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PubMed1992

Induction of skin and thyroid tumors in male rats by N-methyl-N-nitrosourea after sequential treatment with cyproterone acetate and testosterone propionate: effects of castration, rat strain and time of carcinogen injection.

The purpose of this study was to determine the carcinogenic effect in male rats of a single i.v. injection of N-methyl-N-nitrosourea (MNU) after sequential treatment with cyproterone acetate (for 21 days) and testosterone propionate (for 3 days). This treatment has previously been shown to induce carcinomas of the prostate and other male accessory sex glands. A wide spectrum of non-melanoma skin tumors was found in 38-48% of Wistar (Cpb:WU) rats given this sequential treatment, but only in 5% of rats that received only MNU. Castration long and, particularly, early after MNU markedly reduced this skin tumor response to a 10-13% incidence. The skin tumorigenic efficacy of MNU was dependent on the time between the start of the testosterone propionate treatment and carcinogen administration: MNU injection after 48-50 or 60-63 h induced skin tumors in 17-21% of Wistar rats, whereas injection after 72-74 h induced a 48% incidence. The Fischer F344 and Sprague-Dawley strains were not very sensitive to induction of skin tumors by this approach. Thyroid follicular cell tumors were also induced by MNU only after the hormonal pretreatment, and their induction was influenced by the time of MNU injection as well. The time of MNU injection and rat strain used did not significantly influence the induction of sebaceous-squamous neoplasms of the ear-duct/Zymbal's glands or other tumors. These data indicate that endogenous androgens are critically involved in the later stages of rat skin tumorigenesis and suggest that androgen-induced cell proliferation influences the initiation stage of this process and, possibly, of thyroid tumorigenesis.

Animals↗
PubMed1984

Effects of the antiandrogen, cyproterone acetate, on the induction of papillomas, DNA synthesis and ornithine decarboxylase activity in mouse skin.

The antiandrogen, cyproterone acetate (CPA), applied simultaneously with 12-O-tetradecanoylphorbol-13-acetate (TPA) to the dorsal skin of male and female SENCAR mice initiated with 7,12-dimethylbenz[a]anthracene inhibited the production of papillomas of the skin. Although 125 and 250 micrograms of CPA had no effect on the incidence of papillomas per mouse, 500 micrograms of CPA inhibited papilloma production by 95% and 91% in female mice after 20 and 37 weeks of promotion, respectively. Testosterone propionate only partially blocked the inhibitory effect of CPA. In male mice 500 micrograms and 1 mg of CPA inhibited papilloma production by 77% and 88%, respectively. In the two-stage promotion protocol 500 micrograms of CPA was ineffective as an inhibitor when it was applied with TPA during the 1st stage but inhibited papilloma production by 71% when it was applied with mezerein during the 2nd stage. CPA was also observed to inhibit TPA-stimulated epidermal DNA synthesis and inflammation but had no effect on TPA-induced epidermal ornithine decarboxylase activity.

Androgen Antagonists↗
PubMed1987

HPLC method for the analysis of cyproterone acetate in tablets.

A reversed-phase high-performance liquid chromatographic (HPLC) method is described for the analysis of cyproterone acetate in tablets. This steroid is extracted and quantitated using a C18 column. This procedure is shown to be rapid, simple, and valid in terms of recovery, linearity, and precision. Application of this method to analyze dilute samples obtained from dissolution testing is demonstrated.

Chromatography, High Pressure Liquid↗
PubMed1983

The local effects of topically applied estradiol, cyproterone acetate, and ethanol on sebaceous secretion in intact male rats.

Estradiol in ethanol was applied once daily to one flank of intact male rats and sebum production on both flanks was measured over periods of 18 h alternating with 6 h by absorbing the lipid on pads of cigarette paper held in place by a harness, starting on the 15th day. Sebum production was very significantly less on the treated flanks than on the contralateral flanks that received only vehicle, indicating an unequivocal local effect of the estradiol. At the same time, the values on the contralateral flanks were significantly below those of littermate rats which received vehicle only, indicating that the estrogen had been systemically absorbed to produce a distal action. The estradiol also significantly reduced plasma testosterone and the relative weights of the seminal vesicles, ventral prostate, and preputial glands, which demonstrated that part of the general action of the estrogen could have been by suppression of endogenous androgen production. In short-term experiments, in which measurements were started concurrently with treatment, the inhibitory action of estradiol, in contrast to that of cyproterone acetate, was not detected until the 4th day. Indeed, it appeared probable that the estrogen actually stimulated sebum secretion over the first 2 days, suggesting that it had a biphasic effect.

Administration, Topical↗
PubMed1981

Effect of cyproterone acetate on rate of hair growth in hirsute females.

We determined by trichometry the rate of hair growth in ten hirsute patients receiving a combination of cyproterone acetate (CA) 50 mg/daily and 'Diane' (CA 2 mg + ethinyl oestradiol 0.05 mg). In two patients there was a prompt and persistent reduction in hair growth; in three the response was less marked, and in the remaining five patients the rate of hair growth fluctuated during therapy. However, there was an overall reduction in hair growth in all but one patient during the 12 months of treatment and all patients noticed that their hair became softer, thinner and lighter in colour.

Androgen Antagonists↗
PubMed1983

The stimulation of hair growth in the flank organs of female hamsters by subcutaneous testosterone propionate and its inhibition by topical cyproterone acetate: dose-response studies.

A dose-dependent increase in the mass of flank organ hair was produced in 11-week-old female hamsters by subcutaneously injected testosterone propionate. The mass of androgen-stimulated flank organ hair was decreased bilaterally in a dose-dependent manner by cyproterone acetate applied topically to one flank organ of each hamster.

Administration, Topical↗
PubMed1986

A double-blind controlled cross-over trial of cyproterone acetate in females with hidradenitis suppurativa.

In order to examine whether anti-androgen therapy was effective in hidradenitis suppurativa (HS), ethinyloestradiol 50 micrograms/cyproterone acetate 50 mg in a reverse sequential regimen was compared with ethinyloestradiol 50 micrograms/norgestrel 500 micrograms (Eugynon 50) in 24 female patients. Both treatments produced substantial improvement in disease activity. Seven patients cleared and have remained free of disease for 18 months, five patients improved, four remained unchanged, while two deteriorated. Cyproterone acetate was not clinically significantly more effective than E50, and both gave a similar reduction in free androgen index. Anti-androgen therapy appears to be beneficial in the treatment of hidradenitis suppurativa.

Adult↗
PubMed1988

Cyproterone acetate and two doses of oestrogen in female acne; a double-blind comparison.

Cyproterone acetate was used in combination with either 35 or 50 micrograms ethinyl oestradiol in a double-blind comparison of their effects on acne in females. There were no significant differences between the two groups in the degree of improvement in acne as assessed objectively by the investigators, or subjectively by the patients using a visual analogue scale. Oestrogen related side-effects were significantly lower in the 35 micrograms group during the course of the 9-month study.

Acne Vulgaris↗
PubMed1982

Effect of cyproterone acetate-ethinyl oestradiol treatment on adrenal function in hirsute women.

Pituitary adrenal suppression has been assessed in twenty-two patients receiving cyproterone acetate (100 mg) and ethinyl oestradiol (30 micrograms) for the treatment of hirsutism. Cortisol responsiveness to ACTH and to insulin induced hypoglycaemia, and diurnal variations of plasma cortisol levels were measured before and after 6 months of treatment. There was no evidence that adrenal suppression is a significant problem in this group of patients.

Adrenocorticotropic Hormone↗
PubMed1982

Adrenocortical function in children with precocious sexual development during treatment with cyproterone acetate.

Adrenal function was studied in thirty-two children with precocious sexual development who were being treated with cyproterone acetate (CPA) at doses ranging from 68 to 175 mg. m2. day for periods lasting from 2 to 79 months. In eighteen children the adrenocortical function evaluation was made before and during CPA treatment. In these eighteen patients, the mean basal plasma cortisol level during the morning hours was 11.2 +/- 4.6 micrograms/dl (m +/- SD) before treatment and fell significantly to 7.2 +/- 4.1 micrograms/dl (P less than 0.02) during therapy. In fifteen patients tested during insulin hypoglycaemia the cortisol peak fell from 21.6 +/- 5.5 micrograms/dl before treatment to 16.7 +/- 6.8 micrograms/dl (P less than 0.05) during CPA therapy. There was a significant inverse correlation between this peak and the dose of CPA but no correlation was found between the cortisol response and duration of treatment. In eight of twenty patients tested, urinary free cortisol levels were undetectable during treatment. No change in basal plasma ACTH levels were demonstrated using standard radioimmunoassay techniques. In the patient receiving the highest dose of CPA and showing complete suppression of the adrenal axis, prolonged stimulation with ACTH-Depot demonstrated a responsive adrenal gland. Addition of a replacement dose of cortisol to the CPA treatment led to the rapid development of the typical signs of Cushing's syndrome. It was concluded that despite the evidence of adrenal suppression by CPA, cortisol supplementation is not necessary and may not even be contraindicated.

Adrenal Cortex↗
PubMed1984

Androgen levels during cyproterone acetate and ethinyl oestradiol treatment of hirsutism.

Androgen levels were measured before and during 12 months of treatment with cyproterone acetate (50 mg 5th to 16th day of cycle) and ethinyl oestradiol (50 micrograms 5th to 26th day of cycle) in 26 patients suffering from dysfunctional hirsutism. Patients were included in whom androgen levels after a dexamethasone suppression test fell above the range found in normal non-hirsute women on dexamethasone. Eighty percent of patients showed a substantial improvement of their Ferriman and Gallwey score after 12 months of treatment. During the treatment the mean level of testosterone was 64%, androstenedione 55%, testosterone oestradiol binding globulin 365%, apparent free testosterone 30%, dihydrotestosterone 74%, 5-androstanediol 43%, dehydroepiandrosterone 44%, 5-androstenediol 67% and dehydroepiandrosterone sulphate 74% of basal levels. From the results it is concluded that this treatment is effective both clinically and biochemically in reducing hyperandrogenism.

Adolescent↗
PubMed1984

The effects of cyproterone acetate and ethinyl oestradiol on carbohydrate metabolism.

Carbohydrate metabolism was studied in a group of 66 women, taking cyproterone acetate (CA) and ethinyloestradiol (EO) as anti-androgen therapy for the treatment of hirsutism and/or acne. A reverse sequential treatment cycle was used and women were studied in two groups: the first when taking the combination of CA and EO during the first 12 days of the treatment cycle, and the second taking EO alone during days 13 to 22. The combination reduced fasting plasma glucose and raised fasting plasma insulin concentrations. There was deterioration of glucose tolerance with increased plasma insulin concentrations and these effects were progressive with time. The plasma insulin response to intravenous tolbutamide was increased by 50% but there was no accompanying change in the glucose nadir as compared with controls. These results show that the combination of CA and EO causes insulin resistance. Plasma C-peptide concentrations following oral glucose were unchanged compared with controls. This shows that the observed hyperinsulinaemia was due to a reduction of hepatic uptake of insulin rather than its increased secretion. We propose that these effects are due to a CA-induced elevation of fasting plasma insulin resulting in downregulation of hepatic insulin receptors with subsequent induction of insulin resistance and impairment of hepatic insulin uptake. C-peptide concentrations following i.v. tolbutamide were significantly higher on treatment with CA and EO than in controls indicating increased pancreatic secretion of insulin. Tests carried out while patients were taking EO alone showed impairment of glucose tolerance only with no change in insulin levels. There was an increase in plasma insulin in response to tolbutamide but this was not significant. We conclude that these results are explained by a reduced but persisting effect of CA.

Acne Vulgaris↗
PubMed1984

Treatment of precocious puberty with LHRH analogue in combination with cyproterone acetate-further experience.

Six girls and one boy with precocious puberty were treated with a superactive LHRH analogue (D-TRP6-LHRH) for periods ranging from 1 year to 2 years and 3 months. In the first phase of the treatment it was administered in combination with cyproterone acetate (CyA) to counteract an early stimulatory effect until inhibition of gonadotrophin secretion was achieved. The gonadotrophin-dependent signs i.e. gonadarche, showed sustained arrest and even regression. Gonadal sex steroids decreased but the adrenal androgens were unaffected. In four patients who showed progression of the angrogen-dependent signs (adrenarche), despite suppression of gonadotrophins, increasing the dosage of the LHRH analogue was ineffective and combined therapy with CyA was reinstituted in three of them because of accelerated growth and bone maturation. It is concluded that at present the treatment of choice for precocious puberty is the daily administration of a superactive LHRH analogue such as D-TRP6-LHRH, together with CyA in the initial stage, and at a later state if adrenarche progresses too rapidly.

Androgens↗
PubMed1991

Effects of castration, Depo-testosterone and cyproterone acetate on lymphocyte T subsets in mouse thymus and spleen.

The effects of testosterone on the relative proportion of Thy 1.2, CD4 (L3T4) and CD8 (Lyt-2) cells in thymus and spleen were studied after castration and administration of Depo-testosterone (DT) separately or together with cyproterone acetate (CA) (an antiandrogen) in BDF1 mice. Injection of 0.5 mg/100 g body weight of DT during 2 weeks decreased significantly the number and proportion of double positive (DP) (CD4+ CD8+) and increased the percentage of single positive (SP) CD4+ (CD4+ CD8-), whereas there was a slight decrease in the Thy 1.2+ cells in the thymus. In parallel, we observed an increase in CD8+ (CD4- CD8+) cells in the spleen. The androgen deprivation after 3 weeks of castration induced a decrease in the percentage of CD4+ cells in thymus and both CD4+ and CD8+ cells in spleen. Injection of CA (0.5 mg/100 g body weight) had the same qualitative effects as DT on the proportion of lymphocyte T subsets in castrated mice. However, the combined activities of DT and CA were greater than either alone. These data indicate the main role of testosterone in the distribution of CD4+ and CD8+ cells in male mice. The similar effects of CA and DT in the lymphoid organs may suggest a difference between androgen receptors of sexual and lymphoid organs.

Androgen Antagonists↗
PubMedDate not supplied

A long-term study of the epididymal- and fertility-suppressing effects of cyproterone acetate in the mouse.

The influence of cyproterone acetate (CA) (0.1 mg/mouse/day) on the epididymis and male fertility was analyzed in a long-term study in the Swiss albino cc strain. CA inhibits epididymal function in all segments as measured by organ weights, protein content and beta-glucuronidase activity. This antiandrogen also suppresses male fertility. It is important to note that the low dose of CA, used in this study, does not affect spermatogenesis. The effects of CA on epididymis and fertility are reversible and the magnitude of recovery or the period (in days) required for a significant recovery after the discontinuation of CA were seemingly directly proportional to the duration of antiandrogen treatment.

Animals↗
PubMedDate not supplied

Effect of chronic use of cyproterone Acetate on the epididymis of goat.

Effect of chronic treatment of cyproterone acetate, and antiandrogen with antigonadotrophin activity, on the epididymal sperm reserve and sperm maturation was studied in Black Bengal goats (a dwarf breed). It was observed that this compound produced significant reduction in epididymal sperm numbers in the treated groups as compared to the controls. There was significant reduction in progressive sperm motility. Other morphological maturation changes like the length and breath of the sperm head were significantly altered after treatment with CA for 70 days; and greater number of caudal spermatozoa of treated animals retained their cytoplasmic droplets than those of controls.

Animals↗
PubMedDate not supplied

Initial experiments with cyproterone acetate and 1-amino-3-chloro-2-propanol hydrochloride in the male Virginia opossum (Didelphis virginiana).

Cyproterone acetate (CA) was toxic for Didelphis virginiana at a dose range of 22-28 mg/kg IM. A loss of spermatozoal pairing int the cauda epididymidis did not occur until 2 wk after testicular degeneration caused by CA. The isomers of 1-amino-3-chloro-2-propanol hydrochloride (CL 88,236 and CL 88,237) were well tolerated by the opossum at doses up to 30 mg/kg IM. After 8 days of CL 88,236 and CL 88,237 treatment there was no effect on spermatozoal pairing in the cauda epididymidis or on the seminiferous epithelium.

Animals↗
PubMedDate not supplied

Epididymal histoarchitecture of goats under chronic cyproterone acetate.

Epididymis were collected from cyproterone acetate-treated Black Bengal goats. Treatment for 70 days reduced the epididymal weight. Caput epididymidis showed drastic decrease in the height of the epithelium, loss of stereocilia, the number of narrow cells and apical cells. Though the corpus showed dramatic changes after treatment, cauda epididymidis showed moderate changes.

Animals↗