone and Cyproterone Acetate on Lymphocyte T Subsets in Mouse Thymus and Spleen

The effects of testosterone on the relative proportion of Thy 1.2, CD4 (L3T4) and CD8 (Lyt-2) cells in thymus and spleen were studied after castration and administration of Depo-testosterone (DT) separately or together with cyproterone acetate (CA) (an antiandrogen) in BDF1 mice. Injection of 0.5 mg/100 g body weight of DT during 2 weeks decreased significantly the number and proportion of double positive (DP) (CD4+ CD8+) and increased the percentage of single positive (SP) CD4+ (CD4+ CD8-), whereas there was a slight decrease in the Thy 1.2+ cells in the thymus. In parallel, we observed an increase in CD8+ (CD4- CD8+) cells in the spleen. The androgen deprivation after 3 weeks of castration induced a decrease in the percentage of CD4+ cells in thymus and both CD4+ and CD8+ cells in spleen. Injection of CA (0.5 mg/100 g body weight) had the same qualitative effects as DT on the proportion of lymphocyte T subsets in castrated mice. However, the combined activities of DT and CA were greater than either alone. These data indicate the main role of testosterone in the distribution of CD4+ and CD8+ cells in male mice. The similar effects of CA and DT in the lymphoid organs may suggest a difference between androgen receptors of sexual and lymphoid organs.

The clinical activity of cyproterone acetate in advanced ovarian carcinoma. A London Gynaecology Oncology Group Study

The clinical activity of cyproterone acetate in advanced ovarian carcinoma. A London Gynaecology Oncology Group Study

On the potential ‘androgenic’ activity of cyproterone acetate (CPA) in rats

On the potential ‘androgenic’ activity of cyproterone acetate (CPA) in rats

Steroid receptors and hormone responsiveness of human prostatic carcinoma.

AbstractAndrogen (AR), estrogen (ER), and progesterone (PR) receptors have been found in human prostatic hyperplasia (BPH) and prostatic carcinoma (PC) (AR mainly in the epithelial compartment and ER in the stromal compartment). These steroid receptors have been studied in the cytosol of 59 prostatic cancers in order to select patients to be treated with endocrine therapy (orchiectomy, administration of antiandrogens). Tissues were collected through transvesical resection and needle biopsy. Tritiated metribolone (R1881), 17b‐estradiol and promegestone (R5020) with the use of exchange assay and a dextran‐coated charcoal method have been usually employed. In some specimens receptor content was also analyzed in the nuclear fraction. AR was found in the cytosol of 47 of 59 (79.66%), ER in 14 of 26 (53.85%), and PR in 13 of 15 (86.67%) tumors examined. AR was detected in the nuclear fraction of 11 of 26, ER in nine of 13, and PR in two of four tumors examined. AR was found to correlate with the histological grade of the cancers, whereas no correlation could be demonstrated between the histological grade and cytoplasmic or nuclear ER. On the basis of receptor studies, hormonal treatment was started with orchiectomy followed by the administration of cyproterone acetate (CPA) 50 mg twice a day in 26 eligible out of 38 patients available for follow‐up with tumors examined for cytoplasmic AR. The response to hormonal therapy depended strictly on the presence of AR. The endocrine treatment used seems, in our opinion, to be the most advisable form of therapy, and is capable of blocking the uptake of androgens of extratesticular origin by prostatic cells. Although the clinical advantages of progestational therapy for human PC are not yet established, the presence of PR in prostatic carcinoma leads us to believe that progestational compounds as well as the progestational activity of CPA may be effective on tumor growth of tissues that are positive for PR.

Effect of cyproterone acetate on the reproductive system of the female rat

Effects of cyproterone acetate, a synthetic steroidal compound, on the reproductive organs of female rats have been investigated. This agent caused reduction of ovarian weights indicative of suppression of pituitary gonadotrophins. Oestrogenic nature of cyproterone acetate was investigated in intact and ovariectomized rats taking uterine weight and vaginal keratinization as an index of oestrogenicity. Cyproterone acetate in ovariectomized animals induced vaginal keratinization and increased the uterine weights. These effects were parallel to the effect of oestradiol dipropionate in ovariectomized animals, thus indicating oestrogenic activity of cyproterone acetate. We may conclude that the above compound caused antifertility effects due to its oestrogenic nature at the dose level of 2 mg/alternate day in rats when the compound was administered subcutaneously.

Hepatic Metabolism and the Anti-Androgenic Activity of Cyproterone Acetate.

Summary and conclusionsThe effects of splenic vs. subcutaneous depots of pellets of an anti-androgen, cyproterone acetate (Cyp A), were studied in castrate rats receiving daily injections of .1 mg of testosterone pro-pionate per 100 g body weight, Mean loss of weight of pellets was similar in both sites, indicating comparable absorption. Inhibition of growth of seminal vesicles was significantly less with splenic than with subcutaneous depots of Cyp A (P<.05, Exp 1; P<.001, Exp 2). These data provide evidence that (a) this compound does not exert its anti-androgenic effects by increasing the inacti-vation of testosterone propionate in the liver, and that (b) Cyp A can be destroyed in the liver before producing systemic effects as an anti-androgen. The effectiveness of Cyp A as an anti-androgen was shown by a 40% reduction in androgenic response in studies employing a ratio of 2 parts of Cyp A (supplied by pellets) to 1 part of testosterone propionate (supplied in oil).