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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↗
PubMed2004

Metabolic and endocrine effects of treatment with peroral or transdermal oestrogens in conjunction with peroral cyproterone acetate in women with polycystic ovary syndrome.

OBJECTIVE: To compare the influence of transdermal and peroral oestrogen treatments in conjunction with cyproterone acetate (CPA) on metabolic and hormonal parameters in women with polycystic ovary syndrome (PCOS). PATIENTS AND METHODS: Twenty-four women with PCOS, aged 25.4+/-4.3 (mean+/-s.d.) years, body mass index 24.5+/-3.9 kg/m2 were randomly assigned to receive either transdermal oestradiol plus CPA (n=12) or a peroral oestradiol-CPA combination (n=12). Before and after 3 months of treatment, basal blood samples, euglycaemic hyperinsulinaemic clamp combined with indirect calorimetry and arginine tests were performed. ANOVA and Student's t-test or Wilcoxon's test were used for statistical analyses. RESULTS: After peroral oestradiol-CPA, insulin sensitivity (P<0.004) and the disposition index as the function of insulin sensitivity and secretion (P<0.0001) decreased significantly. Fasting insulin (P<0.05), cholesterol (P<0.05), high-density lipoprotein cholesterol (P<0.05) and sex-hormone binding globulin (P<0.0001) increased significantly. Dehydroepiandrosterone (P<0.05) and 17-OH progesterone (P<0.01) decreased significantly. After transdermal oestradiol+CPA, no significant changes were observed in sex-hormone binding globulin and androgen concentrations, insulin sensitivity or disposition index. CONCLUSIONS: In women with PCOS, peroral oestrogens (at doses common in combined oral contraceptives) led to a significant impairment in insulin secretion and action. In contrast, the transdermal application of oestrogens did not significantly influence insulin sensitivity.

Administration, Cutaneous↗
PubMed2005

Effects of metformin and ethinyl estradiol-cyproterone acetate on lipid levels in obese and non-obese women with polycystic ovary syndrome.

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) exhibit risk factors for cardiovascular diseases such as abdominal obesity, insulin resistance and dyslipidemia. Insulin sensitizers, especially metformin, have been shown to improve these metabolic disturbances, but there are only a few studies on their effects on serum lipids in polycystic ovary syndrome. METHODS: Thirty-five women with PCOS (18 obese and 17 non-obese) were randomized to 6-month treatments with metformin or ethinyl estradiol-cyproterone acetate oral contraceptive pills. RESULTS: In the whole-study population (non-obese and obese women) serum levels of high-density lipoprotein cholesterol increased from 1.4+/-0.2 to 1.6+/-0.1 mmol/l (means +/-S.E. throughout) at 3 and 6 months (P < 0.001), the total cholesterol:high-density lipoprotein cholesterol ratio decreased significantly from 3.8+/-0.3 to 3.3+/-0.2 at 6 months (P < 0.001) and a similar trend was observed in serum triglyceride levels during metformin treatment. In the oral contraceptive group, serum levels of total cholesterol increased from 4.9+/-0.3 to 5.4+/-0.3 mmol/l (P < 0.05), high-density lipoprotein cholesterol increased from 1.2+/-0.1 to 1.5+/-0.1 mmol/l (P < 0.001), the total cholesterol:high-density lipoprotein cholesterol ratio decreased from 4.6+/-0.4 to 3.7+/-0.2 (P < 0.001) and triglycerides increased from 1.3+/-0.1 to 1.9+/-0.2 mmol/l at 6 months of treatment (P < 0.001). Serum low-density lipoprotein cholesterol levels remained unchanged during both treatments. Milder but similar changes in the subgroups of obese and non-obese women were observed during both treatments. Moreover, in the whole-study population both systolic (P = 0.02) and diastolic (P = 0.05) blood pressures decreased over the 6 months of metformin treatment. CONCLUSION: In women with PCOS, metformin treatment had beneficial effects on lipid profile and blood pressure, and therefore it could be useful in the prevention of cardiovascular complications in these women.

Adult↗
PubMed1975

Cyproterone acetate diminishes sexual activity in male rabbits.

Cyproterone acetate (CA) was injected daily in eleven rabbits for 3 weeks at a dose of 20 mg/day, and for a further week at a dose of 40 mg/day. After 3 weeks of treatment, the ejaculation frequency was reduced but other measures of sexual behaviour were not significantly changed. There was no reduction in the fructose concentration of the semen, but the volume of the ejaculates decreased. The vesicular glands from the experimental animals showed histological changes typical of those occurring after castration. It was concluded that CA reduced the activity of at least one of the accessory sex glands as well as sexual behaviour. This lends support to the current hypothesis that the endocrine regulation of rabbit sexual behaviour differs from that of the rat.

Animals↗
PubMed1979

Effects of castration, 5 alpha-dihydrotestosterone and cyproterone acetate on enzyme activity in the mouse epididymis.

The influence of castration, androgen replacement therapy and cyproterone acetate on the activity of beta-glucuronidase, acid and alkaline phosphatases and glucose-6-phosphate dehydrogenase was studied in the caput, corpus and cauda epididymidis of the mouse. The results add further evidence that the epididymis is not uniform but has regional differences in activity. Thus beta-glucuronidase was found to be androgen-dependent only in the cauda epididymidis, whereas glucose-6-phosphate dehydrogenase was under androgenic control in the caput epididymidis. The response of alkaline and acid phosphatases to castration and to androgen replacement was different in different segments.

Acid Phosphatase↗
PubMed1980

Short-term effect of cyproterone acetate on testicular FSH binding in immature rats.

Male rats, aged 19 days, were injected with 1 mg cyproterone acetate, an antiandrogen, and killed 24 h later. In 9 out of 10 experiments this increased the apparent FSH-binding capacity by testicular tissue in vitro. In 4 out of 5 similar experiments, injection of 500 micrograms testosterone propionate caused a significant reduction in FSH binding. Observed changes were small but this does not preclude the possibility that androgens contribute to the physiological control of FSH receptor numbers.

Animals↗
PubMed2001

Castration-induced hyperactivity of seminal vesicle in the catfish Clarias batrachus: a case of paradox and blockade by antiandrogen (cyproterone acetate) treatment.

Castration of the catfish Clarias batrachus in late preparatory-early prespawning phase (April-May) caused time-dependent stimulatory effect on morphology, weight, and in the concentrations of biochemical correlates, such as total proteins, fructose, hexosamines and sialic acid in the seminal vesicle (SV). The peak changes were noticed on week 4 of castration. The hyperactivity was related to augmented production of testosterone by the SV of castrates with the levels significantly high from week 3 onwards. As a result, serum testosterone level fluctuated with a significant decrease in the first and fifth weeks, a significant increase in the third week, and no significant difference in the second and fourth weeks. Serum E2 level decreased significantly throughout. Cyproterone acetate treatment (CA; 1 mg/fish daily for 21 days) from the second day of castration decreased the size and weight of the SV and the concentrations of total proteins, hexosamines, fructose and sialic acid. The antiandrogen treatment did not alter serum testosterone level but the E2 level was significantly decreased. It is concluded that the hypersecretory activity of the SV in castrates is a sequel to local synthesis and action of testosterone and the effect could be prevented by CA by blocking androgen actions.

Androgen Antagonists↗
PubMed2005

Disappearance of a virilizing adrenal tumor following therapy with cyproterone acetate.

A 57-year-old woman presented with an apparently obvious diagnosis of iatrogenic virilization. At the age of 51, she began a 4-year treatment with prednisone or cyclosporine, which are known to promote hair growth, for Behçet disease. At the age of 56, osteoporosis was overtreated with the anabolic steroid nandrolone. Insignificant inhibition by dexamethasone of the extremely high serum concentrations of testosterone and less high concentrations of weak androgens prompted us to search for a virilizing tumor. Computed tomography showed a 2.3 x 1.5 cm nodule in the right adrenal gland. As the patient refused surgery, virilization was treated with the antiandrogen cyproterone acetate (CPA), but for only 4 months because clinical and hormone abnormalities reversed and the tumor was no longer visible. The patient remains symptom-free. This first report of a curative effect of CPA on a purely virilizing adrenal tumor opens new avenues in the management of such tumors.

Adrenal Gland Neoplasms↗
PubMed1976

Effect of cyproterone acetate on androgen-dependent synthesis of alpha2u globulin in rats.

Cyproterone acetate (CA, 2-5 mg/100 g body wt) inhibited androgenic induction of alpha2u globulin in spayed rats. In mature male rats, which normally produce alpha2u globulin, ten daily injections of CA did not inhibit synthesis of this protein. Long-term treatment of mature male rats (two injections every week for 12 weeks) showed only slight inhibition of alpha2u synthesis after 10 weeks of CA treatment. CA also failed to compete with 5alpha-dihydrotestosterone for the cytosol androgen-binding protein of male rat liver. The inhibitory effect of CA on the primary induction of alpha2u globulin in the spayed rat and its lack of effect on continued synthesis of this protein in maximally induced mature male rats are consistent with the hypothesis of a two-step mechanism for androgenic regulation of alpha2u synthesis, an initial CA-sensitive step followed later by a CA-insensitive step.

Alpha-Globulins↗
PubMed1984

Somatostatin inhibits prolactin release from the lactotroph primed with oestrogen and cyproterone acetate in man.

The present study investigated the effect of administration of somatostatin (SRIF) on the release of prolactin in men. No effect was observed when SRIF was administered to eugonadal men. Release of prolactin was inhibited, however, when SRIF was administered to oestrogen-treated agonadal subjects (male-to-female trans-sexuals) and to an even greater degree when subjects had been pretreated with a combination of oestrogen and cyproterone acetate. This is consistent with findings in the rat. Thus in man, as in the rat, SRIF can inhibit prolactin secretion, but only after treatment with oestrogen.

Adult↗
PubMed2000

Cyproterone acetate reduced antler growth in surgically castrated fallow deer.

We studied the role of androgens in antler growth. In particular, we investigated whether the onset of antler regrowth is triggered by a short-term pulse of testosterone and if low levels of androgens are required for antler growth. The study was conducted on 12 surgically castrated fallow deer bucks (Dama dama) aged approximately 27 months. Six animals (CA group) were given the antiandrogen, cyproterone acetate (CA, 1000 mg/treatment); the others were given vehicle solution only (control). Before each CA treatment, blood was sampled and analysed for testosterone, androstenedione, IGF-1, cortisol, FSH, and LH. CA treatment and blood sampling were performed 2 days before castration, on the day of castration and afterwards at 2-day intervals until day 22. Subsequently, CA treatment and blood sampling continued at weekly intervals until day 270. All animals cast their antlers, followed by antler regrowth in all control bucks, but in only four of the six CA-treated castrates. Plasma testosterone concentrations were low in all animals (between 0.01 and 0.20 ng/ml), but were significantly (P<0001) greater in the controls. In both groups, a temporary increase in testosterone values was recorded around the time of antler regrowth, the peak being significantly (P<0.01) higher in the controls. Androstenedione showed a similar pattern as testosterone. Plasma IGF-1 concentrations increased sharply during the antler growth spurt and did not differ significantly between the two groups throughout the study period. Cortisol concentrations were greater in controls than in the CA group. However, no link with the antler cycle was apparent. FSH and LH concentrations were higher in the controls for most of the study. Antlers produced by the control bucks were significantly larger than those in the CA group (P<0.03). For antler length, testosterone, androstenedione and IGF-1, areas under the curve (AUC) were calculated over the period of antler growth. For the pooled deer (n=12) significant correlations existed between AUCs of antler length and testosterone, but not for antler length and IGF-1. Also, a trend for a positive correlation between AUCs of antler length and androstenedione was noted. It is concluded that a plasma androgen concentration at least above a minimal threshold level is a necessary prerequisite for normal antler regrowth in fallow deer, and that this androgen effect is not mediated via circulating IGF-1. The biological role of low levels of androgens may be to sensitize antler cells to the stimulating effect of IGF.

Androgen Antagonists↗
PubMed2003

Comparison of the efficiency of anti-androgenic regimens consisting of spironolactone, Diane 35, and cyproterone acetate in hirsutism.

The aim of the present study was to evaluate the effects of three different anti-androgenic drug-therapy regimens, Diane 35 (cyproterone acetate (CPA) [2 mg] and ethinyl estradiol [35 microg]) plus CPA, Diane 35 plus spironolactone, and spironolactone alone, in patients with hirsutism. In this prospective, randomized clinical study, 79 subjects with idiopathic hirsutismus were studied. The patients were divided into 3 groups. Group I patients (n=32) were treated with Diane 35 plus CPA, group II patients (n=25) with Diane 35 plus spironolactone [100 mg], and group III patients (n=22) with spironolactone [100 mg] alone. Serum FSH, LH, testosterone (T), and DHEAS levels were analyzed before and after treatment at 6 and 12 months. Hirsutism scores were graded according to the Ferriman-Gallwey scoring system, and side effects were monitored. All treatment regimens were found to be efficient and well-tolerated, and none of the patients stopped therapy due to any adverse event. However, in hormone screening, only patients on the Diane 35 plus CPA regimen revealed a decrease in serum T levels after therapy. As such, treatment of each hirsute patient should be planned individually, but with regard to both cost-efficiency and potential side effects, we recommend spironolactone alone in the treatment of hirsutismus.

Adolescent↗
PubMed1996

Cyproterone acetate: is it hepato- or genotoxic?

The preclinical safety assessment of cyproterone acetate (CPA) with regard to liver tumorigenesis was based on tumorigenicity studies, which revealed no mutagenic potential. Recently, in vitro studies on the formation of adducts and the enhancement of DNA repair synthesis with CPA have been published. These results are not unique to CPA, and the role of adducts and increased DNA synthesis in mutagenesis is still not clear. Dose-related hepatic toxicity has been reported with the prolonged use of CPA. An active surveillance study of patients taking long term CPA treatment has shown no correlation between the duration of CPA treatment and the prevalence of liver enzyme elevations. In a multicentre surveillance study of long term CPA use in 2506 patients included so far, not a single case of hepatocellular carcinoma has been observed. These findings do not support the theory of an elevated risk of hepatocellular carcinoma as a result of CPA treatment. In conclusion, there have been no observations which could point to an increased risk of proliferative liver change as a result of CPA treatment.

Androgen Antagonists↗
PubMed1997

Follow-up study of children with precocious puberty treated with cyproterone acetate. Ad hoc Committee for CPA.

A total of 1840 children and adolescents treated with cyproterone acetate (CPA) to block gonadal function, as a treatment for precocious puberty, short stature and other disorders, were registered to survey for the risk of developing hepatic tumors. Patients responding to follow-up numbered 1552 (85%). The cumulative dose and duration of CPA therapy for boys and girls were 110.4g and 2.6 years, and 122.9 g and 2.8 years, respectively. Among the 1552 patients, five hepatoma cases were found. Four underwent successful surgery and remain alive and well to date. Two of the 5 cases had been given more than 500g, the other 3 more than 1000 g, of CPA. Three had also been given androgens before CPA administration. Although further follow-up is necessary to monitor for the development of adenoma and hepatoma, the risk of developing these tumors among patients to whom limited doses of CPA were administered appears to be negligible.

Adenoma, Liver Cell↗
PubMed1981

Striking regression of advanced prostatic carcinoma induced by cyproterone acetate (Androcur). A case report.

An 80-year-old man with advanced adenocarcinoma of the prostate received cyproterone acetate, 200 mg orally per day as sole treatment. Striking regression of the tumour was demonstrated by ultrasonograms and excretory urograms. Serum concentrations of acid phosphatases, gonadotrophins, and testosterone decreased significantly. No significant cardiovascular side effects occurred.

Acid Phosphatase↗
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↗
PubMed1977

Mammary gland differentiation in adult male rat--effect of prenatal exposure to cyproterone acetate.

Breast tissue of adult male Holtzman rats exposed to cyproterone acetate during embryonic differentiation showed presence of specific estradiol receptor proteins and C-19 steroid aromatase. We reported similar findings in gynecomastia in man. It is therefore proposed that gynecomastia probably results from failure of adequate testosterone action on the breast primordia during embryonic differentiation.

Androstenedione↗
PubMed2006

Hepatotoxicity induced by cyproterone acetate: a report of three cases.

Cyproterone acetate (CPA) is a steroidal synthetic progestagen and anti-androgenic compound widely administered in prostate cancer which has been evidentially correlated with a severe hepatotoxic potency. Three male patients aged 78-83 years are presented, in whom severe hepatotoxic reactions emerged after CPA administration. Patients were treated with CPA at the doses of 200-300 mg/d for malignant prostate disease for 3-12 mo prior to the acute manifestation of the hepatic disease. Clinical features compatible with mixed hepatocellular and cholestatic liver disease including jaundice, white stools and dark urine, manifested in all three cases whereas encephalopathy and ascites were present in two of the patients. Other primary causes of hepatotoxicity (alcohol consumption and viral hepatitis) were also verified in two cases, and in those patients biopsy findings revealed the presence of cirrhotic lesions in liver parenchyma. Discontinuation of the therapeutic agent led to the amelioration of the clinical profile in all the patients whereas a patient died 40 d after hospital admission due to sepsis, despite acute liver disease improvement. The current article highlights the hepatotoxic potency of a widely administered therapeutic agent and illustrates the importance of clinical surveillance especially in patients with previous hepatic diseases. Three relevant cases are reported and a review of the published literature is made.

Aged↗