SynopsisCyproterone (cyproterone acetate) is a steroidal antiandrogenic agent that inhibits the action of adrenal and testicular androgens on prostatic cells. Additionally, its progestogenic activity causes a centrally mediated reduction in testicular secretion of androgens.Studies have demonstrated the effectiveness of cyproterone monotherapy in patients with prostate cancer, and for those in whom orchiectomy is not an acceptable option cyproterone may be a useful alternative. In addition, the drug may be administered in combination with surgical or gonadotrophin-releasing hormone (GnRH) agonist-mediated castration to ensure ablation of adrenal androgens. However, the effectiveness of cyproterone in combination with these forms of testicular androgen deprivation remains to be fully established. Trials to date have not demonstrated prolonged survival in patients receiving the combination therapy. Importantly, however, cyproterone does prevent acute exacerbation of disease during initial treatment with a GnRH agonist. Furthermore, combination therapy tends to be associated with a lower incidence of hot flushes than GnRH agonist-mediated or surgical castration alone.Thus, cyproterone 200 mgsol;day has proven efficacy in preventing acute flare of disease and reducing the incidence of hot flushes associated with GnRH agonist therapy or orchiectomy. It may also facilitate maximal androgen deprivation in patients receiving GnRH agonist therapy. If this drug is used as monotherapy, dosages of 250 mgsol;day or greater will probably be required.Pharmacodynamic PropertiesCyproterone is a steroidal antiandrogen with affinity for progesterone and glucocorticoid receptors. It inhibits the centrally mediated release of luteinising hormone, thereby inhibiting secretion of testicular testosterone. More importantly, it also inhibits the action of adrenal and testicular androgens at the cellular level by a direct competitive interaction with cellular receptors.Normal prostatic tissue and androgen-dependent neoplastic prostatic tissue depend on the presence of testosterone for growth and development. Cyproterone inhibits the growth of malignant prostatic cell linesin vitroand prevented proliferation of prostatic tumour mass inin vivomodels. Intermittent androgen deprivation achieved by cyclical administration of cyproterone appeared to delay the development of experimentally induced androgen-independent tumours. In patients with prostate cancer, cyproterone in high dosages (300 mgsol;day), or in combination with other methods of castration, indirectly, and reversibly, inhibits sperm production by preventing testosterone release from the testicular Leydig cells.Pharmacokinetic PropertiesLimited data on the pharmacokinetic profile of cyproterone in elderly male patients have been reported in the literature. On the basis of the data available, oral cyproterone is well absorbed in young volunteers and elderly patients, reaching maximal serum concentrations within 4 hours of administration in young volunteers. It is metabolised to the pharmacologically active 15bgr;-hydroxy metabolite, which has a pharmacokinetic profile similar to the parent compound. After oral administration, the systemic concentration of cyproterone declines biphasically, with a terminal elimination half-life of approximately 1.6 to 1.8 days in young volunteers, but possibly as long as 4.3 days.Therapeutic Efficacy in Prostate CancerIn comparative trials, cyproterone 250 or 300 mgsol;day was as effective as goserelin 3.6 mgsol;28 days or diethylstilbestrol 3 mgsol;day, and slightly more effective than intramuscular medroxyprogesterone 500mg administered 3 times weekly in patients with prostate cancer. Therefore, when given in sufficiently large dosages, cyproterone monotherapy may be considered an acceptable alternative to surgery for patients without cardiovascular risk factors for whom orchiectomy is not a satisfactory option.Cyproterone has also been administered in combination with surgical or pharmacological castration. While the combination of cyproterone with orchiectomy appeared to result in objective and subjective improvement in noncomparative studies, the addition of cyproterone to orchiectomy or GnRH agonist therapy did not improve remission rates or response duration, respectively, in comparative trials. However, the addition of cyproterone does appear to prevent the acute exacerbation of tumour and tumour-related symptomatology (tumour flare) that can occur during the initiation of GnRH agonist therapy.Although quality of life has not been investigatedper se,patients receiving cyproterone combined with other forms of castration are less likely to experience hot flushes than those who do not receive cyproterone.More experimental uses of cyproterone in the therapy of prostate cancer include intermittent androgen withdrawal regimens and aggressive therapeutic regimens involving hormone therapy and chemotherapy. Both approaches have produced good results in the limited clinical trials undertaken to date.TolerabilityIn common with alternative treatments, cyproterone therapy is associated with impotence and loss of libido as a result of its effect on serum testosterone levels. Gynaecomastia occurs in approximately 6percnt; of patients.Cardiovascular complications have been associated with the use of estrogens, but these occur much less frequently in patients receiving cyproterone. The potential of cyproterone to adversely affect the plasma lipoprotein profile is unlikely to be of clinical importance in patients with prostate cancer, who are generally elderly.Cyproterone has been associated with isolated reports of hepatocellular carcinoma and hepatotoxicity. Therefore, it would be prudent to monitor liver function on a regular and ongoing basis during cyproterone therapy.Dosage and AdministrationCyproterone may be given as monotherapy or in combination with other forms of pharmacological or surgical castration. When used in combination regimens with GnRH agonist therapy for the prevention of acute flare of disease, the usual dosage is 200 mgsol;day from 7 days prior to the initiation of GnRH agonist therapy. Cyproterone therapy should be continued for at least the first 3 to 4 weeks of GnRH agonist therapy. For the prevention of hot flushes in patients undergoing pharmacological or surgical castration, cyproterone 150 to 300 mgsol;day has been used. In those patients for whom cyproterone monotherapy is considered an appropriate treatment, a dosage of 250 mgsol;day or greater should be used.
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