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PubMed1979

Effect of cyproterone acetate on the genital organs of female rats.

Effects of cyproterone acetate, a synthetic steroidal compound, on the reproductive organs of female rats have been investigated. This agent causes reduction in ovarian weights indicative of suppression of pituitary gonadotrophins. Oestrogenic nature of cyproterone acetate was investigated in intact and ovariectomized animals taking uterine weight, vaginal keratinization and other oestrogen sensitive biochemical parameters. Cyproterone acetate in ovariectomized animals induced vaginal keratinization, increase in uterine weight and uterine protein, RNA, glycogen and sialic acid contents. These effects were parallel to the effect of oestradiol dipropionate in ovariectomized animals, thus indicating oestrogenic activity cyproterone acetate. The histological and biochemical parameters lead to the conclusion that cyproterone acetate possessed antifertility property due to its inherent oestrogenic nature.

Adrenal Glands↗
PubMed1977

Radioimmunological determination of cyproterone acetate.

A sensitive and specific radioimmunoassay for cyproterone acetate in serum has been developed. Antiserum was raised in rabbits by immunization with a conjugate of cyproterone acetate-11 alpha-hemisuccinate and bovine serum albumin. Radioactive tracers with high specific activities were synthesized by coupling the hemisuccinate with [3H]-tyrosine methyl ester of [125I]-iodohistamine. Competition studies with substances structurally related to cyproterone acetate have revealed that the structures of ring A and B are mainly responsible for binding to the antibody.

Antibody Specificity↗
PubMed1977

Estrogenic and antifertility effect of cyproterone acetate in female gerbils, meriones hurriane Jerdon.

Effects of cyproterone acetate, a steroidal synthetic compound, on the reproductive organs of female gerbils have been investigated. This agent causes reduction of ovarian weights indicative of suppression of pituitary gonadotrophins. Estrogenic nature of cyproterone acetate was investigated in intact and ovariectomized gerbils taking uterine weight, vaginal keratinization and glycogen contents are parameters of estrogenic action. Cyproterone acetate in ovariectomized gerbils induced vaginal keratinization, increase in uterine weight, protein, RNA, glycogen and sialic acid contents of uterus, thus indicating an estrogenic activity. The histological and biochemical parameters lead to the conclusion that cyproterone acetate possesses estrogenic properties.

Animals↗
PubMed1995

DNA-damaging activity of the cyproterone acetate analogues chlormadinone acetate and megestrol acetate in rat liver.

The synthetic progestin cyproterone acetate (CPA) has been recently shown to elicit DNA repair synthesis in cultured rat hepatocytes and to form adducts with rat hepatocyte DNA in vitro and in vivo. In the present study we have examined the genotoxic potential of the structural analogues of CPA, chlormadinone acetate (CMA) and megestrol acetate (MGA) in rat liver cells. CPA strongly induced DNA repair synthesis in hepatocyte cultures from females but not from males. In contrast, CMA and MGA (2-50 microM) did not detectably increase repair synthesis in cultured hepatocytes from either gender. CMA and MGA, however, caused the formation of DNA adducts detectable by the 32P-postlabelling technique. At a concentration of 30 microM, between 30 and 50 adducts/10(9) nucleotides were found with MGA and CMA in cultured hepatocytes of female rats, and between 5 and 20 adducts/10(9) nucleotides were found in hepatocytes of males. By comparison, 30 microM CPA has been found to produce 1670 adducts/10(9) nucleotides in hepatocytes from female rats. CMA and MGA also induced low levels of DNA adducts in vivo. When female rats were treated with 100 mg/kg of CMA or MGA per os, the adduct levels were 2 and 19 adducts/10(9) nucleotides respectively. The results indicate that both CMA and MGA show some genotoxicity in rat liver cells, which is, however, much lower than that for CPA. Our findings further suggest that the high genotoxicity of CPA is associated with the presence of the 1,2 alpha-methylene group, which is absent in CMA and MGA.

Animals↗
PubMed1981

Effect of cyproterone acetate on adenohypophysis of castrated mice.

Pituitaries from castrated male mice injected with cyproterone acetate were examined ultrastructurally. LH gonadotrophs showed two types: (a) those containing a dilated RER, a hypertrophied Golgi, and decreased granular content; and (b) those presenting an electron lucent cytoplasm and a nonhypertrophied RER. Following cyproterone acetate treatment both LH cell types showed increased RER cisternal hypertrophy and absence of Golgi membranes. In LH type (a) gonadotroph-increased granular content was noted. No detectable alterations were noted in FSH gonadotrophs following cyproterone acetate treatment. Cyproterone acetate may have stimulated the synthesis of the protein component but inhibited the incorporation of the carbohydrate moiety and LH release.

Animals↗
PubMed1980

[Bioavailability of cyproterone acetate after oral and intramuscular application in men (author's transl)].

Cyproterone acetate was administered orally and intramuscularly to 5 male patients. The level of the active substance in plasma was monitored at intervals during the period of application using radioimmunoassay specific for cyproterone acetate. The areas under the drug level curves were similar after oral and intramuscular application of cyproterone acetate when taking into consideration the different doses used. Accordingly, cyproterone acetate is not dependent upon a "first-pass" effect. The bioavailability of the active substance was complete following oral application.

Administration, Oral↗
PubMed2005

Genotoxic potential of cyproterone acetate: a possible role of reactive oxygen species.

The genotoxicity of cyproterone acetate was studied in human lymphocytes using chromosomal aberrations (CAs), mitotic index (MI) and sister chromatid exchanges (SCEs) as a parameter. Cyproterone acetate was found to be genotoxic at 20 and 30 microM. To study the possible mechanism of the genotoxicity of cyproterone acetate, superoxide dismutase (SOD) and catalase (CAT) were used separately and in combination along with the 30 microM of cyproterone acetate at different doses. SOD treatment increases CAs, SCEs and decreases MI as compared to treatment with 30 microM CPA alone, at both of the tested doses. CAT treatment decreases the frequencies of CAs and SCEs and increases MI in both, as compared to treatment with 30 microM CPA alone, separately and in combination with SOD, suggesting a possible role of reactive oxygen species for the genotoxic damage.

Androgen Antagonists↗
PubMed1981

Estradiol-17 beta inhibition of androgen uptake, metabolism and binding in epididymis of adult male rats in vivo: a comparison with cyproterone acetate.

The effects of estradiol-17 beta on androgen uptake, metabolism and binding were studied in rat epididymis in vivo in comparison with cyproterone acetate. Steroids (250 ug/100 g body weight) were injected 5 min prior to 3H-testosterone in castrate rats. Estradiol-17 beta inhibited 3H-testosterone uptake into epididymal cytosol by 58% as compared to 38% by cyproterone acetate. 3H-Testosterone uptake into epididymal nuclei was inhibited 95% by estradiol-17 beta and 83% by cyproterone acetate. Total bound radioactivity in cytosol fractions was reduced to a greater extent by estradiol-17 beta than cyproterone acetate when either 3H-testosterone or 3H-dihydrotestosterone was injected. Binding of 3H-dihydrotestosterone to nuclear receptors was completely abolished by estradiol-17 beta; whereas approximately 20% binding remained in the nuclear extract after cyproterone acetate treatment. Metabolism of 3H-testosterone in vivo was also altered by estradiol-17 beta, resulting in diminished conversion to 3H-dihydrotestosterone. Cyproterone acetate, on the other hand, did not affect 3H-testosterone metabolism. Estradiol-17 beta and cyproterone acetate inhibited in vitro binding of 3H-dihydrotestosterone to the intracellular cytoplasmic receptor, but not the intraluminal androgen binding protein (ABP). These data suggest that estradiol-17 beta may have a more potent antiandrogenic effect on the epididymis than cyproterone acetate due to inhibition of 5 alpha reduction of testosterone as well as binding to the androgen receptor.

Animals↗
PubMed1990

[Therapy of hirsutism in females with adrenal enzyme defects of steroid hormone biosynthesis: comparison of dexamethasone with cyproterone acetate].

In patients with adrenal hirsutism or enzyme deficiencies in steroidogenesis, elevated adrenal androgens could be normalized by dexamethasone. We were interested to see if dexamethasone would be as effective as cyproterone acetate in treating hirsutism in selected patients with adrenal pathogenesis. Therefore 28 patients with hirsutism of adrenal origin or enzyme deficiency were treated cyclically either with cyproterone acetate and ethinylestradiol (2 mg cyproterone acetate + 0.035 mg ethinyl-estradiol days 1-21, +10 mg cyproterone acetate days 1-15) (n = 15) or with 0.25-0.5 mg dexamethasone daily at 10 pm (n = 13). In the dexamethasone group there was a significant drop in dehydroepiandrosterone and dehydroepiandrosterone sulfate levels within 9 months, but there was a diminution in hirsutism in only four women (31%); in four out of seven menstrual irregularities decreased. In the cyproterone acetate group hirsutism diminished significantly in 66% (n = 10) without suppression of adrenal androgens. Weight gain occurred in a few cases in both groups; other side effects developed in 33% in the cyproterone acetate group. Preselection of patients with hirsutism is useful with respect to diagnosis; adrenal pathogenesis should not generally indicate dexamethasone treatment of hirsutism unless there is a desire for pregnancy, because cyproterone acetate is a more powerful agent in reducing hair growth.

3-Hydroxysteroid Dehydrogenases↗
PubMed1983

Indirect evidence that the action of cyproterone acetate on the skin is due to a metabolite.

Cyproterone acetate, applied as 1% solution in ethanol or isopropyl myristate, did not decrease the sebum excretion rate (SER) when applied to forehead skin of patients with acne, although SER is decreased when the drug is given systemically. The probable explanation is that cyproterone acetate owes its local action to a metabolite formed systemically. The present study shows this is unlikely to be the 17 beta-hydroxy cyproterone acetate.

Acne Vulgaris↗
PubMed1996

Inhibition of growth and induction of TGF-beta 1 in human hepatocellular carcinoma with androgen receptor by cyproterone acetate in male nude mice.

BACKGROUND/AIMS: Hepatocellular carcinoma possesses androgen receptor but its true role is not known. This study aimed to investigate the effect of an anti-androgen cyproterone acetate on the growth of androgen receptor-positive hepatocellular carcinoma. METHODS: Androgen receptor-positive human hepatocellular carcinoma cells (KYN-1/SM-10) were subcutaneously transplanted into male nude mice. When the tumor size was about 10 mm, animals were subcutaneously administered cyproterone acetate (0.1 mg/day and 0.8 mg/day) or solvent alone for 21 days. Animals were serially sacrificed for measurements of testicular weight, tumor size, and cytosolic and nuclear androgen receptor levels in tumor. Proliferating cell nuclear antigen, transforming growth factor-alpha, and transforming growth factor-beta 1 in tumor were investigated immunohistochemically, using monoclonal antibodies. Apoptotic activity was also studied by the in situ DNA nick end labeling method. RESULTS: Cyproterone acetate depressed testicular weight, suppressed tumor growth, and decreased both cytosolic-androgen receptor and nuclear-androgen receptor levels dose-dependently. Numbers of proliferating cell nuclear antigen-positive cells were decreased transiently with the low dose but continuously with the high dose of cyproterone acetate. Transforming growth factor-alpha expression was not influenced by cyproterone acetate, but the high dose of cyproterone acetate induced higher expression of transforming growth factor-beta 1, associated with increased numbers of apoptotic tumor cells, peaking on day 3. CONCLUSIONS: The inhibition of growth of androgen receptor-positive hepatocellular carcinoma with cyproterone acetate in male nude mice could be due to G1-phase cell cycle arrest, and to some extent apoptosis induced by increased synthesis of transforming growth factor-beta 1 in tumor, caused by the direct action of cyproterone acetate through androgen receptors, as well as decreased testosterone levels in blood due to cyproterone acetate-induced testicular atrophy.

Androgen Antagonists↗
PubMed2003

Use of cyproterone acetate, finasteride, and spironolactone to treat idiopathic hirsutism.

OBJECTIVE: To compare the effectiveness of cyproterone acetate, finasteride, and spironolactone in the treatment of idiopathic hirsutism. DESIGN: Prospective randomized clinical study. SETTING: University hospital. PATIENT(S): Forty-one women (median age, 21 years [range, 18-34 years]) with idiopathic hirsutism who had requested to use an oral contraceptive. INTERVENTION(S): Patients were randomly assigned to receive cyproterone acetate (12.5 mg/d for the first 10 days of the cycle), finasteride (5 mg/d), or spironolactone (100 mg/d) for 12 months. Follow-up was done at the end of therapy. MAIN OUTCOME MEASURE(S): Ferriman-Gallwey score before treatment, at 6 and 12 months of treatment, and 1 year after the end of treatment, and androgenic profile before and after treatment. RESULT(S): At the end of therapy, the Ferriman-Gallwey score decreased by 38.9%, 38.6%, and 38.5% in patients who used cyproterone acetate, finasteride, and spironolactone, respectively. One year after therapy, the Ferriman-Gallwey score of patients who used spironolactone was significantly lower (6.74 +/- 1.41) than that of patients who used either cyproterone acetate (7.92 +/- 1.08), or finasteride (9.08 +/- 0.99). The androgenic profile did not change significantly during treatment. CONCLUSION(S): In patients with idiopathic hirsutism, the short-term results of treatment with cyproterone acetate, finasteride, and spironolactone are similar, but spironolactone is effective for a longer time.

17-alpha-Hydroxyprogesterone↗
PubMed1977

A clinical trial of cyproterone acetate for sexual deviancy.

Cyproterone acetate was used in the treatment of ten patients presenting with problems of sexual deviancy. Of these six completed the course of treatment over a period of one year and psychological, medical and endocrinological measures were recorded.

Adult↗
PubMed1997

Formation of DNA adducts by cyproterone acetate and some structural analogues in primary cultures of human hepatocytes.

Recently, we have shown that the therapeutically-used progestin and antiandrogen cyproterone acetate (CPA) causes the formation of high levels of DNA adducts in rat hepatocytes and rat liver [J. Topinka, U. Andrae, L.R. Schwarz, T. Wolff, Cyproterone acetate generates DNA adducts in rat liver and in primary rat hepatocyte cultures, Carcinogenesis 14 (1993) 423-427: J. Topinka, B. Binkova, L.R. Schwarz, T. Wolff, Cyproterone acetate is an integral part of hepatic DNA adducts induced by this steroidal drug, Carcinogenesis 17 (1996) 167-169; S. Werner, J. Topinka, T. Wolff, L.R. Schwarz, Accumulation and persistence of DNA adducts of the synthetic steroid cyproterone acetate in rat liver, Carcinogenesis 16 (1995) 2369-2372; J. Topinka, B. Binkova, H.K. Zhu, U. Andrae, I. Neumann, L.R. Schwarz, S. Werner, T. Wolff, DNA damaging activity of the cyproterone acetate analogues chlormadinone acetate and megestrol acetate in rat liver, Carcinogenesis 16 (1995) 1483-1487]. Its structural analogues, chlormadinone acetate (CMA) and megestrol acetate (MGA) were much less active in this respect [J. Topinka, B. Binkova, H.K. Zhu, U. Andrae, I. Neumann, L.R. Schwarz, S. Werner, T. Wolff, DNA damaging activity of the cyproterone acetate analogues chlormadinone acetate and megestrol acetate in rat liver, Carcinogenesis 16 (1995) 1483-1487]. In the present study we addressed the question whether these compounds and two further analogues, medroxyprogesterone acetate (MPA) and progesterone, induce the formation of DNA adducts in primary cultures of human hepatocytes. Incubation of CPA with human hepatocytes from two male and four female donors induced the formation of significant levels of CPA-DNA adducts detectable by 32P-postlabeling. The by far most prevalent DNA adduct is most likely identical with adduct A formed in CPA-treated rats. DNA binding was found even at 0.03 microM CPA, the lowest concentration used. The maximum effect occurred at about 10 microM in 5 of the 6 cell preparations. At this concentration 480 and 2690 adducts x 10(-9) nucleotides were detected in hepatocytes of the two male donors and 1072, 816, 613 and 659 adducts x 10(-9) nucleotides in the hepatocytes of the four female donors after an exposure of 6 h with CPA. Extending the incubation time to 20 h resulted in a roughly three-fold higher binding. CMA and MGA were assayed in two of the liver cell preparations from the female donors. At a concentration of 20 microM and an incubation time of 6 h, DNA adduct levels for CMA were 21 and 43% and for MGA 31 and 65% of the levels observed with 20 microM CPA. In contrast, DNA binding of MPA amounted to less than 1% of that observed with CPA and DNA binding of the natural occurring progestin progesterone was below the level of detection. The results point to a genotoxic risk associated with the therapeutic use of CPA and possibly of CMA and MGA. Furthermore, the findings suggest that the significant genotoxicity observed with CPA, MGA and CMA is associated with the presence of the double bond in position 6-7 of the steroid, which is absent in MPA and progesterone.

Adult↗
PubMed1996

Induction of micronuclei and initiation of enzyme-altered foci in the liver of female rats treated with cyproterone acetate, chlormadinone acetate, or megestrol acetate.

The synthetic anti-androgen and progestin cyproterone acetate (CPA), recently found to be genotoxic for the liver, and two structurally similar progestins, chlormadinone acetate (CMA) and megestrol acetate (MGA), have been compared for clastogenic and tumor-initiating activities in female rats. In the micronucleus assay, carried out in rats given a single p.o. dose of 100 mg/kg, CPA induced the maximum increase in the frequency of micronucleated hepatocytes (6.6-fold as compared to controls) when treatment was performed 3 days before partial hepatectomy and cell sampling 2 days later. Under the same experimental conditions the clastogenic potencies of CMA and MGA were 69% and 36% of that of CPA respectively. In the liver foci assay, p.o. dosing with 100 mg/kg CPA once a week for 6 successive weeks induced, as compared to controls, a significant increase in the number and area of gamma-glutamyltranspeptidase-positive foci. At the same dosage schedule the tumor-initiating activity of CMA and MGA was 7- to 10-fold lower than that of CPA. These findings suggest that the 1,2 alpha-methylene group, present in CPA but absent in both CMA and MGA, favours the activation to a reactive species and/or hinders the biotransformation to non-toxic metabolites.

2-Acetylaminofluorene↗
PubMed1975

Urinary androgen response of 8 girls with precocious puberty given cyproterone acetate.

The effects of cyproterone acetate (CA), daily oral administration of 100 mg/m2, on the levels of urinary androgen excretion and velocity of skeletal maturation were studied in 8 girl patients with precocious puberty. Under therapy, testosterone excretion fell within a short time, and velocity of skeletal maturation normalized when the treatment was prolonged. Other beneficial effects such as stoppage of vaginal bleeding and no further growth of breast size and public hair, were also observed. Of 3 subjects, who were given CA for a period of 2--3 yrs, 2 showed further increments in testosterone excretion levels.

Androgens↗
PubMed1979

Rouleau formation and fertility of spermatozoa in guinea pigs treated with cyproterone acetate.

The effects of cyproterone acetate (CA) on fertility of spermatozoa and rouleau formation were investigated in male guinea pigs. Twelve of 15 matings during CA treatment resulted in pregnancy even when rouleaux were absent in ejaculates, indicating that the rouleau condition is not necessary for the fertilizing ability of guinea pig spermatozoa. Examination of epididymides and vasa deferentia revealed that rouleaux diminished progressively with treatment time and were absent in the excurrent ducts of all males during the eighth and ninth weeks of treatment. Following a latent period after treatment, rouleaux were first noted in a specific epididymal region and were present throughout the distal excurrent ducts and ejaculates by 6 wk posttreatment. This sequence of rouleau loss and reappearance in the excurrent ducts suggests that rouleau formation is dependent on a regional epididymal influence that requires androgens. Spermatogenesis was not arrested; however, seminal vesicle and body weights were reduced in treated males.

Animals↗
PubMed1979

Biochemical and histological studies on prostates in castrated dogs after treatment with androstanediol, oestradiol and cyproterone acetate.

The effect of cyproterone acetate (CA) on experimentally induced benign prostatic hyperplasia (BPH) in the castrated dog was investigated. BPH was induced by 6 months' treatment with 3 alpha-androstanediol (3 alpha-diol) alone and in combination with 17 beta-oestradiol (Oe2). RNA, DNA and zinc content of the glands were determined in addition to histological examination and measurement of the prostates. Two different types of prostatic enlargement were observed. First, 3 alpha-diol induced typical diffuse canine hyperplasia with replacement of functional activity. DNA, RNA and the zinc content of total glands were increased compared with intact controls. Second, 3 alpha-diol plus Oe2 produced on the one hand a more striking increase of prostatic weights, but on the other a loss of typical morphological structure and function. Histologically, transformation of simple glandular epithelium into stratified squamous metaplasia occurred in addition to stimulation of fibromuscular tissue. Biochemically, a relative decrease of DNA per mg tissue was measured with a fall in the RNA to DNA ratio and zinc to the values of castrates. Administration of CA resulted in an abolition of the 3 alpha-diol effect. Biochemical determinations and histological examinations revealed an effect similar to castration after treatment with 3 alpha-diol plus CA. After treatment with 3 alpha-diol plus Oe2 plus CA fibromuscular stimulation as an oestrogen effect predominated in addition to glandular atrophy and metaplastic changes, especially in prostatic ducts. Epithelial hyperplasia is an effect of 3 alpha-diol, whereas metaplastic proliferation only occurs in oestrogenized and androgenized dogs. In both types of prostatic enlargement CA prevents development of hyperplastic prostate.

Androstane-3,17-diol↗