Effect Of Cyproterone Acetate Research Articles

The Effect of Cyproterone Acetate on Myo‐Inositol Uptake and Secretion in the Reproductive Tract of the Male Rat

A procedure is described for evaluating the uptake of myo‐inositol by measuring the radioactivity (dpm/mg wet weight of tissue) in the male reproductive accessory glands after injection of (2‐3H)myo‐inositol into bilaterally nephrectomized rats. The rate of secretion of the labelled inositol was assessed by measuring the total dpm in fluids expressed from the seminal vesicles and coagulating glands after injection of the tritiated inositol.Cyproterone acetate treatment (15 mg/day), for 2 to 7 days, inhibited secretion of radioactive inositol by the seminal vesicles and decreased the uptake capacity to a greater extent than it inhibited the rate of inositol accumulation into these glands. It had a similar effect on the coagulating glands after 7 days of treatment. The prostate was the least affected by the cyproterone acetate treatment.

The effect of cyproterone acetate on the activity of Δ 5-3 β-hydroxysteroid dehydrogenase in tadpole sex transformation

Tadpoles of Rana catesbeiana were reared in water containing cyproterone acetate (CA) at a dose of 1.5 mg/liter for a period of 2 or 7 months. Histological examination of gonadal differentiation after termination of the experiments showed that CA was capable of transforming tadpole ovaries completely or patially into testes after 7 months of treatment, while 2 months of treatment did not bring about sex transformation. The result of the chronic experiment confirms the finding of Chieffi et al. in tadpoles of R. esculenta ( G. Chieffi, L. Iela, and R. K. Rastogi, 1974, Gen. Comp. Endocrinol. 22, 532–534). The ovaries and livers of the present experiments were assayed for conversion rate of Δ 5-3 β-HSD activity using [ 3H]pregnenolone as the substrate. The result indicates decreased enzyme activity after CA treatment. CA was also injected intraperitoneally into laparotomized female tadpoles. The ovaries and livers showed again decreased Δ 5-3 β-HSD activity after CA injection. Cyproterone, a free alcohol of CA, is known to inhibit Δ 5-3 β-HSD ( W. C. Schwarzel, W. G. Kruggel, and H. J. Brodie, 1973, Endocrinology 92, 866); it seems CA could play the same role because CA can be saponified to cyproterone by tissue esterases. The present data present such evidence. The present findings indicate an intimate relationship between decreased enzyme activity and ovarian masculinization. Similar results were obtained in this laboratory when tadpoles were treated with estradiol-17β, another inhibitor of Δ 5-3 β-HSD. Since activities of Δ 5-3 β-HSD and 17β-HSD were demonstrable in tadpole ovaries, steroidogenesis could be possible in this organ ( C. Y. Hsü, C. H. Chiang, and H. M. Liang, 1977, Gen. Comp. Endocrinol. 32, 272–278). Therefore we suggest that disturbance in ovarian steroidogenesis may play a role in abnormal sex differentiation. This proposal is at variance with that of Chieffi.

Effect of cyproterone acetate (CA) on growth and endocrine function in precocious puberty.

16 girls with precocious puberty have been studied. Following low dosage cyproterone acetate (CA) therapy (mean daily dosage 65 mg/m2BSA) a beneficial effect on growth and skeletal maturation was observed. During high dosage therapy (150 mg/m2 per day) endocrinological studies were performed in 10 of these patients. There was no significant difference in HGH levels (insulin- and arginine-test), T3 and TSH values (TRH-test) between patients and controls, T4 concentration was significantly increased. Basal prolactin levels and prolactin response to TRH was definitely elevated. Oral glucose load and arginine infusion resulted in a significantly enhanced insulin release. There was a significant reduction in basal LH levels and an increase in FSH response to LH-RH. Basal and diurnal plasma cortisol values were markedly reduced and the cortisol release due to corticotrophin injection, lysinevasopressin (LVP) injection and insulin-hypoglycemia as well. A definite increase in basal ACTH levels was observed, during LVP- and insulin-hypoglycemia test ACTH concentrations were within or significantly above normal range. In our patients a primary adrenocortical insufficiency due to CA treatment was evident.

Effect of cyproterone acetate (CPA) on gonadal and adrenal function in men

The circadian variation in the levels of biologically active luteinizing hormone (hLH), testosterone (T), dihydrotestosterone (DHT), 17-hydroxyprogesterone (17-0H-P), androstenedione (A), pregnenolone (Δ 5P), 17-hydroxypregnenolone (17-0H-Δ 5P), dehydroepiandrosterone (DHEA) and cortisol (C) was investigated in peripheral plasma collected continuously during 36 hours from 10 healthy male subjects (26 to 55 years) before and during the third week of the oral administration of daily doses of 20 mg of cyproterone acetate (CPA). These hormonal indices, complemented with immunoreactive follicle-stimulating hormone (hFSH) and the sulphurylated (solyolyzable) forms of Δ 5P, 17-0H-Δ 5P, DHEA, T and DHT, were also assessed in conjunction with a standardized dexamethasone - ACTH test carried out both before and during the third week of CPA administration. Administration of CPA suppressed significantly the levels of hLH (mean suppression: 39%), hFSH (66%), T (73%), DHT (51%), 17-OH-P (59%) and A (30%) in all subjects, but did not affect the pattern of circadian variation. The levels of sulphurylated T (34%) and DHT (35%) were also suppressed. There was no correlation between the levels of hLH and T, and the former exhibited no circadian variation. Considerable individual variation was found in the behavior of cortisol (C) and unconjugated Δ 5-steroids during CPA administration; the levels of C were significantly elevated in 2 and diminished in 1 subject, whereas Δ 5P and 17-0H-Δ 5P levels were suppressed in 4, and those of DHEA in 3 of the subjects. Similar changes in the levels of most steroids (including those of C) were observed after the administration of dexamethasone and ACTH before and during the treatment period with CPA. However, dexamethasone induced an increase in hLH and T levels in the pretreatment period, but not during CPA administration, whereas the levels of sulphurylated T, DHT and DHEA were elevated by dexamethasone during CPA treatment, but not in the pretreatment period. ACTH increased significantly unconjugated DHT levels during CPA administration, but not in the pretreatment period. It is concluded that CPA in oral doses of 20 mg administered daily for 3 weeks is a powerful inhibitor of pituitary gonadotrophin and testicular steroid secretion in men, but does not interfere with the secretion of cortisol. In addition, it appears that the administration of CPA gives rise to alterations in the metabolism of several steroid sulphates.

Effect of cyproterone acetate on the structure of the adrenal cortex.

Adult male C57 BL/6J mice injected with 0.08 mg/g of cyproterone acetate showed an increase in cellular lipid content in the zona fasciculata and zona reticularis of the adrenal cortex. In the perimedullary region, densely staining cells aggregated to form scattered nodules. At the ultrastructural level, in the zona glomerulosa and zona fasciculata the number and size of lipid droplets increased. An apparent decrease in mitochondrial number and size and a noticeable diminution in the amount of smooth endoplasmic reticulum were also noted in the zona fasciculata. It is suggested that cyproterone acetate may have blocked steroid synthesis and increased adrenal cholesterol deposits.

Effect of cyproterone acetate on the reproductive system of the female rat

Effects of cyproterone acetate, a synthetic steroidal compound, on the reproductive organs of female rats have been investigated. This agent caused reduction of ovarian weights indicative of suppression of pituitary gonadotrophins. Oestrogenic nature of cyproterone acetate was investigated in intact and ovariectomized rats taking uterine weight and vaginal keratinization as an index of oestrogenicity. Cyproterone acetate in ovariectomized animals induced vaginal keratinization and increased the uterine weights. These effects were parallel to the effect of oestradiol dipropionate in ovariectomized animals, thus indicating oestrogenic activity of cyproterone acetate. We may conclude that the above compound caused antifertility effects due to its oestrogenic nature at the dose level of 2 mg/alternate day in rats when the compound was administered subcutaneously.

Effect of cyproterone acetate on adrenal cortex of castrated mice

Castrated adult male C57BL/6J mice displayed a wide perimedullary zone (secondary X-zone) whose cells were characterized by proliferated rough and smooth endoplasmic reticulum and elongated mitochondria with lamellar cristae. Castrated mice which received 0.08 mg/g of cyproterone acetate showed a much inhibited secondary X-zone at the light microscopic level, while at the ultrastructural level the perimedullary cells lacked the proliferated rough and smooth endoplasmic reticulum as well as the elongated mitochondria. Cyproterone acetate may inhibit the steroidogenic parameters of the androgen-producing cell population of the adrenal cortex without testicular mediation.

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.

A morphological study on the effect of cyproterone acetate on human prostatic carcinoma.

Sixteen patients with prostatic carcinoma were treated with 200 mg of Cyproterone acetate daily. No other kind of hormonal treatment was given. Transrectal biopsies of the prostate were taken before the treatment was started, and at regular intervals afterwards. The treatment period lasted from 3 to 16 months, with an average of 9 months. A thorough examination of multiple sections from all specimens revealed no convincing signs of cellular involution. The study has demonstrated no specific or significant atrophic changes following Cyproterone acetate therapy. Some possible explanations regarding the effect of Cyproterone acetate on human malignant prostatic tissue are discussed.

Influence of Antiandrogens on Sertoli Cell Function and Intratesticular Androgen Transport

The effect of cyproterone acetate (CA) on spermatogenesis and especially on Sertoli cell function was investigated. Male rats were treated with daily doses of cyproterone acetate ranging from 0.625 to 30 mg/day sc for six weeks.The highest dose of cyproterone acetate inhibits spermatogenesis and reduces testicular weights as well as ABP content and concentration in the capita epididymis of treated rats, whereas serum FSH, LH and testosterone concentrations remain unaffected by cyproterone acetate treatment. These findings demonstrate that cyproterone acetate acts directly upon the testis and inhibits Sertoli cell function, as reflected by decreased ABP production.The binding studies revealed that cyproterone acetate does not compete with androgens for binding to ABP and, therefore, has no other effect on androgen transport in the testis than inhibition of ABP production. The nonsteroidal antiandrogen, flutamide, behaves like cyproterone acetate in respect of its binding to ABP, whereas SKF 7690 competes with DHT.

Endocrine actions and side effects of cyproterone acetate (CA)

16 girls with precocious puberty have been treated with CA (actual dosage 150 mg/m2/die) for a period of 2-6 years. None of the patients showed clinical signs of adrenocortical insufficiency. In 10 treated patients plasma levels of ACTH, HGH, immunoreactive insulin (IRI), LH, FSH, prolactin, TSH, T3, T4 and cortisol were determined by RIA. T3, T4 and TSH (TRH-test) as well as HGH levels (insulin- and arginine-test) did not differ significantly from values in normal controls. CA treated patients showed an elevated prolactin response to TRH-injection. Following LH-RH a 7fold increase in LH and a 1.6fold increase in FSH levels were seen. Arginine and oral glucose load resulted in a significantly higher IRI peak in CA treated patients than in normal controls. Basal ACTH levels were significantly higher in CA treated patients. Following i.m. lysinvasopressin and during insulin-test there was no significant difference in peak ACTH concentrations between CA treated patients and normal controls. CA treated patients showed a significantly subnormal cortisol response to ACTH and during insulintest. Conclusion: CA-induced inhibition of adrenocortical function is not the result of decreased pituitary ACTH secretion.

Alterations in polyamines and nucleic acids in the rat ventral prostate during cyproterone acetate treatment and subsequent withdrawal.

The effect of cyproterone acetate (CA) was examined on polyamines and nucleic acid levels of the ventral prostate at various time intervals after daily administration of this antiandrogen (1.25 mg/100 g, sc) to adult rats. While CA markedly reduced prostatic spermine, spermidine, and putrescine levels after 10 days of treatment, changes in the latter two polyamines appeared to be biphasic with significant elevations being observed at day 1, followed by marked decreases that were evident as early as the 3rd day. Cessation of antiandrogen treatment for 10 days in rats that had been pretreated with CA significantly elevated prostatic spermine levels, while the concentration of spermidine and putrescine remained slightly lower than controls. In contrast, CA failed to exert any marked effect on prostatic spermine and putrescine levels when animals were treated concomitantly with testosterone (5 mg/100 g per day, sc; 10 days). Like prostatic spermidine and putrescine, RNA levels and the RNA:DNA ratio were significantly elevated 24 h after CA administration, but decreased thereafter to levels markedly lower than controls by the 10th day of treatment. DNA concentration was increased slightly during CA administration, although the total content of this nucleic acid remained unaltered. While cessation of CA administration restored RNA and the RNA:DNA ratio to control values, these were significantly increased in rats given both CA and testosterone. Results of the present investigation support the hypothesis that changes in cellular polyamines may be related to alterations in RNA metabolism, and thus cellular differentiation of the prostate gland following androgenic deprivation and (or) depletion.

301. Effect of cyproterone acetate on peripheral and pituitary levels of gonadotropins in the male rats during sexual maturation

301. Effect of cyproterone acetate on peripheral and pituitary levels of gonadotropins in the male rats during sexual maturation

Effects of Cyproterone Acetate (CPA) on Pituitary Gonadotrophin Release and on Androgen Secretion Before and After LH‐RH Double Stimulation Tests in Men

CPA administration at a medium dosage of 10 mg daily for male fertility control resulted in reduced spermiograms and in a distinct decrease in basal T (70% reduction), DHT (50%), LH (30%) and FSH (40%). The episodic fluctuations in gonadotrophin secretion were not affected, but the spiking phenomenon of androgen secretion was completely abolished. Pituitary responses to LH‐RH were reduced significantly for both LH and FSH. Also the gradual increase of T and DHT in the course of the LH‐RH double stimulation tests was reduced. It is concluded that the progestational/antigonadotrophic action of CPA predominates over the antiandrogenic action. In addition, a direct effect at the testicular level is postulated.

Effect of Cyproterone Acetate (CA) on the pituitary, gonadal, thyroidal and adrenocortical function in girls with idiopathic precocious puberty

Effect of Cyproterone Acetate (CA) on the pituitary, gonadal, thyroidal and adrenocortical function in girls with idiopathic precocious puberty

Effect of cyproterone acetate on skin surface lipids

Skin surface lipids in female patients with acne were examined before and after treatment with the oral contraceptive SH 209 AB (2 mg cyproterone acetate and 0.05 mg ethinyl estradiol) by direct extraction with petrol ether and photometrical determination. A significant reduction in the skin surface lipids was seen, together with a remarkable alleviation of the disease.

The effect of cyproterone acetate on adrenal cortical function in children with precocious puberty

8 children with precocious puberty were treated with cyproterone acetate (CPA). During treatment there were no definite clinical signs of depressed adrenocortical function. The plasma cortisol concentrations were grossly depressed and the diurnal cortisol rhythm was abolished. Two months after discontinuation of CPA treatment the adrenocortical function had greatly improved. The lysin-vasopressin stimulation test revealed in one child a normal, in another child an exaggerated ACTH response during CPA therapy. Fasting plasma ACTH concentrations were elevated compared with normal controls, but they were very low compared with patients with Addison's disease. The results suggest that CPA has a twofold effect leading to adrenocortical insufficiency: i.e., inhibition of cortisol secretion by the adrenals themselves and inhibition of ACTH secretion at the hypothalamopitiuitary level.

Radioprotective effects of cyproterone acetate.

The pretreatment of irradiated mice by cyproterone acetate had a better radioprotective effect in comparison with orchidectomy, although the weight of the thymus was lower in the cyproterone acetate group. The radioprotective mechanisms involved in both cases were discussed.

Effect of cyproterone acetate on cells of the pars distalis of the adenohypophysis in the Beagle Bitch

The effects of oral administration of 100 mg per kg per day cyproterone acetate (CPA) for four weeks on cells of the pars distalis, as revealed by the immunoperoxidase technique and chemical staining, were studied in the ovariectomized beagle bitch. For immunochemical staining antisera to the following hormones were used: canine GH, canine PRL, procine ACHT, bovine TSH beta, bovine LH beta and human FSH beta1. The most striking effects of the treatment were an overall increase in the relative proportion of GH cells and a marked morphological indication of high secretory activity in these cells. In contrast, PRL cells were not affected significantly. In all ovariectomized control bitches a marked atrophy of the cells stained for FSH beta (FSH cells) and hypertrophy of the cells shown to contain LH beta (LH cells) were observed. FSH cells became enlarged, while LH cells appeared reduced in size by administration of CPA. In some treated bitches ACTH/MSH cells showed atrophy and regressive changes, whereas TSH cells seemed to become enlarged and were more densely arranged. These structural responses indicate that, in addition to its partial antigonadotropic properties, CPA as a synthetic progesterone derivative may stimulate GH secretion and possibly suppress CRH-ACTH activity in the ovariectomized beagle bitch.

Effect of cyproterone acetate on prolactin secretion in the female rhesus monkey

Adult female rhesus monkeys were given cyproterone acetate orally in doses of 0.04, 0.4, 4 and 40 mg per kg per day for 12 weeks. Its effects were assessed on serum prolactin (PRL) concentration, the morphology of the PRL cells, and the development of the mammary glands. Serum PRL was relatively unchanged in the control animals from the fourth through the twelfth weeks of the study. In contrast, PRL was significantly elevated in each group of drug-treated animals during the same time periods. There was no development of the mammary glands nor was there any evidence of milk secretion in the control animals; however, in the monkeys given cyproterone acetate the mammary glands had extensive lobuloalveolar growth and milk-like secretion that could be expressed as early as the fourth or fifth week of the study. By immunocytochemistry and differential light microscopic staining techniques, the PRL cells in the pituitary glands of the experimental animals were found to be more numerous and much larger than those present in the controls. They displayed a well developed Golgi complex and had an abundance of cytoplasmic RNA. These data suggest that PRL secretion is markedly enhanced by cyproterone acetate.