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PubMed1983

Effect of cyproterone acetate on glucocorticoid secretion in patients treated for hirsutism.

The effect of cyproterone acetate (CA) on adrenal glucocorticoid secretion was studied in 35 women with hirsutism. Patients were treated for 9 months with 100 mg CA orally 10 days each month, administered in reverse sequence with 21 days of a combination oral contraceptive containing 50 micrograms ethinyloestradiol and 2 mg CA. During treatment one patient had a mildly impaired plasma cortisol response to insulin-induced hypoglycaemia and 2 patients showed slight reduction of the plasma cortisol response to ACTH. Responses to metyrapone were normal in all patients tested. Overall, the mean response to these tests was significantly greater during CA treatment compared with pre-treatment measurements, probably due to effects of oestrogen on cortisol-binding globulin. In all patients urinary cortisol excretion remained normal and no patient demonstrated any features of steroid insufficiency. Thus it appears that CA has no untoward effect upon glucocorticoid secretion when given in high dosage for prolonged periods to hirsute women.

17-Hydroxycorticosteroids↗
PubMed1987

Effect of cyproterone acetate in comparison to flutamide and megestrol acetate on the ventral prostate, seminal vesicle, and adrenal glands of adult male rats.

Cyproterone acetate (CPA) has a stronger inhibitory effect than megestrol acetate (MGA) and flutamide (FL) on the prostate and seminal vesicle of intact adult rats. Only in the clinically irrelevant regimen of castration and simultaneous androgen substitution is FL as a competitive androgen antagonist more potent than CPA and MGA. The latter inhibit complete involution of the ventral prostate but not of the seminal vesicle of castrated adult rats. This effect is very small in magnitude, cannot be increased by the use of higher doses, and is only reduced but not blocked by simultaneous treatment with high doses of FL. Further, CPA is unable to stimulate proliferation or restore the function of the involuted rat prostate. CPA and MGA inhibit adrenal weight in rats, thus indicating a glucocorticoidlike activity in this species. A critical review of all available data on the antiandrogenic, glucocorticoidlike, and possible paradoxical androgenlike activities of CPA in different animal experiments has no important bearing on the clinical effectiveness of CPA in the treatment of prostatic cancer.

Adrenal Glands↗
PubMed1988

5 alpha-reductase activity in epithelium and stroma of prostates from intact and castrated dogs treated with androstenedione, the aromatase inhibitor 1-methyl-1,4-androstadiene-3,17-dione, and cyproterone acetate.

In addition to the histology of epithelial and stromal elements of prostates from intact dogs (group 0) and castrated dogs (group I), the latter of which were treated with androstenedione (group II), androstenedione plus the aromatase inhibitor 1-methyl-1,4-androstadiene-3,17-dione (group III), or androstenedione plus aromatase inhibitor and cyproterone acetate (group IV) (Habenicht and El Etreby: The Prostate 11:133-143, 1987) it was of interest to study the influence of such in vivo treatment on the prostatic 5 alpha-reductase, which is responsible for the cellular conversion of testosterone to 5 alpha-dihydrotestosterone. Michaelis constants (KM) and maximal activities (Vmax) of 5 alpha-reductase were determined under optimized incubation conditions in mechanically separated epithelium and stroma. The metabolites were separated by high-performance liquid chromatography and determined radiometrically. The main results were: 1) The mean KM (nM +/- SEM) was significantly (P less than .001) higher in epithelium (892 +/- 132) than stroma (70 +/- 11). The same was true concerning the Vmax (pmol.mg protein-1.h-1 +/- SEM) in epithelium (54.6 +/- 5.8) as compared to stroma (13.0 +/- 2.0). 2) No specific in vivo or in vitro effect of the aromatase inhibitor on the KM and Vmax data was found. 3) In prostates of intact dogs and dogs of group II the proportion of epithelial 5 alpha-reductase exceeded distinctly that of stromal 5 alpha-reductase. 4) In groups I, III, and IV the proportion of epithelial 5 alpha-reductase was rather low. These data were discussed in the light of the histological findings.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1989

Selective inhibition of androstenedione-induced prostate growth in intact beagle dogs by a combined treatment with the antiandrogen cyproterone acetate and the aromatase inhibitor 1-methyl-androsta-1,4-diene-3,17-dione (1-methyl-ADD).

Interference with estrogenic and androgenic actions might result in an inhibitory effect of benign prostatic hyperplasia (BPH). In the present study the effects of the treatment of intact, adult beagle dogs with the antiandrogen cyproterone acetate (CPA) and the aromatase inhibitor 1-methyl-ADD either alone or in combination on androstenedione-induced prostate growth and on testes, epididymides, and the pituitary was investigated. 1-Methyl-ADD induced a marked counterregulatory increase in the serum testosterone and dihydrotestosterone (DHT) concentrations leading to hyperplasia of the glandular part of the prostate. However, the aromatase inhibitor antagonized the androstenedione-induced (estrogen-related) stimulation of the fibromuscular stroma of the prostate. CPA caused a complete atrophy of the prostate that was also present after treatment with both the aromatase inhibitor and CPA in spite of a striking elevation of the serum testosterone and DHT levels and in spite of the antagonization of the inhibition of testes and epididymal weight induced by androstenedione plus CPA. This indicates a selective inhibition of the prostate of intact beagle dogs treated with CPA and 1-methyl-ADD.

Androgen Antagonists↗
PubMed1992

Induction of proliferative lesions of ventral prostate, seminal vesicle, and other accessory sex glands in rats by N-methyl-N-nitrosourea: effect of castration, pretreatment with cyproterone acetate and testosterone propionate and rat strain.

Wistar (Cpb:WU), F344 or Sprague-Dawley rats were sequentially treated with cyproterone acetate (CA) for 21 days, testosterone propionate (TP) for 3 days, followed by a single i.v. injection of N-methyl-N-nitrosourea (MNU). One group of Wistar rats was castrated 4 weeks after MNU injection, and another group 58 weeks after MNU, when the first prostatic carcinoma was detected. Control groups received only CA + TP, CA, MNU, or they remained untreated. Early or late castration inhibited the development of atypical hyperplasia of the ventral prostate in Wistar rats. This lesion was induced by the CA + TP + MNU treatment in F344 rats, but not Sprague-Dawley rats; in Wistar rats, it was induced by CA + TP treatment, irrespective of whether MNU was given. Hypertrophic-hyperplastic lesions of the seminal vesicle were induced by MNU, irrespective of pretreatment, and their development was prevented by early castration and inhibited by late orchiectomy. Dorsolateral prostate carcinomas and preneoplasia occurred only in low incidence in Wistar and Sprague-Dawley rats. These lesions were absent in F344 rats that had received treatment with CA + TP + MNU. No dorsolateral prostate (pre)neoplasia was found in Wistar rats subjected to early orchiectomy, but rats castrated at 58 weeks had an incidence similar to that for the intact group treated with CA + TP + MNU. This finding supports the contention that androgens are required for the development of MNU-induced prostatic cancer in rats but that advanced carcinomas are androgen insensitive. Differences in incidence and localization of prostatic proliferative lesions between F344 and Wistar rats and between dorsolateral and ventral prostate could not be explained by differences in epithelial cell proliferative responses to CA + TP treatment at the time of MNU injection, since they were similar in ventral and dorsolateral prostate and were more prominent in F344 rats than in Wistar rats. DNA damage as estimated by MNU-induced unscheduled DNA synthesis also did not differ between dorsolateral and ventral prostate.

Androgens↗
PubMed1982

Teratogenic effects of cyproterone acetate and medroxyprogesterone treatment during the pre- and postimplantation period of mouse embryos. I.

Pregnant mice were treated with a single subcutaneous injection of either cyproterone acetate (CA) or medroxyprogesterone acetate (MPA). In the first experiment the animals received 5-900 mg/kg of the hormone before implantation (day 2 of pregnancy). CA treatment on day 2 caused a dose-dependent decrease in fetal weight and a significant dose-dependent increase in the rates of cleft palate and urinary tract abnormalities. Exencephaly and heart abnormalities were also significantly more frequent, but this increase was not dose-dependent. MPA treatment on day 2 was followed by sporadic increases in dead and resorbed fetuses, a decrease in fetal weight and an increase in the rates of cleft palate, and malformed or abnormally developed fetuses. None of these effects, however, was dose-dependent. In the second experiment the mice were given one single injection (30 mg/kg) of CA or MPA on any one of days 1-12 of gestation. Treatment with CA on one day between days 1 and 12 revealed that the specific sensitivity for abnormalities of the urinary tract was on days 5 and 6, for the respiratory tract on days 8 and 9, and for cleft palate on days 10 and 11. Treatment with MPA on one day between days 1 and 12 only revealed a high rate of respiratory and urinary tract abnormalities on day 9. After treatment with MPA cleft palate was again significantly more frequent in all treated groups, however, days of peak sensitivity were not detected. The long half-life of CA (60 hours) explains the teratogenic effect of high doses of this progestin after treatment on day 2 and also the pattern of abnormal development found after treatment with a single dose of CA on one of the days between day 1 and day 12.

Abnormalities, Drug-Induced↗
PubMed1983

Effects of cyproterone acetate and ethinylestradiol on endometrial histology.

The influence of cyproterone acetate (CPA) containing drugs on the endometrium has not yet been investigated. Therefore, endometrial biopsies were obtained in 22 hirsute patients between day 14 and 28 of the cycle after 7-18 months of oral antiandrogen therapy. The effects of various regimens consisting of different doses of CPA in combination with ethinylestradiol (EE) were evaluated. The low-dose standard regimen (50 micrograms of EE plus 2 mg of CPA daily from day 5 to 25) caused regressive changes in the endometrium, i.e., sparse atrophic glands, relatively compact stroma, islands of stromal edema. These alterations correspond to those induced by conventional balanced low-dose combined oral contraceptives. High-dose reversed sequential regimen (40 micrograms of EE daily from day 5 to 25 plus 100 mg of CPA daily from day 5 to 14) resulted in pseudodeciduation and massive stromal edema. Pseudodeciduation during the early secretory phase is taken as a sign of the progestational depot effect of CPA, while the stromal edema is regarded as a result of the relatively unopposed estrogen intake during the second half of the treatment cycle. Thus, the effects of CPA containing drug on the endometrium depend essentially on their type, dosage and mode of administration.

Adult↗
PubMed1991

Morphofunctional study of the effects of fetal exposure to cyproterone acetate on the hypothalamo-pituitary-gonadal axis of adult rats.

Fetal exposure to cyproterone acetate (CPA), while allowing, normal sexual morphogenesis, has previously been shown to lead to functional endocrine abnormalities in adult rats of both sexes. Because of this, we examined morphologically and morphometrically the hypothalamic nuclei involved in sexual dimorphism as well as the pituitary lactotropes of rats exposed in utero from day 15 to 20 of gestation to CPA. Male and female offspring was studied at the age of 70-80 days. In both sexes the brain weight was lower (p less than 0.05) in CPA-treated than in control rats. Morphometrical investigations showed that the surface density (Sv) and the volume density (Vv) of the ventromedial nucleus were higher (p less than 0.05) in CPA-treated male than in control rats. By comparing sexes the Sv and Vv of the ventromedial nucleus were higher (p less than 0.01) in CPA-treated male than in corresponding female rats. Also the nuclear surface of the tyrosine hydroxylase-immunoreactive neurons of the arcuate nucleus was higher (p less than 0.05) in CPA-treated male than in female rats. In lactotropes of the pituitary gland the immunoreactive prolactin (PRL) was densitometrically increased (p less than 0.05) in CPA-treated female compared with control rats. By electron microscopy, PRL granules and autophagocytosis appeared to be more abundant in CPA-treated rats of both sexes. These data show that fetal exposure to CPA results in long-term anatomical and physiological alterations of hypothalamic and preoptic nuclei as well as of the pituitary lactotropes. These permanent changes support the functional endocrine abnormalities observed in adult rats.

Androgen Antagonists↗
PubMed1986

Growth, regression and cell death in rat liver as related to tissue levels of the hepatomitogen cyproterone acetate.

Previous studies have shown that "xenobiotic" compounds such as the environmental pollutant alpha-hexachlorocyclohexane (alpha-HCH) and the synthetic sex steroid cyproterone acetate (CPA) induce growth of rat liver by hypertrophy and hyperplasia. After withdrawal of the growth stimuli, liver hypertrophy was usually found to be readily reversible. Conflicting observations were made concerning the fate of liver hyperplasia: hepatic hyperplasia persisted when induced by alpha-HCH but was found to be partially reversible when induced by CPA. The present study confirms the reversibility of hepatic hyperplasia induced by CPA in rats: about 30% of liver DNA present at maximal liver enlargement disappeared within 6 days after cessation of CPA treatment. Simultaneously, a dramatic increase in the rate of cell elimination by apoptosis was found. Glutamate-pyruvate transaminase and alkaline phosphatase in serum did not show major increases, suggesting that cell death was not due to lytic membrane damage. Furthermore, if treatment with CPA was continued or resumed, the enhanced DNA content persisted and the number of apoptotic bodies was greatly reduced. These observations suggest that the occurrence of cell death is due to withdrawal of the growth stimulus CPA. It may reflect a regulatory phenomenon serving to maintain homeostasis of cell number. Further studies showed that CPA is rapidly eliminated from rat liver and serum: t 1/2 in the liver is about 11 h. In contrast, alpha-HCH was previously found to be eliminated more slowly: t 1/2 approximately 144 h. The present study revealed that alpha-HCH, CPA and nafenopin lower the number of apoptotic bodies. This suggests that inducers of liver growth can inhibit hepatocellular death by apoptosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1989

Induction by cyproterone acetate of DNA synthesis and mitosis in primary cultures of adult rat hepatocytes in serum free medium.

The aim of this study was to elucidate whether serum-free conditions could be found in primary hepatocyte cultures under which the growth inducing properties of xenobiotics and hormones could be tested. Cyproterone acetate (CPA), a steroid with anti-androgenic and progestogenic activity, was chosen as a model compound because of its known strong mitogenic properties in rat liver in vivo. EGF served as a positive control. Induction of DNA synthesis was studied by [3H]-thymidine labeling and autoradiography. Mitoses were counted in hematoxylin stained specimens. The main steps which led to an efficient stimulation of DNA synthesis by CPA were (i) reduction of hormone concentrations to levels approaching (approx. 10x) physiological concentrations better than the previously used pharmacological ones (up to 2500x); (ii) supplementation with glucocorticoid (most effective at 10-100 nM dexamethasone); (iii) selection of the interval for cumulative labeling with thymidine at 44-68 h; (iv) lowering of cell density at seeding to 50,000 cells/cm2 (subconfluency); (v) treatment with concentrations of 10-100 microM CPA. With these conditions CPA labelling was 13-20% (increase 4- to 9-fold). Mitotic incidence was 0.56% (CPA) versus 0.08% in controls. From a dose response study (0.1-100 microM) a no-effect-level for induction of DNA synthesis was found in the range of 0.1-1 microM. None of the high concentrations of CPA did cause cytotoxicity as estimated by morphological observations or release of lactate dehydrogenase into the medium. This work demonstrates that CPA under appropriate, defined culture conditions induces DNA synthesis and mitosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Effect of cyproterone acetate-ethinyl estradiol treatment on the proportions of linoleic and sebaleic acids in various skin surface lipid classes.

The effect of high-dose cyproterone acetate-ethinyl estradiol treatment on rates of sebum secretion and on the proportions of linoleic acid (18:2 delta 9,12) and sebaleic acid (18:2 delta 5,8) in the skin surface lipids of three female acne patients was examined. Changes in rates of sebum secretion were evaluated indirectly by measuring the ratio of wax esters/(cholesterol + cholesterol esters) in the subjects' skin surface lipid. In two of the subjects, this ratio indicated a reduction of sebum secretion rates to the childhood range. Concomitantly, there was an increase in linoleic acid and a decrease in sebaleic acid in all lipid classes. In the third subject, in whom there was only a small reduction in sebum secretion rate, the proportion of linoleic acid in the cholesterol esters more than doubled, but the changes in the other lipid classes were small or nonexistent. The results indicate that the proportions of linoleic acid and sebaleic acid in sebum are influenced by sebum secretion rates.

Acne Vulgaris↗
PubMed1985

Ultrasound study of ovarian and uterine morphology in women with polycystic ovary syndrome before, during and after treatment with cyproterone acetate and ethinyloestradiol.

Women with the polycystic ovary syndrome were treated cyclically for two years with an oral oestrogen/progestogen combination of 50 mg of cyproterone acetate and 0.05 mg of ethinyloestradiol. Ovarian volume, ovarian texture and uterine size were monitored by ultrasound before, during and after treatment. Menstrual rhythm, ovulation and the degree of hirsutism were also studied clinically. A significant decrease in the ovarian volume and in the number of cystic areas was observed during treatment. Hirsutism was also markedly improved. Some of these beneficial effects persisted after treatment was stopped. The number of subjects who had regular, ovulatory cycles increased after stopping treatment. Growth of uterine muscle occurred during treatment.

Adolescent↗
PubMed1987

Liver structure and function during long-term treatment with cyproterone acetate.

Animal experiments and clinical observations have raised the question of liver function in patients on long-term, high-dose administration of sex steroids. The effective treatment of androgenisation demands the prolonged administration of the antiandrogen cyproterone acetate (CPA), which is also a highly effective progestogen. Biochemical tests of liver function and ultrasonographic examinations were performed in 77 women who had been treated with CPA given in the reverse sequential scheme - 100 mg CPA/day from the 1st-10th day combined with 2 mg CPA + 0.05 mg ethinylestradiol/day from the 1st-21st day of each treatment cycle - for 3 to 11 years. No disturbances of the liver structure or function were found.

Adult↗
PubMed1985

Effect of calf and rat serum on the induction of DNA synthesis and mitosis in primary cultures of adult rat hepatocytes by cyproterone acetate and epidermal growth factor.

Induction of hepatocyte DNA synthesis in culture by cyproterone acetate (CPA), a potent hepatomitogen in vivo, was studied. Adult rat hepatocytes were grown on collagen gels in primary culture for 3 to 10 d. Epidermal growth factor (EGF) was used as a model inducer to establish appropriate culture conditions. (a) In serum-free medium EGF stimulated a wave of DNA synthesis in 10 to 30% of the hepatocytes. CPA had only a weak effect. (b) Increasing concentrations of newborn bovine serum (NBS) at 5 to 95% progressively inhibited the stimulatory effect of EGF. A similar inhibition was obtained by adding bovine serum albumin; 20% NBS, however, had a slightly stimulatory effect on the induction of DNA synthesis by CPA. (c) Portal rat serum (RS) at concentration of 5 to 95% markedly stimulated DNA synthesis, a plateau being reached between 20 and 95%. EGF had a distinct enhancing effect on DNA synthesis in the presence of 5 and 20% RS but not at 50 and 95%. CPA stimulated DNA synthesis in the presence of 20, 50, and 95% RS in a synergistic way. (d) Mitoses were found after treatment with EGF or with CPA. These results show that CPA can induce DNA synthesis in cultured hepatocytes and that RS contains factors facilitating the response to CPA.

Animals↗
PubMed1987

The effects of reverse sequential anti-androgen therapy (cyproterone acetate and ethinyl estradiol) on hematological parameters.

Hematological parameters were studied in female patients receiving reverse-sequential anti-androgen therapy for hirsutism and acne. A significant fall in hemoglobin, total red cell count and packed cell volume occurred after 3-month treatment in 30 patients during the 10-day cyproterone acetate and ethinyl estradiol phase; this change was sustained in 14 patients studied to 12 months. A fall in hemoglobin and packed cell volume alone occurred after 3 months in 31 patients in the ethinyl estradiol phase. Reverse-sequential therapy may influence hemopoiesis by its anti-androgenic action on erythropoiesis, although we found no relationship between changes in hematological parameters and total testosterone levels.

Acne Vulgaris↗
PubMed1985

Activation of PRL secretion by combined treatment with cyproterone acetate and ethinylestradiol.

Two groups of patients affected by idiopathic androgenization have been treated with ethinylestradiol (EE) associated with two different (high and low) dosages of cyproterone acetate (CA); the aim of this study was to evaluate the possible endocrine side effects at the pituitary level. After three and six months of treatment gonadotropins secretion appeared significantly inhibited with higher evidence for LH than for FSH and especially in the patients on high dose of CA. Nevertheless the most impressive finding was represented by the increase in PRL responses to TRH documented when higher doses of CA were employed without significant change in TSH secretion. The Authors suggest that such PRL hyperresponsiveness cannot be completely disregarded in the management of idiopathic androgenization.

Adult↗
PubMedDate not supplied

Cyproterone acetate treatment in precocious puberty.

Seven girls with precocious puberty, idiopathic in 6 and associated with the McCune Albright syndrome in 1, were treated with 70 mg/M2/die of cyproterone acetate (CPA) for 11 to 36 months. Before and during treatment clinical parameters (weight, height, bone age, height velocity, prediction of adult height and pubertal development) were evaluated and plasma hormone assays in basal conditions (LH, FSH, 17 beta-estradiol, progesterone, testosterone, PRL, ACTH and cortisol) and after stimulation (LH, FSH, cortisol, GH) were carried out to assess the efficacy and eventual side effects of CPA. The regression observed in the clinical signs of puberty was considered satisfactory and the increase observed in the developmental quotient indicated an improved prognosis for adult height. No symptoms of adrenal insufficiency were observed but an adrenal suppressive effect of CPA was evident from the response to insulin hypoglycemia observed in 4 patients.

Child↗
PubMed1990

Effects of ethinyl estradiol combined with desogestrel and cyproterone acetate on glucose tolerance and insulin response to an oral glucose load: a one-year randomized, prospective, comparative trial.

To investigate the effects of two slightly estrogen-dominant, monophasic, low-dose oral contraceptives on carbohydrate metabolism, 40 healthy young women were randomly allocated to receive either 30 micrograms of ethinyl estradiol + 150 micrograms of desogestrel, a 19-nortestosterone-derived progestin (Marvelon; n = 21) or 35 micrograms of ethinyl estradiol + 2 mg of cyproterone acetate, a 17-acetoxyprogesterone derivative (Diane-35; n = (19) for a prospective observation period of 1 year. At baseline, 6, and 12 months, blood glucose, plasma insulin, and plasma C-peptide levels were measured during an oral glucose tolerance test. Although the changes were absent (Marvelon) or minimal (Diane-35) at 6 months, both groups had a slight increase in blood glucose levels at 12 months; overall glucose tolerance remaining, however, within the normal range. Plasma insulin levels remained unchanged in the Diane-35-group, which suggested increased insulin resistance, but were significantly decreased in the Marvelon group despite significant rises in plasma C-peptide levels. Comparison of plasma C-peptide and insulin changes suggests enhanced pancreatic insulin secretion and increased hepatic insulin metabolism with both Marvelon and Diane-35.

Adult↗