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PubMed1981

Glucocorticoids and aspirin inhibit and cyproterone acetate enhances the androgenic response in mouse kidney.

Glucocorticoids and aspirin antagonize the androgenic response in mouse kidney, but not in ventral prostate or seminal vesicles. These agents impeded the testosterone-mediated increase in kidney weight, cytochrome c oxidase, and lysosomal hydrolases and urinary excretion of lysosomal hydrolases and proteins. They also attenuated the testosterone-induced decrease in enzyme latency and membrane stability of kidney lysosomes. In contrast, the antiandrogen cyproterone acetate is weakly androgenic in kidney and potentiates testosterone-induced lysosomal enzymuria and proteinuria (synandrogenic effect).

Animals↗
PubMed1988

Microsomal effects of cyproterone acetate and flutamide in rat testis.

1. Effects of two doses of cyproterone acetate (CA) and flutamide (FLU) (50 and 100 mg/kg/3 days) on the testicular steroidogenesis in male rats have been investigated, by measuring the content of cytochrome P-450, cytochrome b5 and cytochrome c reductase activity in the microsomal fraction. 2. CA provoked a significant decrease in cytochrome P-450 content while FLU induced an increase with the lowest dose but a significant decrease after administration of 100 mg/kg. 3. On the other hand, in all cases the cytochrome b5 and cytochrome c reductase activity remained unchanged. 4. The plasma levels of LH and testosterone were measured after CA and FLU injection (50 and 100 mg/kg/3 days). 5. CA administration provoked a reduction in blood levels of these hormones while FLU induced a significant increase in both. 6. These data suggested that CA and FLU modified the cytochrome P-450 in rat testes by an indirect mechanism, probably through the modification of LH plasma levels.

Androgen Antagonists↗
PubMed1985

15-Hydroxycyproterone acetate and cyproterone acetate levels in plasma and urine.

15 beta-Hydroxycyproterone acetate (15HOCPA) and cyproterone acetate (CPA) have been quantitated in human plasma and urine by a selective high-performance liquid chromatographic assay. The levels of 15HOCPA in plasma are generally twice those of its precursor CPA, although both compounds appear to have similar clearance rates. Approximately 6% of the dose is excreted into the urine, predominantly (greater than 90%) as the free form of 15HOCPA and CPA.

Chromatography, High Pressure Liquid↗
PubMed1990

Orchidectomy versus Buserelin in combination with cyproterone acetate, for 2 weeks or continuously, in the treatment of metastatic prostatic cancer. Preliminary results of EORTC-trial 30843.

This prospective randomized phase III trial compares orchidectomy as standard androgen-deprivative therapy of advanced (metastatic) prostatic cancer with treatment using the LHRH agonist Buserelin administered as nasal spray 3 daily doses of 400 micrograms, and combined with cyproterone acetate (CPA) 3 daily doses of 50 mg orally for 2 weeks initially to prevent flare-up of the disease, or continuously as complete androgen blockade. The trial was closed to entry in September 1989 when 367 patients were recruited. Patients were stratified for performance status (WHO) and metastatic status prior to randomization. According to patient and disease characteristics spreading of patients over the 3 arms was without statistical significant differences. Ineligibility was 5 and 4% of the patients were only partly evaluable. In March 1990 a first, preliminary analysis was performed. At that time 207 patients were off-study for progression or death and median follow-up was 1 yr. As to time-to-progression and survival there were no significant differences between the 3 arms. The meaning of this in regard to results of other trials with complete androgen blockade is discussed.

Aged↗
PubMed1992

Androgens and androgen-receptors in prostate tissue from patients with benign prostatic hyperplasia: effects of cyproterone acetate.

Testosterone, 5 alpha-dihydrotestosterone and cyproterone acetate (CPA) were estimated in samples of prostate tissue, obtained from benign prostatic hyperplasia (BPH) patients who were or were not pretreated with CPA. Furthermore, these steroids were estimated in various fractions of the BPH tissue, and the number of nuclear androgen-receptor sites was determined. CPA-treatment caused a 4-fold, significant suppression of 5 alpha-dihydrotestosterone levels in total prostate tissue and its subfractions, without affecting testosterone levels or the androgen-receptor contents of the nuclear extracts. Nuclear concentrations of CPA were twice as high as those of 5 alpha-dihydrotestosterone. It is concluded that effects of CPA may have been caused through a combination of the following mechanisms: (1) suppression of peripheral androgen levels; (2) competition with androgens for (nuclear) androgen-receptors; and (3) suppression of prostatic 5 alpha-reductase.

5-alpha Reductase Inhibitors↗
PubMed1980

Medium dose cyproterone acetate (CPA): effects on hormone secretion and on spermatogenesis in men.

Medium dose cyproterone acetate (CPA; 10 mg daily p.o.) was administered to 10 fertile men for 12 weeks. Hormonal measurements and semen analyses were performed before, during (4th and 12th week) and after CPA treatment. At the hypothalamo-pituitary level CPA significantly reduced the hypophyseal storage and synthesis capacity for gonadotropins. Basal LH and FSH concentrations were suppressed by 30% and 40%, respectively; while basal prolactin was elevated by 75%. The episodic fluctuations of peripheral gonadotropins remained unaffected. At the testicular level CPA significantly decreased basal testosterone and dihydrotestosterone concentrations by 70% and 50%, respectively. The pulsatile pattern of androgen secretion was abolished. CPA also inhibited spermatogenesis and motility. No serious clinical side effects were observed. All changes appeared to be completely reversible. It is concluded that medium dose CPA induces progestational/anti-gonadotropic effects at the hypothalamo-pituitary level in addition to its antiandrogenic action at the testicular level.

Adult↗
PubMed1990

Monthly cyproterone acetate in the treatment of hirsute women: clinical and laboratory effects.

Cyproterone acetate given as a single intramuscular dose of 300 mg monthly for 6 months resulted in significant reduction of hirsutism without appreciable side effects. This regimen resulted in decreased levels of luteinizing hormone (LH) and estradiol in the eight women studied. No significant changes were observed in total serum testosterone (T) levels, however, there was a reduction in sex hormone binding globulin (SHBG), resulting in lowered SHBG-bound T, and an increase in non-SHBG-T over this time. Serum androstanediol glucuronide levels decreased in three of four women, although not to normal levels.

Adolescent↗
PubMed1991

Long-term treatment of hirsutism: desogestrel compared with cyproterone acetate in oral contraceptives.

OBJECTIVE: Effectiveness of 2-year treatment of hirsutism with low estrogen oral contraceptives (OCs) containing nonandrogenic or antiandrogenic progestogen. Evaluation of changes in plasma lipids. DESIGN: Ten patients treated with desogestrel 150 micrograms + 30 micrograms ethinyl estradiol, 6 with desogestrel 150 micrograms + 50 micrograms ethinyl estradiol, 10 with cyproterone acetate 2 mg + 35 micrograms ethinyl estradiol. Random allocation. Paired comparisons. CONTROL GROUP: 19 normal women, not treated. SETTING: Academic tertiary care. PATIENTS: Women with hirsutism (idiopathic and/or polycystic ovary), 24 of 26 completed treatment. INTERVENTION: Two-year treatment. MAIN OUTCOME MEASURES: Hirsutism score, plasma testosterone, and lipids. RESULTS: Initial hirsutism scores (11.8 +/- 0.6 SE) declined with treatment (-7.2 +/- 0.4, P less than 0.01) to 4.7 +/- 0.6, almost reaching control (3.6 +/- 0.3). Initial plasma cholesterol (4.33 mmol/L +/- 0.30 SE), similar to control (4.78 +/- 0.24), increased slowly over 2 years (+2.04 +/- 0.34, P less than 0.01). High-density lipoproteins cholesterol (1.05 mmol/L +/- 0.04 SE), similar to control (1.12 +/- 0.07), did not change the 1st year and increased at 2 years (+0.57 +/- 0.11, P less than 0.01). No differences appeared among treatment groups. CONCLUSIONS: Treatment is very effective, 2 years for best results. The OCs tested are equally efficacious. Changes in plasma lipids are of some concern but of difficult interpretation.

Adult↗
PubMed1981

D-TRP5-analogue of luteinising hormone releasing hormone in combination with cyproterone acetate to treat precocious puberty.

A 6-year-old girl with central (true) precocious puberty was successfully treated with a combination of the luteinising hormone releasing hormone analogue (D-Trp6)-LH-RH and cyproterone acetate. This treatment led to an almost complete arrest of gonadotrophin and oestrogen secretion, induced regression of pubertal signs, and markedly slowed bone maturation. It is suggested that the paradoxical refractoriness of the gonadotrophic and gonadal cells induced by long-term treatment with LH-RH agonists can be exploited in the treatment of precocious puberty.

Bone Development↗
PubMed1988

Clinical and endocrine effects of cyproterone acetate in postmenopausal patients with advanced breast cancer.

A phase II study with cyproterone acetate (CPA) was done as the primary treatment in female breast cancer patients. Twenty-three patients, mean age 64 years, range 52-75 years, were entered and treated with CPA 400 mg daily. Twenty patients were evaluable and responses were sparse. There was one partial and one complete remission, 17 patients were stable and one patient progressed within 3 months. Side-effects were frequent: five patients complained of nausea, three had severe weight loss, one suffered from depression and seven showed disturbed liver function tests. Six patients had to stop treatment for side-effects, while two other patients were taken off treatment because they developed an acute necrotizing hepatitis. The hepatitis recovered after drug withdrawal in both patients. The serum levels of CPA, cortisol, androstenedione, DHAS, LH, FSH and prolactin were measured during CPA treatment. The levels of cortisol and androstenedione did not change, while LH, FSH and DHAS were suppressed. The DHAS showed an inverse relation to serum CPA concentrations. The prolactin levels rose uniformly. The therapeutic effect of CPA in postmenopausal patients with advanced breast cancer is disappointing, and inferior to that of other progestins. Side-effects are frequent, possibly as a result of the high dosage used in this study. The hormonal changes are different from those of other progestins, which may explain the different efficacies.

Aged↗
PubMed1989

A prospective randomised controlled trial of tamoxifen and cyproterone acetate in pancreatic carcinoma.

In a prospective controlled clinical trial, 108 patients with pancreatic adenocarcinoma were randomly allocated to receive tamoxifen 20 mg b.d., cyproteron acetate 100 mg t.d.s. or no active treatment. The median survival of those receiving tamoxifen was longer than either of the other two groups (5.25 compared to 4.25 and 3 months, respectively) but this difference did not achieve statistical significance. Cox regression analysis of 12 clinical and biochemical features showed that, for the entire group of patients, survival was significantly longer in younger patients, those undergoing surgical bypass and those with better initial performance status. However, even when adjustment was made to allow for the distribution of these prognostic variables within the three groups, the difference in survival still did not achieve statistical significance. No side-effects attributable to treatment was observed.

Adenocarcinoma↗
PubMed1987

The effect of progesterone and progestational antiandrogen cyproterone acetate on the ovaries and the adrenal glands of neonatally androgenised rats.

The influence of the graded doses of progesterone and progestational antiandrogen, cyproterone acetate, is studied on the vaginal cycles, follicular dynamics and steroidogenic potential of the ovaries and adrenal glands in neonatally androgenised rats with persistent vaginal estrous. Of the different doses of progesterone, 0.5 mg progesterone/day is found to reinstate more or less normal vaginal cycles. None of the doses of progesterone and CPA induced ovulation in cystic ovaries and hence the vaginal cycles thus reinstated are not the reflection of ovarian cycles and the diestrous smear is not an indication of functional CL in these ovaries. The treatment of progesterone and CPA brought about degenerative changes in the antral follicles above stage IV and in cystic type I follicles. It mobilised the growth of type 0 follicles up to the early antral stage of type III, thereby indicating the presence of the negative feedback of progestational steroids on FSH secretion in PVE rats. The minimum change in the activity of carbohydrate metabolising enzymes and the steroid dehydrogenases in the ovaries subsequent to the treatment with especially the higher doses of progesterone, and CPA suggests the absence of any impact on LH secretion, albeit indirect. There was a marked reduction in the steroidogenic potential in the adrenal glands of the CPA treated rats; however, it did not show any positive impact on the structure of the polycystic ovary.

Adrenal Glands↗
PubMed1991

Cyproterone acetate in the treatment of sexual disorders: pharmacological base and clinical experience.

Cyproterone acetate (CPA) has been discovered more than 25 years ago and it was the first antiandrogen suitable for clinical use. CPA inhibits the action of endogenous and exogenous androgens at all androgen target organs; these include the prostate, seminal vesicles, testes, and the vas deferens. However, this antiandrogen also antagonizes less sex-specific effects of androgens, for example ossification of the epiphyseal cartilage, sebaceous gland function and skin thickness. Indications for CPA: Prostate cancer, androgen induced disorders of the skin (acne, seborrhoea, hirsutism, alopecia), precocious puberty and sexual disorders in men. Concerning sexual deviations clinical trials started in 1966. CPA leads to loss of libido and the ability to achieve erection, followed by the inability to achieve orgasm, after about 14 days of treatment (100-200 mg daily orally or 300 mg weekly i.m.). These effects are reversed in the same order as the onset. About 75 to 80% of patients respond to this therapy. CPA is generally well tolerated. Tiredness, lack of drive, listlessness and depressive moods have been reported as non-specific side-effects. Slight gynecomastia occurs in about 20% of patients. There are no good alternatives in this indication. Pure antiandrogens are unsuitable, because these are unable to inhibit libido sufficiently. Tranquilizers are not very effective, high doses of estrogens are associated with severe (cardiovascular) side effects. Orchidectomy is an irreversible intervention, LHRH analogues are associated with hot flushes and the initial increase in testosterone (flare phenomenon).

Androgen Antagonists↗
PubMed1990

Metabolic effect at six and twelve months of cyproterone acetate (2 mg) combined with ethinyl estradiol (35 micrograms) in 31 patients.

The metabolic effects of cyproterone acetate (2 mg) combined with a new dose level of ethinyl estradiol (35 micrograms) were studied over a one-year period in 31 patients presenting moderate clinical hyperandrogenism. The following tests were performed before treatment, at 6 and 12 months, an oral glucose tolerance test (OGTT) with measurement of insulinemia, total cholesterol, HDL cholesterol and the LDL + VLDL/HDL ratio, A1 and B apoproteins. At six months and at one year of treatment, the weight and body mass index (kg/m2) were not modified. Glucose tolerance and insulinemia had not changed significantly at one year. Lipid test results showed an increase in triglycerides, as well as in total and HDL cholesterol levels. However, the LDL + VLDL/HDL and A1/B apoprotein ratios did not change during the study. We conclude from these results that the new combination does not have any adverse effects on glucose tolerance and has a predominantly estrogenic effect on lipid parameters, characterized by increases in total cholesterol, HDL cholesterol and triglycerides.

Adolescent↗
PubMed1987

Effects of cyproterone acetate (CPA) on serum lipoproteins when administered alone and in combination with ethinyl estradiol (EE).

The effects of serum lipids and lipoproteins of 2 mg cyproterone acetate (CPA) given alone and in combination with 35 or 50 micrograms ethinyl estradiol (EE) were studied in 21 oophorectomized women in a study with a cross-over design. CPA in this low oral dose was rather inert in its effects on lipoprotein lipids. It induced only a small decrease in the free cholesterol and phospholipid content of the high density lipoprotein (HDL) fraction. As regards the CPA-EE combinations, they induced a slight increase in the HDL fraction, a small decrease in the low density lipoprotein (LDL) fraction and a substantial increase in triglycerides both in the serum and in the very low density lipoprotein (VLDL) fraction. This lipoprotein pattern is invariably induced after the administration of an alkylated estrogen or an "estrogen dominated" oral contraceptive. An increase in triglycerides is a "biochemical" adverse effect which may have clinical implications for some patients.

Adult↗
PubMed1986

The effect of cyproterone acetate alone and in combination with ethinylestradiol on the hypothalamic pituitary adrenal axis, prolactin and growth hormone release in male-to-female transsexuals.

This study investigated the effects of long-term cyproterone-acetate (CA) treatment on the hypothalamus-pituitary-adrenal axis and further on the release of prolactin and growth hormone. Thirty-one male-to-female transsexuals, treated at least 3 months either with 100 mg CA alone or in combination with 50 micrograms ethinyloestradiol (EO)/day, were studied. In all of them the cortisol response to 250 micrograms Synacthen administration was comparable to that measured in controls. Six subjects treated with CA alone (group I) and six subjects treated with CA + EO (group II) underwent an insulin-hypoglycemia test. Seven eugonadal men served as controls. Compared with control values: in two subjects of group I and one subject of group II a low cortisol response was found. The mean growth hormone response was found to be lower in both groups, whereas the mean prolactin response was lower in group I.

Adult↗
PubMed1992

Cyproterone acetate induces DNA damage in cultured rat hepatocytes and preferentially stimulates DNA synthesis in gamma-glutamyltranspeptidase-positive cells.

The synthetic anti-androgen and progestin cyproterone acetate (CPA) is known to increase the liver tumor rate in rats. The tumorigenicity of CPA has been attributed to a tumor-promoting activity of the steroid. In order to discover whether CPA acts directly on preneoplastic liver cells or via indirect effects, we investigated whether CPA stimulates replicative DNA synthesis in vitro in hepatocytes isolated from carcinogen-treated rats (two-thirds hepatectomy, 1 x 30 mg diethylnitrosamine per kg and 0.1% phenobarbital in the drinking water) and whether the degree of stimulation differs in gamma-glutamyltranspeptidase (GGT)-positive, putatively preneoplastic and GGT-negative, 'normal' hepatocytes. The possibility that CPA might also have initiating potential was investigated by studying its effects on DNA repair synthesis. Stimulation of [3H]thymidine incorporation into the DNA by CPA was only observed in the presence of epidermal growth factor (EGF) (10 ng/ml) and insulin (10 mU/ml). Maximal effects were obtained between 2 and 10 microM. DNA synthesis in the presence of EGF/insulin was reduced by the 'pure' anti-androgen flutamide, but stimulated by the 'pure' progestin promegestone. In the presence of CPA, EGF and insulin, the labelling index was twice as high in GGT-positive as in GGT-negative liver cells, regardless of whether mitogens were added at 48 or 72 h. The labelling index did not differ in the GGT-positive and negative hepatocytes when CPA was omitted. These findings are consistent with the idea that CPA has tumor-promoting activity. CPA significantly induced repair synthesis in the isolated hepatocytes from both untreated and carcinogen-treated rats. This increase was detected at a concentration as low as 2 microM and maximal effects were obtained at 20 microM. These results indicate that CPA is not only a tumor-promoting, but also a genotoxic chemical, i.e. that it might also have an initiating potential.

Animals↗