6-Chlor-1-β,2-β-dihydro-17-hydroxy-3'H-cyclopropa[1,2]pregna-1,4,6-trien-3,20-dion-17-acetat

At high therapeutic cyproterone acetate doses of three times 100 mg per day, cyproterone acetate may inhibit CYP2C8. Thiazolidinediones (ie the anti-diabetics pioglitazone and rosiglitazone) are substrates or CYP2C8 (increased blood levels of these anti-diabetics may require dose adjustment).

Alcohol appears to reduce the effect of /cyproterone/ which is of no value in chronic alcoholics.

The risk of statin-associated myopathy or rhabdomyolysis may be increased when those HMG-CoA inhibitors (statins) which are primarily metabolised by CYP3A4 are co-administered with high cyproterone acetate doses, since they share the same metabolic pathway.

Drugs acting on androgen receptors modify opioid transmission in the central nervous system. To investigate a direct interaction, /investigators/ studied whether the binding of [3H]diprenorphine to mouse brain membranes was modified by cyproterone acetate (progesterone derivative with antiandrogen activity), flutamide (non-steroidal antiandrogen), 5alpha-dihydrotestosterone and progesterone. Only cyproterone acetate inhibited [3H]diprenorphine binding (IC50 = (1.62 +/- 0.33) x 10(-6) M) without modifying its association rate. These results suggest that cyproterone acetate binds to opiate receptors independently of its classical androgenic intracellular receptor effect.

The direct antiandrogenic effect of cyproterone is blockage of the binding of dihydrotestosterone to the specific receptors in the prostatic carcinoma cell. In addition, cyproterone exerts a negative feed-back on the hypothalamo-pituitary axis, by inhibiting the secretion of luteinizing hormone resulting in diminished production of testicular testosterone.

/BIRDS and MAMMALS/ To gauge the relative regulative roles of adrenal, gonadal, and thyroid hormones on uropygial gland of male adult pigeons, morphometric, histological, and histochemical observations have been made on a seasonal basis in normal as well as experimentally manipulated birds. Normal birds showed a parallel adrenal-gonadal-uropygial relationship and inverse adrenal-thyroid, thyroid-gonadal, and thyroid-uropygial relationships. Induced hypocorticalism by dexamethasone in the breeding season and hypercorticalism by ACTH or corticosterone treatment in the nonbreeding season were marked by inhibitory and stimulatory changes respectively in the uropygial gland and testis and by inverse thyroid activity. Further, cyproterone acetate treatment in the breeding season completely suppressed testicular functions and increased thyroid activity without affecting either adrenal or uropygial weight, structure, and functions. Based on the observations it is concluded that adrenal steroids are principally involved in regulating the uropygial gland while the gonadal steroids are involved in qualitative aspects of secretion during the breeding phase and thyroid hormones in maintaining the general metabolic profile.

/AQUATIC SPECIES/ A short-term gonadal recrudescence bioassay using the mummichog (Fundulus heteroclitus) was employed to examine the consequences of environmentally relevant and pharmacological exposures (1-1000 ng/L) of the androgen, 17alpha-methyl testosterone, and the anti-androgen, cyproterone acetate, on reproductive endocrine endpoints. Recrudescing male (GSI = approx. 2%) and female (GSI = approx. 10%) fish were exposed to graded concentrations of 17alpha-methyl testosterone and cyproterone acetate for 7 or 14 days. In the first experiment (7-day exposure), 17alpha-methyl testosterone concentrations of 250 or 1000 ng/L decreased circulating testosterone and estradiol in female fish, and 11-ketotestosterone in male fish. Plasma T, 11-ketotestosterone and estradiol were decreased following cyproterone acetate exposure (250 and 1000 ng/l). Gonadal steroid biosynthetic capacity was also inhibited in both sexes after exposure to 17alpha-methyl testosterone or cyproterone acetate, as evidenced by decreased in vitro production of testosterone and estradiol. In experiment 2 (14-day exposure), exposures to lower 17alpha-methyl testosterone and cyproterone acetate concentrations (1, 10 and 100 ng/L) resulted in decreased plasma testosterone, with females showing greater sensitivity than males. Both 11-ketotestosterone and estradiol were significantly reduced beginning at 10 ng/L 17alpha-methyl testosterone. In vitro gonadal testosterone production was impaired at 100 ng/L 17alpha-methyl testosterone in both males and females while 1 ng/L cyproterone acetate caused a significant decrease in female fish. In experiment 2, in vitro estradiol production was decreased in females at all concentrations of 17alpha-methyl testosterone and cyproterone acetate, while only 100 ng/L reduced 11-ketotestosterone synthesis in males. Plasma vitellogenin was reduced in females exposed to 1000 ng/L (experiment 1) and 100 ng/L (experiment 2) 17alpha-methyl testosterone, while cyproterone acetate did not alter plasma vitellogenin at any concentration.

/AQUATIC SPECIES/ This study was focused on determining the effects of exposure to antiandrogens on the gonadal development of Japanese medaka (Oryzias latipes). Test compounds included the fungicide, vinclozolin and the clinical antiandrogen, cyproterone acetate. Newly hatched medaka were exposed to aqueous solutions of vinclozolin (2500 ug/L) and the vinclozolin fungicide formulation, Ronilan (1000 and 5000 ug/L) and cyproterone acetate (1 and 10 ug/L), for 3 months. Histological evaluation of the gonadal tissues of exposed fish indicated that the 5000 ug/L concentration of the vinclozolin formulation (Ronilan) induced a low incidence of intersex (ie testis-ova) and the 2500 ug/L concentration of vinclozolin-affected spermatogenesis in males. Also, the vinclozolin treatments induced moderate ovarian atresia. Cyproterone acetate also induced a low incidence of testis-ova, but in contrast to the vinclozolin treatment the amount of ovarian tissue in the testis-ova was equal to or greater than the amount of testicular tissue. In the cyproterone acetate treatments, both oogenesis and spermatogenesis were moderately inhibited at all test concentrations. ...

/AQUATIC SPECIES/ The objective of this study was to identify specific physiologic parameters in crustaceans that are targeted by chemicals known to be antiandrogenic in vertebrates. /It was/ hypothesized that chemicals capable of binding to the vertebrate androgen receptor would also elicit toxicity to crustaceans by binding to specific steroid hormone receptors in an antagonistic manner. This hypothesis was tested by evaluating the effects of the antiandrogen cyproterone acetate on growth, molting, sexual differentiation, and reproduction of Daphnia magna. Exposure of daphnids to concentrations of cyproterone acetate appreciably below those that elicited mortality reduced growth but had no effect on molting. These concentrations of cyproterone acetate had no effect on various developmental and maturation parameters. Cyproterone acetate also reduced the number of offspring produced by parthenogenetically reproducing daphnids, but this effect appeared to be a consequence of the reduced size of the daphnids and their inability to accommodate a brood of more than approximately 10 eggs. These results indicate that the antiandrogen cyproterone acetate specifically targets a process critical to growth of daphnids that is independent of molting. Additional studies are warranted to established whether this is an endocrine-related toxicity to crustaceans that is associated with environmental antiandrogens such as some pesticide metabolites.

/AQUATIC SPECIES/ The effects of suspected endocrine disrupting chemicals on freshwater and marine prosobranch species were analysed in laboratory experiments. ... The responses of the fresh water snail Marisa cornuarietis and of two marine prosobranchs (Nucella lapillus, Nassarius (Hinia) reticulatus) to the antiandrogenic model compounds cyproterone acetate and vinclozolin (VZ) are presented. The snails were exposed to nominal cyproterone acetate concentrations of 1.25 mg/L alone and simultaneously to a potent synthetic estrogen (ethinylestradiol), androgen (methyltestosterone) or an indirectly acting xeno-androgen (tributyltin) in experiments with adult specimens and in a life cycle test for 12 months. Marisa and Nucella were furthermore exposed to nominal concentrations of 0.03-1.0 microgram vinclozolin/L for up to 5 months. The antiandrogens induced a number of biological responses in all three species. The length of the penis and of accessory male sex organs (e.g., penis sheath, prostate) were significantly reduced. For Marisa, this effect occurred only in sexually immature specimens and was reversible as the males attained puberty. Typical androgen-mediated responses (imposex development, delayed spermatogenesis, tubulus necrosis of the testis with orchitis and Leydig cell hyperplasia) were partially or totally suppressed by a simultaneous administration of cyproterone acetate. In the two marine species even adult, sexually mature males responded to antiandrogens with a reduction of the male sex organs and an advancement of the sexual repose phase. The results for cyproterone acetate and vinclozolin are compared with the effects of an exposure to xeno-estrogens (bisphenol A, octylphenol) and xeno-androgens (triphenyltin, tributyltin) in the same species. Each group of endocrine disruptors induces a characteristic set of toxicological effects in prosobranch snails which can be used as endpoints in an organismic invertebrate test for the identification of endocrine mimetic test compounds. Estrogens cause primarily an induction of superfemales resulting in an increased female mortality by the enhancement of spawning mass and egg production. The main effects of androgens are a virilization of females by imposex development and a marked decrease of the fecundity. Compared with estrogens and androgens, the antiandrogen responses seem to be less drastic and might have--in contrast to the two other disruptor classes--no biologically significant effects at the population level.

/HUMAN EXPOSURE STUDIES/ One daily dose of either 5 mg or 10 mg cyproterone acetate (CA) was administered to 2 groups of 4 fertile men for 6 months. The medication was preceded by a 3 months placebo period and followed by a recovery phase of 5 to 8 months. During CA-treatment the sperm count/mL decreased and the percentage of abnormal spermatozoa increased slightly (0.991 less than P less than 0.05). Sperm penetration assessed by the Kremer test did not show any decrease during treatment. Serum levels of testosterone and FSH decreased, but those of LH remained unchanged during treatment. Two pregnancies occurred after 13/4 and 51/2 months of CA-treatment. The serum-CA concentration in these 2 volunteers did not differ from that of the remainder. Three subjects who began the study were withdrawn because of depressive mood changes (2) and weakness combined with dizziness (1). Data from these subjects were not included. The results indicate that daily doses of 5 mg and 10 mg of cyproterone acetate are not effective as a male contraceptive.

/SIGNS AND SYMPTOMS/ Overdose may cause nausea, vomiting and, in females, withdrawal bleeding. There are no specific antidotes and further treatment should be symptomatic.

/CASE REPORTS/ The multiplicity of meningiomas or abrupt lesion growth in patients treated with cyproterone acetate suggests that this progestative treatment may promote lesion growth. /The authors/ report the rapid regression of an incidental meningioma after discontinuation of a 10-year cyproterone acetate treatment. This unique observation suggests that conservative management of meningiomas may be the best option among users of high doses of cyproterone acetate, given that spontaneous regression may occur after hormonal treatment discontinuation.

/CASE REPORTS/ ... Three male patients aged 78-83 years are presented, in whom severe hepatotoxic reactions emerged after cyproterone acetate (CPA) administration. Patients were treated with CPA at the doses of 200-300 mg/day for malignant prostate disease for 3-12 months prior to the acute manifestation of the hepatic disease. Clinical features compatible with mixed hepatocellular and cholestatic liver disease including jaundice, white stools and dark urine, manifested in all three cases whereas encephalopathy and ascites were present in two of the patients. Other primary causes of hepatotoxicity (alcohol consumption and viral hepatitis) were also verified in two cases, and in those patients biopsy findings revealed the presence of cirrhotic lesions in liver parenchyma. Discontinuation of the therapeutic agent led to the amelioration of the clinical profile in all the patients whereas a patient died 40 d after hospital admission due to sepsis, despite acute liver disease improvement. ...

For more Human Toxicity Excerpts (Complete) data for CYPROTERONE ACETATE (20 total), please visit the HSDB record page.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ ... Male and female C57BL/10J mice were fed 0 or 800 ppm cyproterone acetate (CPA) in the diet for 13 weeks. Body weight was reduced (P > 0.001 at 13 weeks) by approximately 33%. Seminal vesicle weights were reduced (P > 0.001) and showed histological atrophy, changes consistent with the anti-androgenic activity of the compound. Liver weights were increased (P > 0.001) by +90% of control mean weights; hepatocyte hypertrophy and increased fat and glycogen were seen by light microscopy, and hyperplasia of smooth endoplasmic reticulin by transmission electron microscopy. Assessment of liver mixed function oxidase activity demonstrated induction of cytochrome P450 enzymes, and increased isozyme 2B1/2 in males and 3A1 in both sexes was confirmed by immunohistochemical staining of liver sections. An increase in bromodeoxyuridine (BrdU) labelling index of the liver was seen in females only. ...

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ ... A 52 week CPA study in the mouse strain C57Bl/10J has been reported not to produce liver tumors, although CPA induced significant liver enlargement and induction of the mixed function oxidase CYP3A. The present study is a further investigation of the effects of CPA in mice of the C57Bl/10J strain dosed for 104 weeks. A group of 40 mice/sex were fed 800 ppm CPA in the diet for 104 weeks with a control group of eight/sex. Mortality was high in females after 40 weeks due to hormonal effects in the uterus; no female and only four CPA-dosed males survived to 104 weeks. Liver cell hypertrophy with increased fat and glycogen and single cell or small multifocal areas of hepatocellular necrosis were universal. Proliferating cell nuclear antigen demonstrated an increase in proliferating cells within tumors and within the non-tumor bearing liver of CPA-dosed mice compared with normal livers of control mice. Hepatocellular tumors developed in 44% of males and 22% of females dosed with CPA, compared with none in the controls (the strain has a low, <10%, incidence of spontaneous liver tumors compared with other mouse strains). In addition, over 85% of both sexes dosed with CPA developed adenomatous polyps of the pyloric antrum and pancreatic islet cell hyperplasia, shown by immunostaining to be chiefly of insulin-secreting cells. Adrenocortical atrophy was also observed with other widespread effects in the endocrine system. The results suggest that the liver tumors, as in the rat, are likely to be related to effects on liver growth and mitogenesis. It is suggested that the tumors of the stomach and the pancreatic islet cell hyperplasia are manifestations of the effects of CPA in the endocrine system.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In long-term carcinogenicity studies in rats cyproterone acetate increased the incidence of liver tumors including carcinomas at high doses which concomitantly caused liver toxicity and exceeded the maximum human dose. Further investigations into rodents at lower, non-hepatotoxic doses revealed benign liver proliferations similar to effects described for other steroid hormones. However, it must be borne in mind that sex steroids can promote the growth of certain hormone dependent tissues and tumors.

In patients with a history of thromboembolic processes or suffering from sickle-cell anemia or severe diabetes with vascular changes, the risk: benefit ratio must be considered carefully in each individual case before Cyprostat is prescribed.

Cyprostat must not be used in patients with: Meningioma or a history of meningioma; Liver diseases (including Dubin-Johnson syndrome and Rotor syndrome); Malignant tumors (except for carcinoma of the prostate); Previous or existing liver tumors (only if these are not due to metastases from carcinoma of the prostate); Wasting diseases (with the exception of inoperable carcinoma of the prostate); Existing thromboembolic processes; Hypersensitivity to the active substance or any of the excipients.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

LD50 Rat intraperitoneal 565 mg/kg

LD50 Mouse intraperitoneal 3300 mg/kg

MEDICATION

For the palliative treatment of patients with advanced prostatic carcinoma.

Mixture of acetate with ethinyl estradiol

... Commercially available as tablets and as an injectable solution.

Oral: Tablet: 50, 100 mg cyproterone acetate, Cyprostat (Bayer plc).

Oral: Tablet: 2 mg cyproterone acetate 35 ug ethinylestradiol, Dianette (Bayer plc)

Oral: Tablet: 50 mg cyproterone acetate, Androcur (Bayer plc).