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PubMed2003

Absolute and attributable risk of venous thromboembolism in women on combined cyproterone acetate and ethinylestradiol.

OBJECTIVE: To achieve absolute risk estimates of venous thromboembolism (VTE) among women on cyproterone acetate plus ethinylestradiol (CPA/EE), and among women on combined oral contraceptives (COCs). METHODS: From the Danish National Register of Patients (NRP), 1996 to 1998, the records of 1.1 million Danish women, ages 15 to 44 years, were searched for evidence of VTE. COC use was ascertained through mailed questionnaires. Sales statistics of COCs and CPA/EE were provided through Danish Drug Statistics. RESULTS: During the time frame of the study, 330 women were found to have had VTE while on COCs. Of these women, 67 were on levonorgestrel-containing COCs. Eleven were on CPA/EE. The corresponding absolute risk of VTE was 3.4 (range, 3.1-3.8) per 10 000 women years among the women on COCs, 4.2 (range, 3.2-5.2) per 10 000 women years among women on levonorgestrel-containing COCs, and 3.1 (range, 1.3-4.9) per 10 000 women years among the women on CPA/EE. CONCLUSION: Our results suggest the absolute risk of VTE among Danish women on COCs is similar to that among women taking CPA/EE.

Adolescent↗
PubMed2003

Low-dose cyproterone acetate treatment of sexual acting out in men with dementia.

Increased sexual activity in patients with dementia is problematic for caregivers and has no proven treatment. This report describes two male patients who had dementia with pronounced sexual acting out. One patient had vascular dementia and the other patient had Parkinson's disease with associated dementia. After nonresponse to neuroleptics and sedatives, low-dose cyproterone acetate successfully reduced sexual acting out without relevant side effects in both patients.

Acting Out↗
PubMed2000

'Hot flush', an unpleasant symptom accompanying antiandrogen therapy of prostatic cancer and its treatment by cyproterone acetate.

From 1995 to 1997 the authors have assessed 31 patients with histologically verified advanced carcinoma of the prostate (CaP) and the ensuing symptom of 'hot flush'. Patients underwent transurethral resection of the prostate (TURP), bilateral orchiectomy (OE) and combined androgen blockade (CAB) by the administration of non-steroid antiadrogens. The authors present the mechanism of the genesis of the 'hot flush' symptom as well as its subjective manifestations, methods of laboratory monitoring as well as their experience with the treatment of this symptom. 50 mg tablets cyproterone acetate administered twice daily or Androcur depot 300 mg i.m. inj. once in 14 days were the main factors in the treatment of 'hot flushes' which reduced subjective difficulties in 80.6% of the patients studied.

Aged↗
PubMed2001

Effects of endocrine disruptors on prosobranch snails (Mollusca: Gastropoda) in the laboratory. Part III: Cyproterone acetate and vinclozolin as antiandrogens.

The effects of suspected endocrine disrupting chemicals on freshwater and marine prosobranch species were analysed in laboratory experiments. In this last of three publications, 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 (CPA) and vinclozolin (VZ) are presented. The snails were exposed to nominal CPA 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 VZ/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 CPA. 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 CPA and VZ 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.

Androgen Antagonists↗
PubMed2002

Altered cognitive function in men treated for prostate cancer with luteinizing hormone-releasing hormone analogues and cyproterone acetate: a randomized controlled trial.

OBJECTIVE: To report the first systematic investigation of the cognitive effects of luteinizing hormone-releasing hormone (LHRH) analogues in male patients, as LHRH analogues have been associated with memory impairments in women using these drugs for gynaecological conditions. PATIENTS AND METHODS: Eighty-two men with extraprostatic prostate cancer were randomly assigned to receive either continuous leuprorelin, goserelin (both LHRH analogues), cyproterone acetate (a steroidal antiandrogen) or close clinical monitoring. These patients underwent cognitive assessments at baseline and before starting treatment (77), and then 6 months later (65). RESULTS: Compared with the baseline assessments, men receiving androgen suppression monotherapy performed worse in two of 12 tests of attention and memory; 24 of 50 men randomized to active treatment and assessed 6 months later had a clinically significant decline in one or more cognitive tests but not one patient randomized to close monitoring showed a decline in any test performance. CONCLUSION: Pharmacological androgen suppression monotherapy for prostate cancer may be associated with impaired memory, attention and executive functions.

Aged↗
PubMed2001

Avascular necrosis of the femoral head in patients with prostate cancer treated with cyproterone acetate and radiotherapy.

We report the case histories of two patients with histologically confirmed adenocarcinoma of the prostate, both of whom had been treated with steroidal anti-androgen therapy in the form of cyproterone acetate prior to radical or palliative pelvic irradiation, and who subsequently developed femoral head avascular necrosis. This is a diagnosis that should be considered in patients with prostate cancer who present with hip pain in the absence of biochemical evidence of disease progression.

Adenocarcinoma↗
PubMed2002

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 beta-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 beta-galactosidase and treated with 2-acetylaminofluorene (2-AAF) to promote the growth of CPA-initiated hepatocytes. The presence of beta-galactosidase-positive hepatocyte clones showed that hepatocytes divided during treatment with 2-AAF. Only 3% of beta-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 beta-galactosidase-labeled hepatocytes. In conclusion, our results show that the mitogenic and tumor-initiating activities of CPA are directed toward different hepatocyte populations.

Animals↗
PubMed1995

Experience in the long-term treatment of patients with hirsutism and/or acne with cyproterone acetate-containing preparations: efficacy, metabolic and endocrine effects.

The effects and side effects of long-term treatment with cyproterone acetate (CPA) are described. Hammerstein's reverse sequential regimen (10 days 100 mg CPA, 21 days 50 micrograms ethinylestradiol (EE)) was used in most cases, although postmenopausal and hysterectomized women received 50 mg CPA/day continuously as monotherapy. The degree of androgenization was assessed in 143 of a total group of 188 women treated from 1968 to the present. The results of the treatment were good or very good in about 75% of hirsutism patients and in more than 90% of acne patients. Adverse events were recorded in 23% of cases. Most were mild and transient, and caused discontinuation of the therapy in only 9% of patients. From this population representing all cases treated and analysed retrospectively, a subgroup of patients was selected for a prospective investigation. Thirty-five patients with good response to CPA and longlasting therapy were included into this 2-year follow-up study; of these, 24 had previously received CPA for 5 or more years, 9 for more than 10 years and 2 for more than 15 years. Treatment in these patients consisted of 5 different regimens of various doses of CPA combined with EE and CPA alone in order to evaluate possible effects of concomitant estrogen treatment as well as a possible dose- or time-dependency of potential side effects. Clinicochemical, metabolic and endocrine parameters were determined at the start and end of the study. The hematological and clinicochemical parameters were within the normal ranges. There was a slight decrease of glucose tolerance and a moderate increase of insulin and C peptide after oral glucose loading. The effects of CPA and EE on lipometabolism were slight and apparently dependent on the dose of CPA and the therapeutic regimen. No suppression of adrenal function or of responsiveness to ACTH was seen. Fasting prolactin levels and serum prolactin concentrations after provocation with metoclopramide did not show any gross deviations. Sonography of the breast and liver did not show any abnormalities apart from adenofibrosis or mastopathy in 2 patients. In conclusion, CPA with or without EE was in our hands an effective and safe method of long-term treatment of hirsutism and/or acne in women.

Acne Vulgaris↗
PubMed1984

[Medium-dose oral cyproterone acetate therapy in women with moderate androgenization. Results of a multicenter double-blind study].

The low-dose oral standard antiandrogen treatment with cyproterone acetate (CPA), Diane, is frequently associated with unsatisfactory results regarding moderate to severe seborrhoea/acne/acne and/or mild to moderate hirsutism. This multicenter double-blind study (n = 164) was, therefore, initiated to analyze the effectiveness of a medium dose oral regimen, i.e. the addition of 10 mg of CPA during the first 15 days of the Diane-treatment cycle. Good or satisfactory results after 3, 6, 9 and 12 months were observed in 61, 81, 95 and 97% of patients with moderate to severe seborrhoea (n = 79); in 53, 95, 98 and 100% of patients with moderate to severe acne (n = 62); and in 10, 28, 45 and 55% of patients with mild to moderate hirsutism (n = 89), respectively. The regression of moderate facial hirsutism and severe facial acne occurred faster and was more complete under the medium-dose than with the low-dose regimen. Side effects corresponded to those of conventional oral contraceptives except for a higher frequency of mastodynia. Both regimens caused a significant suppression of plasma dehydroepiandrosterone sulfate, while testosterone, triiodothyronine and thyroxine were lowered insignificantly. In contrast, cortisol, prolactin and insulin increased significantly. The extent of these changes did not differ in both modes of treatment. The medium-dose regimen (total dosage per cycle: 192 mg of CPA) is more effective than the low-dose regimen (42 mg of CPA per cycle) in the treatment of patients with moderate hyperandrogenism who do not require the high-dose oral standard antiandrogen therapy (1000 mg of CP A per cycle).

Acne Vulgaris↗
PubMed1983

[Treatment of virilized women with intramuscular administration of cyproterone acetate].

Management of hirsutism with high-dose oral cyproterone acetate (CPA) is associated with a failure rate of about 30%. The present investigation analyses the efficacy of parenteral CPA administration in non-tumorous hyperandrogenism. Medium-dose CPA (300 mg) was injected intramuscularly once per month, followed by oral ethinylestradiol (40 micrograms daily) for 21 days in 42 patients (total of 293 treatment cycles). The onset of withdrawal bleeding was 3 to 8 days later. This regimen was used as primary therapy (group A; n = 18) as well as follow-up therapy in low-dose (group B; n = 10) and high-dose oral standard CPA failures (group C; n = 14). The following satisfactory or good response rates were observed in regard to hirsutism: group A 83,5%, group B 100%, group C 57%; seborrhea A and B 100%, C 89%; acne and androgenetic alopecia A and B and C 100%. Clinical side effects occurred in 20 patients; they corresponded in type and frequency to those elicited by the high-dose oral standard medication and resulted in termination of treatment in only 3 patients. Pilot studies regarding the pharmacokinetics of CPA as well as the effects on plasma total and free testosterone and prolactin failed to explain the therapeutic superiority of parenteral CPA (n = 7 women). Still, it may be concluded that intramuscular CPA administration represents a new and highly effective means of managing hirsute females.

Acne Vulgaris↗
PubMed1992

The long-term use of cyproterone acetate in pedophilia: a case study.

This investigation reports the long-term use of the antiandrogen cyproterone acetate (CPA) in a pedophile, who was studied continuously over 38 months. Measures of sexual arousal, serum testosterone, and gonadotropin levels were significantly reduced by the drug as compared with placebo and no treatment; prolactin levels were significantly elevated. Some workers have observed that long-term administration of CPA (more than one year, which was then discontinued) produced enduring (in some cases apparently permanent) anti-libidinal effects; however, in the case described, within three weeks of stopping the drug, all measures had returned to pretrial levels. The importance of continuous long-term monitoring in sex offenders receiving an antiandrogen is discussed.

Adult↗
PubMed2003

Urinary 6-sulfatoxymelatonin excretion in hyperandrogenic women with polycystic ovary syndrome: the effect of ethinyl estradiol-cyproterone acetate treatment.

The role of melatonin in human reproduction is still unknown. Data obtained in patients with hypogonadism and precocious puberty suggest that melatonin and the reproductive hormones are interrelated. The aim of this study was to determine melatonin production in hyperandrogenic women. We studied 12 women with polycystic ovary syndrome (PCOS) and 10 women with idiopathic hirsutism (IH). Patients were treated with cyproterone acetate-ethinyl estradiol (Diane 35) for 4 months. Fasting blood samples for the determination of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and dehydroepiandrosterone sulfate (DHEAS) and 24-h urine collections for the determination of 6-sulfatoxymelatonin (alpha MT6s) excretion were obtained from all patients at baseline and after 4 months of treatment. The results were compared with those obtained in 15 control women. At baseline, women with PCOS had significantly higher LH and testosterone levels than those with IH and controls. Their alpha MT6s values (52.6 +/- 20.3 micrograms/24 h) were significantly higher than the values in women with IH (34.3 +/- 7.1) and controls (30.5 +/- 6.5) (p < 0.001). Diane 35 treatment significantly decreased LH, FSH, testosterone and alpha MT6a values in PCOS (28.0 +/- 13.9 micrograms/24 h) (p < 0.0001). These results indicate that women with PCOS have increased melatonin production. The normalization of alpha MT6s and testosterone values during Diane 35 treatment suggests that sex steroids modulate melatonin secretion in these patients either directly or through the suppression of gonadotropin.

Adolescent↗
PubMed2000

A stability-indicating HPLC method to determine cyproterone acetate in tablet formulations.

A simple and accurate liquid chromatographic method was developed to estimate cyproterone acetate (CA) in pharmaceuticals. The drug was chromatographed on a reversed-phase C18 column. Eluents were monitored at a wavelength of 254 nm utilizing a mixture (60:40) of acetonitrile and water. Solution concentrations were measured on a weight basis to avoid the use of an internal standard. The method was statistically validated for linearity, accuracy, precision, and selectivity. Due to its simplicity and accuracy, we believe that the method can be used for routine quality control analysis. No specific sample preparation is required except for the use of a column guard and a suitable prefilter attached to the syringe.

Androgen Antagonists↗
PubMed1993

Cyproterone acetate generates DNA adducts in rat liver and in primary rat hepatocyte cultures.

Cyproterone acetate (CPA), an active component of certain contraceptive and antiandrogenic drugs, has been shown recently to induce DNA repair synthesis in rat hepatocytes in vitro. In the present study we examined whether CPA can cause the formation of DNA adducts detectable by the 32P-postlabeling technique in hepatic cells in vitro and in vivo. Incubation of primary cultures of hepatocytes from male Wistar rats with CPA resulted in the occurrence of radioactive spots in the radiochromatograms of 32P-postlabeled DNA digests indicating the formation of two DNA adducts ('A' and 'B'). At 30 microM CPA, the highest concentration tested, approximately 50 'A' adducts and five 'B' adducts were found per 10(9) nucleotides. DNA of hepatocyte cultures from female rats was found to contain adduct A and a minor adduct termed 'D', but adduct B was not observed. Between 1 and 10 microM CPA, the relative level of adduct A was approximately 20-fold higher than the level observed in male hepatocytes. In vivo DNA adducts were detected almost exclusively in hepatic DNA. Hepatic DNA from male Wistar rats treated with single doses of CPA (1-100 mg/kg) by gavage, showed the major adducts A and B and two further spots of minor intensity ('C' and 'D') in the radiochromatograms. No adducts were detectable in extrahepatic tissues. The adduct pattern of liver DNA from females exposed to single oral doses between 0.1 and 30 mg CPA/kg body wt was similar to that observed in males; however, the relative levels for adducts A and D were approximately 100-fold higher. In females, linear relationships between dose and adduct levels were observed for all four adducts. The present findings show that CPA causes damage to hepatic DNA not only in vitro, but also in vivo. Thus it appears possible that DNA adduct formation is involved in the formation of hepatic tumors during long-term treatment of rats with the synthetic steroid.

Animals↗
PubMed1993

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.

Adenosine Triphosphatases↗
PubMed1995

In vitro mutagenicity studies on cyproterone acetate using female rat hepatocytes for metabolic activation and as indicator cells.

The synthetic sex steroid cyproterone acetate (CPA) was shown to induce DNA repair in primary hepatocytes from female rats, confirming previous reports about a sex-specific genotoxic potential of CPA in female rat liver. CPA did not induce gene mutations or chromosomal aberrations in V79 Chinese hamster cells co-cultivated with hepatocytes from female rats as the metabolizing system. Hepatocytes from the same rats under identical exposure conditions as in the positive unscheduled DNA synthesis (UDS) test were used in these experiments. The maximum concentrations tested in the mutagenicity assays were 30-100 times higher compared with the lowest observed effect concentration of 3 x 10(-6) mol/l in the DNA repair test. The requirement for cell-cell transfer of the putative genotoxic metabolites in the co-culture experiments may be the reason for the discrepancy between positive UDS effects and negative mutagenicity and clastogenicity results. To further investigate if CPA can induce chromosomal mutations within the same cells that provide metabolic activation an in vitro micronucleus assay with proliferating female rat hepatocytes was performed. The results gave some indications of a micronucleus-inducing potential of CPA. However, under the conditions of the micronucleus assay CPA was also shown to increase the proliferative activity of hepatocytes. Since micronucleus formation is also dependent on mitotic activity, it cannot be determined whether the increase in micronucleus formation after CPA exposure indicates a clastogenic potential or whether it is just a consequence of the mitogenic potential of CPA. Although CPA or its metabolites obviously have a DNA damaging potential and stimulate considerable DNA excision repair, our findings do not establish a clear mutagenic potential.

Animals↗
PubMed1995

Accumulation and persistence of DNA adducts of the synthetic steroid cyproterone acetate in rat liver.

Cyproterone acetate (CPA) is a synthetic steroid which is widely used in antiandrogenic and gestagenic drugs. We have recently shown that CPA induces DNA adducts in cultured rat hepatocytes and in rat liver (1). In the present investigation, we studied the persistence and accumulation of CPA-derived DNA adducts in the liver of rats using the 32P-postlabeling technique. To study the persistence of CPA-DNA adducts, rats were treated with a single oral dose of 10 (female rats) or 100 mg CPA/kg body wt (male rats). Four DNA adducts were detected in the liver of both gender. In female rats, maximal total DNA adduct levels of 3.40 +/- 0.04 adducts/10(6) nucleotides were observed after 1 week. Eleven weeks later, 40% of the adducts determined after 1 week were still detectable. In male rats, maximal hepatic DNA adduct levels of approximately 98 +/- 3/10(9) nucleotides were attained after 2 weeks. The adduct level decreased during the following 4 weeks to approximately 40% of the earlier observed maximal level. To study the accumulation of the CPA-DNA adducts, rats were treated daily with a low oral dose of 50 micrograms CPA/kg body wt for 42 days. During this treatment period, the level of the four adducts increased continuously from approximately 10 to approximately 380 adducts/10(9) nucleotides in the liver of female rats. DNA adducts were formed at much lower levels in male rats; only one type of DNA adduct was detectable, the level of which increased to approximately 6 adducts/10(9) nucleotides after 42 days. In conclusion, CPA induces DNA adducts in rat liver; binding of the steroid is much higher in female compared to male rats. The CPA-DNA adducts show a high persistence and as a consequence of their long half life, CPA-DNA adducts accumulate significantly in the liver of rats.

Androgen Antagonists↗
PubMed1995

DNA repair synthesis and DNA fragmentation in primary cultures of human and rat hepatocytes exposed to cyproterone acetate.

Cyproterone acetate (CPA), a synthetic steroid used in human therapy, has recently been shown to cause DNA damage in cultured rat hepatocytes and in rat liver. In the present study we have investigated whether CPA also induces genotoxic effects in human hepatocytes. Genotoxicity of CPA was determined by measuring the capability of the compound for inducing DNA repair synthesis and for causing the formation of DNA single-strand breaks. Autoradiography and alkaline elution were used to quantitate DNA repair and DNA fragmentation, respectively. Exposure of hepatocytes to CPA for 20 h induced DNA repair synthesis in two hepatocyte preparations derived from males and in four of the five preparations derived from females. In cultures from some donors, induction of repair was detected at 1 microM CPA, the lowest concentration tested. The maximum effect generally occurred at 10-20 microM. Only a very slight increase in the frequency of DNA single-strand breaks was found following exposure of the hepatocytes to 50 microM CPA for 20 h. For comparative purposes, the effects of CPA on DNA repair and DNA fragmentation were also determined in cultured rat hepatocytes. A strong induction of DNA repair synthesis, but only a slight enhancement in DNA fragmentation was observed in CPA-treated hepatocytes derived from female rats. These results indicate that the measurement of repair is a more sensitive indicator for the genotoxicity of CPA than the measurement of DNA fragmentation. No genotoxic effects of CPA were detectable in hepatocyte cultures derived from male rats. The present findings show that CPA is genotoxic in human hepatocytes and that the striking sex difference in the genotoxicity of CPA in rat cells is not observed with human cells.

Aged↗