Effect Of Cyproterone Acetate Research Articles

Effects of cyproterone acetate and vertically transmitted microsporidia parasite on Gammarus pulex sperm production.

Endocrine disruption compounds (EDCs) and parasitism can both interfere with the reproduction process of organisms. The amphipod Gammarus pulex is the host of the vertically transmitted microsporidia Dictyocoela duebenum, and this work was devoted to the investigation of the effect of an exposure to the anti-androgen compound, cyproterone acetate (CPA), and/or of the presence of D. duebenum on the spermatozoa production and length. Significant reduction of the spermatozoa production was observed when G. pulex males were uninfected and exposed to CPA. There also appeared a lower number of spermatozoa when D. duebenum infects G. pulex, whatever the exposure condition. Moreover, we highlighted that CPA has no effect on spermatozoa production when males are infected by D. duebenum, and no treatment has impacted the spermatozoa length. Our results suggest CPA and D. duebenum could impact the endocrine system of G. pulex and especially processes close to the spermatozoa production (e.g., androgenic gland, androgen gland hormone released, gonad-inhibiting hormone synthesized by X-organ). However, as no mechanism of action was highlighted, further testing need to be performed to improve the understanding of their impacts. Finally, results confirm that vertically transmitted microsporidia could be a confounding factor in the endocrine disruption assessments in Gammaridae.

Cyproterone acetate enhances TRAIL-induced androgen-independent prostate cancer cell apoptosis via up-regulation of death receptor 5

BackgroundVirtually all prostate cancer deaths occur due to obtaining the castration-resistant phenotype after prostate cancer cells escaped from apoptosis and/or growth suppression initially induced by androgen receptor blockade. TNF-related apoptosis-inducing ligand (TRAIL) was an attractive cancer therapeutic agent due to its minimal toxicity to normal cells and remarkable apoptotic activity in tumor cells. However, most localized cancers including prostate cancer are resistant to TRAIL-induced apoptosis, thereby creating a therapeutic challenge of inducing TRAIL sensitivity in cancer cells. Herein the effects of cyproterone acetate, an antiandrogen steroid, on the TRAIL-induced apoptosis of androgen receptor-negative prostate cancer cells are reported.MethodsCell apoptosis was assessed by both annexin V/propidium iodide labeling and poly (ADP-ribose) polymerase cleavage assays. Gene and protein expression changes were determined by quantitative real-time PCR and western blot assays. The effect of cyproterone acetate on gene promoter activity was determined by luciferase reporter assay.ResultsCyproterone acetate but not AR antagonist bicalutamide dramatically increased the susceptibility of androgen receptor-negative human prostate cancer PC-3 and DU145 cells to TRAIL-induced apoptosis but no effects on immortalized human prostate stromal PS30 cells and human embryonic kidney HEK293 cells. Further investigation of the TRAIL-induced apoptosis pathway revealed that cyproterone acetate exerted its effect by selectively increasing death receptor 5 (DR5) mRNA and protein expression. Cyproterone acetate treatment also increased DR5 gene promoter activity, which could be abolished by mutation of a consensus binding domain of transcription factor CCAAT-enhancer-binding protein homologous protein (CHOP) in the DR5 gene promoter. Cyproterone acetate increases CHOP expression in a concentration and time-dependent manner and endoplasmic reticulum stress reducer 4-phenylbutyrate could block cyproterone acetate-induced CHOP and DR5 up-regulation. More importantly, siRNA silencing of CHOP significantly reduced cyproterone acetate-induced DR5 up-regulation and TRAIL sensitivity in prostate cancer cells.ConclusionsOur study shows a novel effect of cyproterone acetate on apoptosis pathways in prostate cancer cells and raises the possibility that a combination of TRAIL with cyproterone acetate could be a promising strategy for treating castration-resistant prostate cancer.

Is the suppressive effect of cyproterone acetate on serum anti-Müllerian-hormone levels in women with polycystic ovary syndrome stronger than under oral contraceptive pill?

Objective: To compare the suppressive effect of anti-androgen therapy by cyproterone acetate (CPA) and by oral contraceptive pill (OCP) on anti-müllerian hormone (AMH) levels in women with polycystic ovary syndrome (PCOS) in order to detect a putative direct anti-androgen effect on AMH excess.Methods: This is a prospective longitudinal study including 58 women with PCOS between January 2010 and April 2014 at the Lille University Hospital. A total of 47 women with clinical hyperandrogenism were treated by CPA (50 mg/d was administered 20 days out of 28) and 11 women with PCOS but without clinical hyperandrogenism received OCP.Result(s): Serum AHM levels at baseline were similar in CPA and OCP groups (median [5–95th percentiles]: 60.4 pmol/l [25.1–200.2] versus 58 pmol/l [27.6–100], respectively, p = 0.39). After 3 months of treatment, serum AMH levels decreased significantly by 28% ± 20% and by 22% ± 27% in CPA and OCP groups, respectively. The decrease under both treatments was similar (p = 0.48).Conclusion(s): That any anti-androgen effect could be observed on AMH in our CPA group in addition to the gonadotropin-suppressing effect suggests that either androgens are not involved in AMH regulation or that they act by interfering with gonadotropin effects on granulosa cells.

The curative effect analysis of cyproterone acetate combined with letrozole in the treatment of patients with polycystic ovary syndrome and infertility

Objective To explore the clinical effect of cyproterone acetate combined with letrozole in the treatment of patients with ovulation disorder infertility caused by polycystic ovary syndrome (PCOS).Methods 124 patients with PCOS and infertility were selected and divided into three groups.Letrozole Group (42 cases) received cyproterone acetate combined with letrozole; Control Group (40 cases) received oral cyproterone acetate treatment; Clomiphene Group (42 cases) received oral cyproterone acetate combined with clomiphene.Record the sex hormone levels,cycle ovulation rate and pregnancy rate in three groups.Results The levels of T,LH,LH/FSH significantly reduced (P ＜ 0.01).In 42 ovulation induction cycles,35 cycles (87.5％) had advantaged follicle,34 cycles (85.0％) had ovulation,with 7 cases of pregnancy (17.5％).There were statistically significant differences in sex hormone levels,cycle ovulation rate,pregnancy rate between Letrozole Group and Control Group (P ＞ 0.05).E2 levels in ovulation phase and luteal phase and LH level in ovulation phase of Clomiphene Group were higher than those of Letrozole Group,without statistically significant differences (P ＞ 0.05).Conclusions Cyproterone acetate combined with letrozole in the treatment of patients with ovulation disorder infertility caused by polycystic ovary syndrome has good curative effect,can obtain same effect as clomiphene,offer one more choice for patients with ovulation disorder infertility caused by polycystic ovary syndrome. Key words: Polycystic ovary syndrome; Infertility; Letrozole; Cyproterone acetate; Clomiphene

Effects of cyproterone acetate on spontaneous contractility of the rat epididymis.

The spontaneous contractility of the rat epididymis was recorded in vivo and the effects of cyproterone acetate were studied. At 7 days after cyproterone acetate daily administration the records of the epididymal contractility did not show significant differences from the records obtained in control animals. On the contrary, in animals injected during 11 days the amplitude and frequency of epididymal contractions showed a significant decrease, and this activity completely ceased at 14 days of treatment.

Effects of cyproterone acetate on the ultrastructure of the human epididymis.

The effects of cyproterone acetate (CPA), an antiandrogenic steroid, on the ultrastructure of the epithelial cells of the human epididymis were studied. Alterations in the cell size, in the cytoplasmic and surface characteristics, and in the morphology of different organelles are described. The different ultrastructural changes observed suggest that the absorptive and secretory functions of the principal cells are impaired following the CPA treatment. By contrast, with the drastic response of the principal cells of the ductuli efferentes and caput epididymidis, the epithelial cells of the cauda epididymidis appeared less affected. The suggestion of a differential androgen dependence among the different regions of this androgen target organ, as well as between the major cell-types of the epididymal epithelium, is briefly discussed.

Effects of cyproterone acetate on the reproductive tract and pituitary-gonadal axis of the golden hamster.

The effects of cyproterone acetate (CA) on the reproductive tract and serum levels of gonadotropins and testosterone in male golden hamsters exposed to long days, were studied. The daily injection of CA at 100 mg kg-1 body weight during 8 weeks reduced sperm count, both in caput and cauda epididymidis. The weight of epididymis and seminal vesicles were also reduced, while testicular weight and histology were not affected. Serum levels of testosterone and LH were increased 3.6 and 1.8 fold, respectively, above controls, while FSH was not affected by the treatment with CA. The absence of an inhibitory action of CA on the testis could be explained through an increase in LH stimulation, thus suggesting that in the golden hamster CA is devoid of progestagenic partial effects.

Lectin Staining of Rat Testis and Epididymis: Effect of Cyproterone Acetate and Testosterone

Control and castrated (C) adult rats were treated with cyproterone acetate (CA), testosterone (T) or their combination (CA + T) for 15 days and the affinity of the testicular and epididymal tissue for seven rhodamine-conjugated lectins was analysed in fluorescence microscopy. In the testis CA caused the appearance of degenerating cells in the basal part of the seminiferous epithelium. These cells (spermatogonia, early spermatocytes) appear to be the most vulnerable germinal cells to anti-androgen treatment and this effect could be prevented by simultaneous administration of T. Castration caused a marked reduction in lectin staining of principal and light cells of distal caput (Dcp) and distal cauda (Dcd) epididymidis accompanied by the disappearance of the intratubular sperm mass. In castrated animals CA caused a moderate and T as well as CA + T a marked increase in the stainability of these cells and the appearance of homogeneous secretory material in the tubules. This material gave moderate or strong affinity for most of the lectins. Some minor differences were found in the staining pattern of the cells and the secretory material in Dcp and Dcd as well as after different treatments. This is consistent with local and qualitative differences in the epididymal secretory and absorptive activity, which can be further modified by the hormonal milieu.

Sex steroids in the female zebrafish ( Danio rerio) : Effects of cyproterone acetate and leachate-contaminated sediment extract

In Molnbyggen, a leachate-contaminated lake in Sweden, effects on the reproductive system of perch included a decreased frequency of sexually mature female perch, reduced gonadosomatic index and decreased plasma levels of androstenedione and testosterone, but the contaminants responsible for these effects have not yet been identified. A biomarker-directed fractionation approach could be used to narrow the search for the compound(s) responsible for the adverse effects in Molnbyggen female perch. Thus, it is important to develop and test a suitable biomarker, which can be used in this type of approach. We evaluated if decreased concentrations of sex steroids could work as an in vivo end-point in female zebrafish fed an organic extract of bottom sediments from Molnbyggen. The responsiveness of zebrafish to endocrine alteration was evaluated using a positive control substance, cyproterone acetate (CA), which is known to inhibit steroid biosynthesis. After the 21-day exposure period the concentrations of testosterone (T) and estradiol (E2) were successfully determined by HRGC/HRMS in whole-body homogenates of individual fish. Median T concentrations were 1.7 pmol/g fish in controls and were decreased after exposure both to CA (0.55 pmol/g fish) and Molnbyggen sediment extract (1.2–1.3 pmol/g fish). Median E2 concentrations were 5.3 pmol/g fish in controls and were decreased after CA exposure (2.3 pmol/g fish) and after exposure to Molnbyggen sediment extract (4.0–4.5 pmol/g fish). This suggests that sex steroid concentrations in zebrafish are responsive to endocrine alteration and indicates that compounds with endocrine altering potency are present in Molnbyggen sediments.

Effect of cyproterone acetate on alpha1-adrenoceptor subtypes in rat vas deferens.

Gonadal hormones regulate the expression of alpha1-adrenoceptor subtypes in several tissues. The present study was carried out to determine whether or not cyproterone acetate, an anti-androgenic agent, regulates the alpha1-adrenoceptor subtypes that mediate contractions of the rat vas deferens in response to noradrenaline. The actions of subtype selective alpha1-antagonists were investigated in vas deferens from control and cyproterone acetate-treated rats (10 mg/day, sc, for 7 days). Prazosin (pA2 approximately 9.5), phentolamine (pA2 approximately 8.3) and yohimbine (pA2 approximately 6.7) presented competitive antagonism consistent with activation of alpha1-adrenoceptors in vas deferens from both control and treated rats. The pA2 values estimated for WB 4101 ( approximately 9.5), benoxathian ( approximately 9.7), 5-methylurapidil (approximately 8.5), indoramin ( approximately 8.7) and BMY 7378 ( approximately 6.8) indicate that alpha1A-adrenoceptors are involved in the contractions of the vas deferens from control and cyproterone acetate-treated rats. Treatment of the vas deferens from control rats with the alpha1B/alpha1D-adrenoceptor alkylating agent chloroethylclonidine had no effect on noradrenaline contractions, supporting the involvement of the alpha1A-subtype. However, this agent partially inhibited the contractions of vas deferens from cyproterone acetate-treated rats, suggesting involvement of multiple receptor subtypes. To further investigate this, the actions of WB 4101 and chloroethylclonidine were reevaluated in the vas deferens from rats treated with cyproterone acetate for 14 days. In these organs WB 4101 presented complex antagonism characterized by a Schild plot with a slope different from unity (0.65 0.05). After treatment with chloroethylclonidine, the complex antagonism presented by WB 4101 was converted into classical competitive antagonism, consistent with participation of alpha1A-adrenoceptors as well as alpha1B-adrenoceptors. These results suggest that cyproterone acetate induces plasticity in the alpha1-adrenoceptor subtypes involved in the contractions of the vas deferens.

P222 Effects of cyproterone acetate and medroxyprogesterone acetate on endometrial levels of IGF-IR and IGFBP-I in endometrial hyperplasia

P222 Effects of cyproterone acetate and medroxyprogesterone acetate on endometrial levels of IGF-IR and IGFBP-I in endometrial hyperplasia

Serumhormone vor und unter Therapie mit Cyproteronazetat und Spironolacton bei Patientinnen mit Androgenisierungserscheinungen

The effect of cyproterone acetate (CPA) and spironolactone (SPL) on the serum androgen concentrations of premenopausal women with symptoms of hyperandrogenism were investigated in a total of 39 women. The observation period was 12 months. CPA was administered according to the Hammerstein regimen: cyproterone acetate (CPA) [Androcur] 100 mg/die 5.-14. day of the cycle; ethinylestradiol (EE) [Progynon C]: 40 mg/die 5.-25. day of the cycle; Spironolactone (SPL) was given in a dosage of 100 mg/die from day 1.-21. of the cycle. During the therapy with CPA a significant decrease of total testosterone (61%), free testosterone (78%), LH (48%) and 17 alpha-Hydroxyprogesterone (72%) was observed; during the medication with spironolacton only a significant decrease of 5 alpha-dihydrotestosterone (81%), which could not be seen during CPA use, was observed. Serum concentrations of total testosterone, free testosterone, LH and 17 alpha-Hydroxyprogesterone remained unchanged. DHA and DHAS did not change during neither medication. Since peripheral androgens were not suppressed by SPL the positive therapeutical effect of SPL can be explained by the antiandrogenic effect at the level of the receptor. A disadvantage of spironolacton is the lack of contraceptive efficacy. In cases where contraindication for oral contraceptives are present SPL can be considered as a good alternative to CPA. The suppressive effect of CPA/EE on total testosterone, LH addition to the antivulatory effect makes it the preferable medication for hyperandrogenemic patients with polycystic changes of the ovaries (PCOD).

Cyproterone acetate–-mechanism of action and clinical effectiveness in prostate cancer treatment

Endocrine treatment of prostate cancer is palliative in nature. Only very rare instances of complete disappearance of prostate cancer due to endocrine management have been reported; even evidence for prolongation of life because of endocrine management is scarce. There is no randomized trial available in the literature that gives a conclusive answer to this question. The best evidence for the effectiveness of endocrine management is indirect and is derived from differences in time to progression, survival corrected for cancer death, and overall survival between treatment arms of some of the trials reported in the literat~re.'-~ As with any other type of palliative management of human disease, the issue of side effects is particularly sensitive if a cure is not an option. The effectiveness of cyproterone acetate (CPA) is well established in monotherapy in comparison to standard forms of treatment.'f4 The available informa tion has been summarized recently by Goldenberg et al.' The side effects of CPA have been studied carefully within prospective randomized and phase I1 studies and have been found to be infrequent and acceptable to patien ts. 'A The usefulness of CPA in the management of prostate cancer, especially in total androgen blockade regimens, recently has been challenged by findings in experimental systems that suggest that CPA is androgenic.',* Because of its proven effectiveness in monotherapy and because of its favorable side effect profile, CPA is used widely in many countries for the management of metastatic or locally extensive prostate

Effects of cyproterone acetate on sexual arousal patterns of pedophiles

The antiandrogen treatment of sexual offenders has been shown to reduce the recidivism rate. The mechanism of action has been assumed to be through asexualization with its secondary effects on sexual behavior. This study shows that the mechanism may be more complex and may involve a differential effect on sexual arousal patterns. Treatment responses may differ in high and low plasma testosterone groups.

Effect of cyproterone acetate on structure and function of rhesus monkey reproductive organs

A low dose of Cyproterone acetate (CPA; 1 mg/kg body weight/day for 70 days) was administered to adult male rhesus monkeys to assess its effects on testicular and epididymal structure and function in a nonhuman primate species. CPA caused extensive degenerative changes in morphology of seminiferous, efferent duct, and epididymal epithelia, including decrease in diameter of seminiferous and epididymal tubules and their lumen, height of epididymal epithelium, and an increase in intertubular connective tissue. The protein profile of spermatozoa showed alterations during their epididymal transit in control and CPA-treated monkeys. In CPA-treated animals, 19 polypeptides were acquired and nine were eliminated during epididymal transit in contrast to acquisition of 12 and loss of 14 polypeptides in control animals. Treatment with CPA also resulted in the appearance of 14 new polypeptides in epididymal cytosol and luminal fluid, probably of lysosomal origin. The protein pattern of caput and cauda epididymal tubule cytosol, maintained in organ culture and exposed to 100 microM CPA for 3 days, showed absence of eight polypeptides. These results indicate that even at the low dose used in this study, CPA has caused spermatogenic arrest, degenerative changes in the epididymal structure, and alterations in epididymal and sperm protein profile. Suppression of serum testosterone levels indicates the need for androgen supplementation if CPA is to be used for male contraception.

Androgens and androgen-receptors in prostate tissue from patients with benign prostatic hyperplasia: Effects of cyproterone acetate

Testosterone, 5α-dihydrotestosterone and cyproterone acetate (CPA)_were estimated in samples of prostate tissue, obtained from benign prostatic hyperplasia (BPH) patients who were or were not pretreated with CPA. Furthermore, these steroids were estimated in various fractions of the BPH tissue, and the number of nuclear androgen-receptor sites was determined. CPA-treatment caused a 4-fold, significant suppression of 5α-dihydrotestosterone levels in total prostate tissue and its subfractions, without affecting testosterone levels or the androgen-receptor contents of the nuclear extracts. Nuclear concentrations of CPA were twice as high as those of 5α-dihydrotestosterone. It is conclude that effects of CPA may have been caused through a combination of the following mechanisms: (1) suppression of peripheral androgen levels: (2) competition with androgens for (nuclear) androgen-receptors; and (3) suppression of prostatic 5α-reductase.

The effects of cyproterone acetate on sleeping and waking penile erections in pedophiles: possible implications for treatment.

This study reports the short term effects in five pedophiles of the antiandrogenic drug cyproterone acetate (CPA) on nocturnal penile tumescence (NPT); penile responses to erotic stimuli in the laboratory; and sex hormones (testosterone, LH, FSH and prolactin). During the administration of CPA, NPT, laboratory arousal and hormone measures (except prolactin) all decreased. Waking laboratory measures were influenced less and were more variable (one subject showed greater arousal) than NPT measures. The changes in NPT closely paralleled the reduction in testosterone. The results are discussed with reference to the known psycho-neuroendocrinology of sleeping and waking erections.

Effects of cyproterone acetate on testicular and plasma androgen levels in the frog, Rana esculenta

The effects of an androgen antagonist, cyproterone acetate (CPA) on androgen production, was studied in intact and hypophysectomized (PDX) frogs,Rana esculenta. CPA, by competition with androgens for the same receptor sites, causes a decrease of androgen production both in plasma and in testis. These findings confirm the positive feedback exerted by testicular androgens either through the pituitary or at testicular level. Therefore in ranid species the regulation of testicular androgen production appears to be different from that of mammals.

Sex Difference in Triglyceride/Fatty Acid Substrate Cycling of Rat Adipose Tissue: Indirect Regulation by Androgens

Male Sprague-Dawley rats displayed significantly higher rates of triglyceride/fatty acid (TG/FFA) substrate cycling in subcutaneous, perigenital, and mesenteric white adipose tissue, compared to females. To investigate possible regulation via androgens and estrogens, male rats were treated with the androgen antagonist, cyproterone acetate (10 mg daily in subcutaneous injections), or estradiol polyphosphate (0.3 mg intramuscularly, given as a single dose). Estradiol treatment did not affect TG/FFA cycling. Treatment with cyproterone acetate significantly decreased TG/FFA cycling in perigenital (epididymal) tissue. This effect could however largely be ascribed to concomitant inhibition of food intake by cyproterone acetate. The effects of cyproterone acetate on the two axes of TG/FFA cycling (lipolysis and re-esterification) were further studied in vitro. Norepinephrine-stimulated glycerol release from perigenital adipocytes was inhibited, whereas activities of esterification enzymes (GPAT and PPH) was essentially unaffected. We conclude that androgens seem to affect TG/FFA cycling indirectly via the lipolytic axis.

Effect of Cyproterone Acetate on Active and Inactive Renin Secretion in Patients with Precocious Puberty and Genetic Short Stature

To evaluate the effect of cyproterone acetate (CA) on the renin-angiotensin-aldosterone axis, we measured the plasma active, inactive and total renin concentrations (PARC, PIRC and PTRC) during and after CA treatment in patients with precocious puberty and genetic short stature. CA was administered at a daily dose of 150-170 mg/m2 in all subjects. PARC and PTRC were measured by immunoradiometric assays. During CA treatment, PARC, PIRC, PTRC and the PARC/PTRC ratio were significantly decreased. The plasma renin activity, measured by enzymatic assay, and the plasma aldosterone concentration were also decreased. After CA discontinuation, all of these were increased immediately along normal ranges. PARC closely correlated with plasma renin activity. These results suggest that CA produces mineralocorticoid action and suppresses the production and activation of renin.