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PubMed1991

Testosterone and cyproterone acetate modulate peripheral but not central benzodiazepine receptors in rats.

Sixteen days of testosterone acetate (TA) treatment in male rats induced an increase in the densities of peripheral benzodiazepine receptors (PBR) in the adrenal and Cowper's glands and a decrease in PBR density in the testis. TA did not alter PBR density in the heart, cerebral cortex, or pituitary, or central benzodiazepine receptor (CBR) density in the cerebral cortex or hypothalamus. The antiandrogenic agent cyproterone acetate induced a decrease in PBR density in the testis, adrenal, and pituitary, but did not affect PBR density in Cowper's glands, heart, or cerebral cortex, or CBR density in the cerebral cortex or hypothalamus. In all of the above organs, affinity values did not change following the treatment with both agents. The receptoral changes may be relevant to the physiological and neurobehavioral effects of the chronic exogenous androgenic and antiandrogenic treatment.

Androgen Antagonists↗
PubMed1981

Terminal half-lives in plasma and bioavailability of norethisterone, levonorgestrel, cyproterone acetate and gestodene in rats, beagles and rhesus monkeys.

Norethisterone, levonorgestrel, cyproterone acetate and gestodene have been used for a long time in oral contraception and other indications, or are in the process of development for such indications. However, very little is known concerning the bioavailability and plasma levels of unmetabolized gestagens in the animal species used for chronic toxicity testing and pharmacological investigation. In this study the gestagens were administered intravenously, subcutaneously and orally to rats, beagles and rhesus monkeys. The drug plasma levels were determined by specific radioimmunoassay. The half-life of the terminal disposition phase was calculated following intravenous administration, and the extent of bioavailability was determined from the area under the drug level curves following subcutaneous and oral administration. The terminal half-lives of a particular compound in different animal species differed considerably. Furthermore, comparison of the different gestagens showed large variations in this parameter in all the animal species. In addition, inter-animal species comparison of a particular substance, and comparison of different substances in a single species, also showed great differences in bioavailability. The results are compared with the corresponding parameters in man. This investigation illustrates the fundamental problems inherent in the extrapolation of the results of toxicity studies and pharmacological investigations in animals, to man. The best tolerance and the lowest degree of pharmacological effect seem to occur where the bioavailability of a gestagen is poor and its terminal half-life short.

Administration, Oral↗
PubMed1983

Effects of cyproterone acetate with combination of testosterone enanthate on seminal characteristics, androgenicity and clinical chemistry in langur monkey.

Daily oral administration of 1 mg/kg b.w. of cyproterone acetate and simultaneously administered testosterone enanthate (2 mg/kg b.w./15 days; i.m.) to adult male langur monkeys over a period of 90 days caused a gradual decrease in the count (to azoospermia) and motility of spermatozoa, concurrently with an increase in the percentage of non-motile as well as abnormal and immature sperm. Semen weight, volume, seminal fluid volume and circulating testosterone levels decreased nonsignificantly. Semen pH, libido and body weight remained unimpaired. The levels of SGOT, SGPT, serum alkaline phosphatase, LDH, bilirubin, Na+, K+ and hematological values did not alter significantly. All the changes were reversible. The results indicate that the combination regimen seems to affect the fertility in two ways, i.e. by inhibiting spermatogenesis in the testis and maturation process in the epididymis without altering the androgenicity.

Androgen Antagonists↗
PubMed1990

Cyproterone acetate/ethinyl estradiol in the treatment of acne. A comparative dose-response study of the estrogen component.

The investigators compared 2 mg cyproterone acetate (CPA) in combination with either 0.035 mg or 0.050 mg ethinyl estradiol (EE2) (Diane -35 versus Diane -50) in the treatment of acne. Both formulations of Diane were highly effective in improving acne, even in women who had been refractory to other types of medication. Cycle control with both formulations was excellent and adverse effects were generally mild and confined to the first two cycles of treatment. Mean plasma lipid levels increased with both treatments, yet most individual values remained within normal limits after one year of therapy while the LDL-cholesterol/HDL-cholesterol ratio was stable throughout the study period. Plasma testosterone and DHEA-S levels paralleled the decline in the clinical severity of the acne. There was no loss of clinical effectiveness with Diane -35 and it provided the advantage of a 30% decrease in the amount of estrogen.

Acne Vulgaris↗
PubMed1993

Pharmacokinetics of cyproterone acetate and ethinylestradiol in 15 women who received a combination oral contraceptive during three treatment cycles.

The pharmacokinetics of cyproterone acetate (CPA) and ethinylestradiol (EE2) were determined in 15 healthy women (age 19 to 34 years), following single dose administration of a combination oral contraceptive, containing 2.0 mg CPA together with 0.035 mg EE2 (Diane-35R). After a wash-out period of one week, the same preparation was administered during a treatment period of three months. After single dose administration, maximum concentrations of CPA in the serum were 15.2 +/- 6.6 ng/ml. Post maximum drug levels declined biphasically with half-lives of 0.8 +/- 0.4 h and 54.0 +/- 26.0 h, respectively. The apparent clearance was calculated to be 3.6 +/- 0.9 ml x min-1 x kg-1 and the volume of distribution (Vz) was 986 +/- 4371. The free fraction of CPA was 3.5 +/- 1.9% and the fractions bound to heat labile proteins and albumin were 4.6 +/- 2.2% and 92.0 +/- 3.5%, respectively. Trough levels of CPA in the serum increased during a treatment cycle, reaching a steady-state around day 16. An about two-fold accumulation of CPA was observed, which was less than expected theoretically. SHBG concentrations in the serum increased by a factor of three during a cycle, without having any effect on the protein binding of CPA. At the end of treatment cycle three, the terminal half-life of CPA had increased to a mean value of 78.6 +/- 16.0 h and the volume of distribution to a value of 1304 +/- 427 1. The apparent clearance showed a small, although significant decrease to a value of 3.0 +/- 0.4 ml x min-1 x kg-1. The observed changes Vz and t 1/2 during the treatment period were attributed to the distribution of CPA into a deep compartment and the slow release of the drug from this compartment. The AUC(0-4h) values of EE2 following single dose administration of the combination oral contraceptive were found to be 187.5 +/- 79.7 pg x ml-1 x h. On the last day of cycles one and three, the AUC(0-4h) values were 311.2 +/- 109.3 and 304.8 +/- 121.5 pg x ml-1 x h, respectively, which corresponds to an about 60% increase as compared to single dose administration. Total and free testosterone concentrations decreased during treatment cycles one and three by about 39% and 62%, respectively, compared with the corresponding values measured prior to treatment.

Adult↗
PubMed1986

Effects of cyproterone acetate and flutamide on the testis and epididymis of the Indian wall lizard, Hemidactylus flaviviridis (Ruppell).

Intramuscular injections of 0.2 mg cyproterone acetate (CA) or flutamide every other day for 6 weeks resulted in the inhibition of spermatogenesis. While CA treatment reduced the weight of the testis significantly, flutamide did not. Inhibition of steroidogenesis, indicated by an accumulation of sudanophilic lipid and a decrease in delta 5-3 beta-hydroxysteroid dehydrogenase and glucose-6-phosphate dehydrogenase activity, was evident in the Leydig cells of CA-treated testis. Flutamide, on the other hand, had no effect on the activity of Leydig cells. A marked decline in epididymal weight, as well as reduction in epithelial cell height, was caused by both CA and flutamide. The epithelial cells of epididymes of treated lizards exhibited an accumulation of sudanophilic lipid material in their cytoplasm. However, sudanophilic secretions present in the lumina of epididymal tubules were greatly reduced. This indicates either lack of synthesis of lipid or decrease in its turn over. Our results are in agreement with those obtained in mammalian species after CA or flutamide treatment where a decrease in fertility is suggested.

Anilides↗
PubMed1991

The effects of exogenous 11-ketotestosterone, testosterone, and cyproterone acetate on prespawning and parental care behaviors of male bluegill.

This study investigated the effect of exogenous 11-ketotestosterone (11KT) and testosterone (T), two important androgens involved in fish reproduction, as well as cyproterone acetate (CYA), an antiandrogen, on behaviors of male bluegill (Lepomis macrochirus) during prespawning and parental care periods. Parental male bluegill build nests in colonies, spawn with females, and then remain alone on these nests to provide care for their developing offspring. Implantation of pellets containing either 11KT or T did not induce parental males to build nests in early spring, before the onset of natural spawning, or during late spring and early summer, when the reproductive season was in progress. Treatment with pellets containing CYA inhibited reproduction in male bluegill and these fish did not spawn for the remainder of the reproductive season. The release of appropriate steroids from pellets to the serum was confirmed in all cases by a radioimmunoassay. Interestingly, nesting males that spawned successfully and were implanted with 11KT at the onset of the parental care phase displayed increased rim-circling, a behavior characteristic of the late prespawning period. Treatment with T or CYA, however, did not induce such behaviors in nesting bluegill. Finally, none of these treatments significantly affected antipredator aggressive behavior displayed by nesting males. Our results suggest that parental care behaviors in male bluegill are most likely expressed through nonandrogenic mechanisms.

Androgen Antagonists↗
PubMed1984

Androgen metabolism in hirsute patients treated with cyproterone acetate.

Cyproterone acetate (CPA) in association with percutaneously administered estradiol has been used for the treatment of 150 hirsute patients for periods ranging from 6 months to 3 years. A spectacular clinical improvement ensued. Plasma testosterone (T) and androstenedione (A) fell from 69.0 +/- 24 to 33.0 +/- 8 and 210 +/- 103 to 119 +/- 25 ng/dl (mean +/- SD) respectively after 3 months of treatment and remained low thereafter. In contrast, T glucuronide (TG) and 3 alpha-androstanediol (Adiol) remained high during the whole course of treatment: 37 +/- 9 and 115 +/- 43 micrograms/24 h respectively. In vitro T 5 alpha-reductase activity (5 alpha-R) in pubic skin decreased from 147 +/- 34 to 79 +/- 17 fmol/mg skin after 1 year of treatment. To elucidate the discrepancy between plasma and urinary androgens levels, T production rate (PR) and metabolic clearance rate (MCR) were measured with the constant infusion technique in 7 patients before and after 6 months of treatment. PR decreased from 988 +/- 205 to 380 +/- 140 micrograms/24 h (mean +/- SD). In contrast MCRT increased from 1275 +/- 200 to 1632 +/- 360 1/24 h; this increase in MCRT explains the striking plasma T concentration fall and the high TG and Adiol excretion relative to the decrease in PR. Antipyrine clearance rate (n = 8) increased from 36.3 +/- 5.2 to 51.5 +/- 7.4 ml/min whereas 6 beta hydroxycortisol remained unchanged. In conclusion, CPA acts through several mechanisms: (1) it lowers the androgen input to the target cells by (a) depressing T production through its antigonadotropic effect and (b) accelerating T metabolic inactivation due to a partial enzymatic inducer effect on the liver; (2) at the target cell level it competes with any remaining T for the receptor binding sites; (3) the decrease in the androgen-dependent skin 5 alpha-R is a consequence of both actions of androgen suppression and androgen receptor blockade; it reinforces the antiandrogenic effect of CPA.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1987

Inhibition of rat testicular 17 alpha-hydroxylase and 17,20-lyase activities by anti-androgens (flutamide, hydroxyflutamide, RU23908, cyproterone acetate) in vitro.

Flutamide, hydroxyflutamide, RU23908 and cyproterone acetate (CPA) inhibited rat testicular microsomal 17 alpha-hydroxylase and 17,20-lyase activities in vitro. The Km of [3H] progesterone for 17 alpha-hydroxylase was 45 +/- 0.62 nmol/l (+/- SEM, n = 12) and the Km of [3H] 17 alpha-hydroxyprogesterone for 17,20-lyase was 192 +/- 0.42 nmol/l (+/- SEM, n = 12). The Ki values for 17 alpha-hydroxylase, determined from Lineweaver-Burk plots were 102 +/- 3.2 mumol/l (+/- SEM, n = 6), 363 +/- 3.8 mumol/l (+/- SEM, n = 6), 118 +/- 1.4 mumol/l (+/- SEM, n = 6) and 123 +/- 2.1 mumol/l (+/- SEM, n = 6) for flutamide, hydroxyflutamide, RU23908 and CPA respectively. Flutamide and CPA were mixed-type inhibitors, whereas hydroxyflutamide and RU23908 were competitive inhibitors of 17 alpha-hydroxylase activity. Ki values for 17,20-lyase were 33 +/- 3.1 mumol/l (+/- SEM, n = 6), 112 +/- 3.1 mumol/l (+/- SEM, n = 6), 69 +/- 4.4 mumol/l (+/- SEM, n = 6) and 71 +/- 3.2 mumol/l (+/- SEM, n = 6) for flutamide, hydroxyflutamide, RU23908 and CPA, respectively. Inhibition was found to be competitive in each case. Although the characteristic action of anti-androgens is at the receptor level, these results demonstrate that anti-androgens may also have inhibitory effects on androgen biosynthesis which could prove to be of clinical significance.

Aldehyde-Lyases↗
PubMed1988

The effect of short term treatment with cyproterone acetate or flutamide on the metabolism of 5 alpha-dihydrotestosterone in human testicular tissue.

Testicular tissue obtained from ten patients orchiectomized for prostatic cancer was incubated with [3H]5 alpha-dihydrotestosterone (DHT) in order to study the metabolic transformation into 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-diol) and 5 alpha-androstane-3 beta,17 beta-diol (3 beta-diol). Throughout 5 days before surgery four subjects were treated with cyproterone acetate (CA). To three patients flutamide (F) was administered for the same period of time. Three subjects remained untreated. Compared to the control group the administration of CA decreased the formation of 3 beta-diol whereas that of 3 alpha-diol increased. Treatment with F lead to an elevated formation of both diols. However, the 3 alpha/3 beta ratio did not change. As 3 beta-diol is considered to be an index of tubular function in the human testis it is concluded that CA has a direct inhibitory effect upon this testicular compartment whereas F has none.

Aged↗
PubMed1989

Long-term alterations on the male mouse genital tract associated with neonatal exposure to cyproterone acetate biochemical data.

The effects of neonatal administration of cyproterone acetate on the growth, hormone responsiveness, DNA and protein concentrations, protein profiles, protein synthetic patterns and nuclear androgen binding sites of epididymis, vas deferens and seminal vesicles were investigated in adult mice. The weight of epididymis and seminal vesicle was significantly depressed and the reductions observed were secondary to cellular hypoplasia in epididymis and to cellular hypotrophy in seminal vesicle. The 3 organs studied showed a limited response to exogenous androgens at adulthood. When assessed by the number of cells the response of the 3 organs was similar to that of controls but it was significantly reduced from 25 to 35% when measured in term of cellular concentration of proteins. The protein profiles from homogenates of whole organs and the protein synthetic patterns after [35S]methionine incorporation, analyzed by polyacrylamide gel electrophoresis, showed reproducible persistent alterations. The total number of nuclear androgen binding sites was significantly reduced in seminal vesicles.

Aging↗
PubMed1989

Testosterone-estradiol binding globulin (TeBG) in hirsute patients treated with cyproterone acetate (CPA) and percutaneous estradiol.

Testosterone-estradiol binding globulin (TeBG) was studied in 50 hirsute women, before and after 6-month treatment with cyproterone acetate (CPA). 50 mg CPA was administered orally from the 5th to the 25th day of the menstrual cycle and combined with 3 mg 17 beta-estradiol (E2) administered percutaneously from days 16-25 of the cycle. TeBG was evaluated by a filter assay measuring [3H]-DHT binding capacity. Before treatment, the mean plasma TeBG level was 40 +/- 12 nM in hirsute patients, which is significantly lower than TeBG value in normal women (60 +/- 9 nM, n = 20, P less than 0.01) and intermediate between normal women and normal men (30 +/- 8 nM, n = 20). After a 6-month treatment, TeBG strikingly decreased to 22 +/- 8 nM, which is significantly lower than pretreatment values (P less than 0.01) and even less than TeBG level in normal men. Parallel TeBG assay by immunoelectrodiffusion in 8 of these hirsute patients provided similar results. With this treatment, plasma testosterone and delta 4-androstenedione, measured between the 20th and 25th days of the cycle, decreased from 68 +/- 21 to 25 +/- 8 ng/dl, and 210 +/- 95 to 98 +/- 31 ng/dl respectively. Plasma estradiol decreased from 150 +/- 62 pg/ml to 75 +/- 25 pg/ml. In contrast, urinary 3 alpha-androstanediol glucuronide remained high: 112 +/- 51 and 123 +/- 55 micrograms/24 h respectively before and with CPA treatment. Three mechanisms have been proposed to explain TeBG decrease under CPA + E2perc. treatment (1) relative competition of CPA with labelled DHT in the TeBG-binding capacity assay, (2) relative hypoestrogenism with this treatment, (3) a progestagen or even a partial agonistic androgen effect of CPA on TeBG synthesis in the liver. The third mechanism appears to be predominant. In any case. TeBG decrease combined with the partial enzymatic induction effect of CPA on the liver contributes to the increase in the metabolic clearance rate of T and the high urinary Adiol levels previously reported with CPA treatment.

Adolescent↗
PubMed1990

Serum protein binding characteristics of cyproterone acetate, gestodene, levonorgestrel and norethisterone in rat, rabbit, dog, monkey and man.

Protein binding characteristics including percentage of total binding, total binding capacity (pmol/mg protein), degree of specific binding, competition with dihydrotestosterone (DHT) and estradiol (E2) binding sites and dissociation constants (Kd) of low and high affinity binding sites were investigated for the progestins cyproterone acetate (CPA), gestodene (G), norethisterone (NET) and levonorgestrel (LN) in serum or plasma pools from man and four laboratory animal species (rat, rabbit, dog and monkey). Serum pools from animals were constructed from samples obtained either prior to or 1 day after pretreatment with ethinyl estradiol (EE2) (5 micrograms/kg/day for 7 days). Human plasma pools differed by SHBG levels (normal/induced). All serum pools were characterized by protein content and distribution. Equilibrium dialysis or dextran-coated charcoal (DCC) methods were used to separate bound and free steroids labelled with tritium. All progestins were highly (greater than 80%) bound to proteins in all undiluted samples. Total binding capacity was highest in rat and lowest in monkey. Human plasma showed a capacity of 1.5-2.1 microgram steroid/ml. In man, monkey and rabbit LN and G were specifically bound to the same degree as DHT, whereas NET binding was 50% lower. Specific binding of CPA to dog serum was 2-3 times higher than for other steroids. Two (high and low affinity) binding sites were found for LN, G and NET in man, monkey and rabbit and in dog for LN. Kd values for high affinity binding ranged from 3.5 (G in man) to 23 (NET in man) x 10(-9)M. Kd values of low affinity binding varied from 0.5 (CPA in dog) to 4 (NET in man) x 10(-6)M. E2 and DHT competition experiments confirmed the concept of SHBG as a carrier protein of 19-nor-progestins and DHT and its occurrence in man, monkey and rabbit. A sex hormone binding protein (SBP) in the dog seems to be responsible for the relatively high specific binding of CPA. SHBG is inducible by means of EE2 in man and monkey, but not in rabbit. EE2 may induce SBP in the dog. Comparison of in vitro Kds (high affinity binding) and in vivo metabolic clearance rates showed the same rankings for LN, G and NET in man, monkey and rabbit.

Animals↗
PubMed1984

Plasma levels of levonorgestrel, gestodene, norethisterone and cyproterone acetate on single-dose subcutaneous administration in oily solution in the rat, beagle and rhesus monkey.

This report describes the pharmacokinetics of levonorgestrel, gestodene, norethisterone and cyproterone acetate following subcutaneous administration of oily solutions in the rat, beagle dog and rhesus monkey. The plasma levels of the progestogens were measured by means of specific radioimmunoassays. Half-lives calculated for the disposition process of a particular metabolically unchanged drug in plasma revealed marked differences in different animal species. Furthermore, comparison of the different progestogens showed large variations in this parameter in all the animal species. It became obvious that there are physico-chemical properties as well as metabolic rate limitations effecting the release and elimination of synthetic progestogens administered in oily solution. The results are compared with the half-lives of these progestogens administered intravenously as reported previously. A prolongation of half-life as a result of the depot effect of subcutaneous administration was demonstrated for all the progestogens in the rat, the beagle dog and the rhesus monkey.

Animals↗
PubMedDate not supplied

Interaction of cyproterone acetate with rat prostatic androgen receptors.

We have investigated the binding of cyproterone acetate (CA) to cytosolic androgen receptors (RC) and translocation of the RCCA complex into the nucleus. In a cell-free system (3H)CA binds to cytosolic androgen receptors with high affinity (KD = 11.6 nM) and limited capacity (180-200 femtomoles/mg protein). (3H)CA, however, dissociates very rapidly from the cytosolic and nuclear androgen receptors (Rn) at 0 degree C. Incubation of RC (3H)CA at 20 degrees C increased its ability to bind to nuclei. Translocation of RC (3H)CA to nuclei of intact cells was demonstrated after incubation of prostatic tissue with (3H)CA in tissue culture medium at 37 degrees C. In vivo administration of CA to castrated rats promoted RCCA translocation but did not induce androgen receptor replenishment. These data demonstrate that CA binds to and translocates androgen receptors to nuclei without concomitant receptor replenishment.

Androgen Antagonists↗
PubMed1981

The effect of cyproterone acetate on shock elicited aggression in rats.

The aggressive behavior of male rats treated chronically with cyproterone acetate was measured following electric footshock. Shock elicited fighting behavior and body weight was recorded once every week for 4 weeks. The level of plasma testosterone, brain 5-HT and 5-HIAA and weight of testes were measured 24 hours after the last injection. No significant change was observed in the level of testosterone or brain 5-HT and 5-HIAA. A trend towards an increase in plasma testosterone and shock elicited fighting in rats treated with a higher dose of CA (10 mg/kg) may be indicative of some androgenic property of CA. On the other hand a slower gain in the body weight and a significant reduction in the testes weight of CA treated rats corroborate the well known antiandrogen property of this steroid. The balance of these androgenic and antiandrogenic properties of CA may account for the absence of significant changes in behavioral and biochemical measures.

Aggression↗
PubMed1987

Response to cyproterone acetate treatment in primary hepatocellular carcinoma is related to fall in free 5 alpha-dihydrotestosterone.

The male preponderance in cirrhotic patients with primary hepatocellular carcinoma (HCC) and the presence of androgen receptors in tumour tissue suggest possible benefit from anti-androgenic therapy. Twenty-five cirrhotic patients with irresectable HCC (23 male) were treated with cyproterone acetate (CPA) 300 mg daily. Hepatic ultrasound, alpha-fetoprotein and total and free sex steroid levels were monitored. Five patients had an objective response to therapy with a median duration of 8 weeks and survival in excess of 29 weeks. Median survival for all patients was 14 weeks. Apart from transient paranoia in two cases, side-effects were minimal. Total androgen levels (measured in 13 patients) had fallen significantly at 10 weeks, but free 5 alpha-dihydrotestosterone (DHT) which had fallen by 4.8 pM (median) in five responders, had risen by 5.05 pM in eight non-responders: P less than 0.025. The apparent correlation of response with reduction in free DHT suggests that hormonal manipulation may be effective in HCC if free DHT is reliably reduced. This has been achieved in other conditions by the combination of CPA with low dose oestrogen or with LHRH agonists.

Adult↗
PubMed1983

Adenocarcinomas of the prostate induced by N-nitroso-N-methylurea in rats pretreated with cyproterone acetate and testosterone.

Prostatic adenocarcinomas were induced in 5 out of 20 Wistar rats upon a single administration of 50 mg/kg N-nitroso-N-methylurea (NMU). The rats were pretreated with a daily dose of 50 mg/kg cyproterone acetate for 3 weeks followed by 3 daily injections of 100 mg/kg testosterone. All tumours developed in the dorsolateral prostate and were invasively growing. In 2 cases distant metastases were found. Three proliferative lesions classified as carcinomas in situ were also found in the dorsolateral prostate. A total of 7/20 animals (35%) carried an adenocarcinoma and/or a carcinoma in situ. In addition, 6 epithelial hyperplasias were observed in the dorsolateral and 1 in the ventral prostate of non-tumour-bearing rats. The method described may provide a good animal model for cancer of the prostate and lead to a better understanding of prostatic carcinogenesis.

Adenocarcinoma↗