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PubMed1995

DNA-damaging activity of the cyproterone acetate analogues chlormadinone acetate and megestrol acetate in rat liver.

The synthetic progestin cyproterone acetate (CPA) has been recently shown to elicit DNA repair synthesis in cultured rat hepatocytes and to form adducts with rat hepatocyte DNA in vitro and in vivo. In the present study we have examined the genotoxic potential of the structural analogues of CPA, chlormadinone acetate (CMA) and megestrol acetate (MGA) in rat liver cells. CPA strongly induced DNA repair synthesis in hepatocyte cultures from females but not from males. In contrast, CMA and MGA (2-50 microM) did not detectably increase repair synthesis in cultured hepatocytes from either gender. CMA and MGA, however, caused the formation of DNA adducts detectable by the 32P-postlabelling technique. At a concentration of 30 microM, between 30 and 50 adducts/10(9) nucleotides were found with MGA and CMA in cultured hepatocytes of female rats, and between 5 and 20 adducts/10(9) nucleotides were found in hepatocytes of males. By comparison, 30 microM CPA has been found to produce 1670 adducts/10(9) nucleotides in hepatocytes from female rats. CMA and MGA also induced low levels of DNA adducts in vivo. When female rats were treated with 100 mg/kg of CMA or MGA per os, the adduct levels were 2 and 19 adducts/10(9) nucleotides respectively. The results indicate that both CMA and MGA show some genotoxicity in rat liver cells, which is, however, much lower than that for CPA. Our findings further suggest that the high genotoxicity of CPA is associated with the presence of the 1,2 alpha-methylene group, which is absent in CMA and MGA.

Animals↗
PubMed1996

Cyproterone acetate is an integral part of hepatic DNA adducts induced by this steroidal drug.

We have recently shown that cyproterone acetate (CPA), an active component of some antiandrogenic drugs, induces the formation of DNA adducts detectable by the 32P-DNA postlabelling technique in rat liver. The postlabelling technique, however, does not provide evidence for the chemical nature of the adducts observed. To ascertain whether the CPA-induced adducts do contain CPA, we have incubated tritiated CPA with cultured hepatocytes from female rats, digested the DNA to 3'-monophosphonucleosides, extracted the DNA adducts formed into butanol and phosphorylated the adducts in the extract with unlabelled ATP. One major and one minor 3H-labelled adduct spot were detectable on the TLC chromatograms. The spots appeared at positions identical to those observed in the 32P-postlabelling experiments with unlabelled CPA. Furthermore, the ratio of 3H activity for the major versus the minor adduct spot was 11.9 +/- 1.8, which agreed with the corresponding ratio for the 32P activities, which was 13.2 +/- 3.5. These findings indicate that the CPA-induced DNA adducts, which we have previously detected by 32P-postlabelling do contain CPA or CPA metabolites.

Androgen Antagonists↗
PubMed1996

Time-related induction of DNA repair synthesis in rat hepatocytes following in vivo treatment with cyproterone acetate.

Cyproterone acetate (CPA), a synthetic steroid hormone widely used as a human pharmaceutical, has recently been shown to induce unscheduled DNA synthesis (UDS) in vitro in primary cultures of rat and human hepatocytes. In the present study CPA was evaluated for its ability to initiate UDS in the liver of female rats in vivo by means of the in vivo/in vitro hepatocyte DNA repair test. Using the standard sampling time of 16 h after single oral dosing, a dose-related UDS response at >50 mg CPA/kg body wt was observed. In order to examine the time course of CPA-induced UDS, different sampling times (4, 16, 48, 72, 96 and 144 h) after a single oral administration of 100 mg CPA/kg body wt were used. Whereas no UDS was induced in liver cells isolated 4 h after treatment, continuous DNA repair activity was observed after 16 h, with a maximum effect of approximately 10 net nuclear grains on day 4 after dosing. After a post-application period of 6 days the net grain counts returned to near control level. In contrast to the data with CPA, DNA damage induced by the positive control compound 2-acetylaminofluorene was removed much faster, within 2 days after administration. The time course of UDS activity during the first 4 days after administration of CPA parallels the previously reported time course of DNA adduct formation. However, a subsequent decrease and final cessation of UDS on day 6 takes place, although significant levels of CPA-DNA adducts have been reported to occur at that time point in rat liver cells. Whereas the time-related onset of UDS is suggested to reflect the pharmacokinetics of the activation of CPA to DNA-reactive intermediates, it remains unclear why the excision repair of DNA adducts did not continue. In addition to DNA repair synthesis, CPA was also shown to clearly increase the incidence of S phase cells under the test conditions applied, confirming the known mitogenic potential of CPA in rat liver.

Androgen Antagonists↗
PubMed1996

Induction of micronuclei and initiation of enzyme-altered foci in the liver of female rats treated with cyproterone acetate, chlormadinone acetate, or megestrol acetate.

The synthetic anti-androgen and progestin cyproterone acetate (CPA), recently found to be genotoxic for the liver, and two structurally similar progestins, chlormadinone acetate (CMA) and megestrol acetate (MGA), have been compared for clastogenic and tumor-initiating activities in female rats. In the micronucleus assay, carried out in rats given a single p.o. dose of 100 mg/kg, CPA induced the maximum increase in the frequency of micronucleated hepatocytes (6.6-fold as compared to controls) when treatment was performed 3 days before partial hepatectomy and cell sampling 2 days later. Under the same experimental conditions the clastogenic potencies of CMA and MGA were 69% and 36% of that of CPA respectively. In the liver foci assay, p.o. dosing with 100 mg/kg CPA once a week for 6 successive weeks induced, as compared to controls, a significant increase in the number and area of gamma-glutamyltranspeptidase-positive foci. At the same dosage schedule the tumor-initiating activity of CMA and MGA was 7- to 10-fold lower than that of CPA. These findings suggest that the 1,2 alpha-methylene group, present in CPA but absent in both CMA and MGA, favours the activation to a reactive species and/or hinders the biotransformation to non-toxic metabolites.

2-Acetylaminofluorene↗
PubMed1996

Comparative study of DNA repair induced by cyproterone acetate, chlormadinone acetate and megestrol acetate in primary cultures of human and rat hepatocytes.

Cyproterone acetate (CPA), a synthetic progestin recently found to induce genotoxic effects in hepatocytes from female rats and from humans of both genders, and two structural analogues, chlormadinone acetate (CMA) and megestrol acetate (MGA), have been compared for their capacity to induce DNA repair synthesis as measured by quantitative autoradiography. Exposure of primary human hepatocytes for 20 h to concentrations of CPA, CMA and MGA ranging from 2 to 50 microM induced positive responses in cultures from donors of both genders and the amounts of DNA repair elicited by the three progestins were similar. Under the same experimental conditions substantial differences were observed in the amounts of DNA repair elicited by the three progestins in primary hepatocytes from female rats, their potency decreasing in the following order CPA > CMA > MGA, and the three compounds failed to induce DNA repair in hepatocytes from male rats. These results, which agree with previous findings, suggest that for these sex steroids extrapolation to humans of results obtained in rats might be questionable.

Animals↗
PubMed1996

Carcinogenicity of cyproterone acetate in the mouse.

The synthetic progestin cyproterone acetate (CPA) has been shown to be a hepatocarcinogen in the rat, but little is known of its effects in mice. A 52 week CPA study in the mouse strain C57Bl/10J has been reported not to produce liver tumours, although CPA induced significant liver enlargement and induction of the mixed function oxidase CYP3A. The present study is a further investigation of the effects of CPA in mice of the C57Bl/10J strain dosed for 104 weeks. A group of 40 mice/sex were fed 800 p.p.m. CPA in the diet for 104 weeks with a control group of eight/sex. Mortality was high in females after 40 weeks due to hormonal effects in the uterus; no female and only four CPA-dosed males survived to 104 weeks. Liver cell hypertrophy with increased fat and glycogen and single cell or small multifocal areas of hepatocellular necrosis were universal. Proliferating cell nuclear antigen demonstrated an increase in proliferating cells within tumours and within the non-tumour bearing liver of CPA-dosed mice compared with normal livers of control mice. Hepatocellular tumours developed in 44% of males and 22% of females dosed with CPA, compared with none in the controls (the strain has a low, <10%, incidence of spontaneous liver tumours compared with other mouse strains). In addition, over 85% of both sexes dosed with CPA developed adenomatous polyps of the pyloric antrum and pancreatic islet cell hyperplasia, shown by immunostaining to be chiefly of insulin-secreting cells. Adrenocortical atrophy was also observed with other widespread effects in the endocrine system. The results suggest that the liver tumours, as in the rat, are likely to be related to effects on liver growth and mitogenesis. It is suggested that the tumours of the stomach and the pancreatic islet cell hyperplasia are manifestations of the effects of CPA in the endocrine system.

Adenomatous Polyps↗
PubMed1998

The DNA damaging drug cyproterone acetate causes gene mutations and induces glutathione-S-transferase P in the liver of female Big Blue transgenic F344 rats.

The gestagenic and antiandrogenic drug cyproterone acetate (CPA) is mitogenic, tumorigenic and induces DNA-adducts and DNA-repair synthesis in rat liver. Thus CPA is expected to be mutagenic. However in vitro mutagenicity test systems were negative. To examine whether CPA induces mutations in rat liver, the in vivo mutation assay based on Big Blue transgenic F344 rats was employed. Single oral doses of 25, 50, 75, 100 and 200 mg CPA/kg b.w. respectively were administered to female Big Blue rats. Six weeks after treatment, liver DNA was assayed for mutations. At the highest dose, 200 mg CPA/kg b.w., the frequency of (17 +/- 4) x 10(-6) spontaneous mutations was increased to a maximum of (80 +/- 8) x 10(-6) mutations. One-hundred and 75 mg CPA/kg b.w. resulted in mutation frequencies of (35 +/- 5) and (27 +/- 5) x 10(-6), respectively. The mutation frequency at doses of 50 and 25 mg CPA/kg b.w. was similar to that of vehicle treated controls. Statistical analysis of the dose-effect relationship revealed that it was not possible to decide whether a threshold dose exists or not. DNA adducts were analyzed by the 32P-postlabelling technique. The total level of the major and the two minor adducts observed in the autoradiograms increased between doses of 25 to 75 mg CPA/kg b.w. to a maximum of approximately 12,000 +/- 3000 adducts per 10(9) nucleotides. The level did not further increase significantly with 100 and 200 mg CPA/kg b.w. After CPA treatment no preneoplastic liver foci were observed. However, single glutathione-S-transferase placental form (GST-P) positive hepatocytes were observed and the frequency was dependent on the dose. These cells are not supposed to represent initiated cells, since they occurred only transiently after 6 weeks and disappeared thereafter completely. In conclusion, our results demonstrate that CPA is mutagenic in vivo. The mutation frequency increased at high CPA doses, when the increase of the DNA adduct formation had already ceased. This suggests that the mitogenic activity of CPA is required to express the mutations.

Animals↗
PubMed1999

Sex-specific induction of apoptosis by cyproterone acetate in primary rat hepatocytes.

The synthetic steroid cyproterone acetate (CPA) has been reported to be hepatogenotoxic in female rats depending on sex-specific expression of a hydroxysteroid sulfotransferase (HST) which is involved in the bioactivation of CPA to reactive metabolites. In the present study the ability of CPA to initiate apoptosis in rat hepatocytes in vitro was investigated with respect to sex-specific effects and dependency on HST activity. Incubation of primary hepatocytes of female rats with CPA (0.1-30 microM) caused a strong increase in percent of cells undergoing apoptosis. The lowest concentration leading to apoptosis was 0.3 microM. In contrast, hepatocytes isolated from male rats showed a very weak response at high exposure to CPA (30 microM) only. Treatment with transforming growth factor-beta1 induced high levels of apoptotis in hepatocytes of both genders. Megestrol acetate and chlormadinone acetate, two structural analogues of CPA with a much lower genotoxic potency, did not induce apoptosis. Pre-addition of 10 or 50 microM dehydroepiandrosterone (DHEA), a known inhibitor of hepatic HST, almost completely inhibited CPA-induced apoptosis in hepatocytes of female rats. Using similar test concentrations, DHEA also reduced CPA-induced DNA excision repair as measured in the unscheduled DNA synthesis test. The results suggest that apoptosis induction is directly related to DNA damage induced by HST-dependent CPA metabolites.

Animals↗
PubMed1997

Clinical and hormonal effects of the combination gonadotrophin-releasing hormone agonist plus oral contraceptive pills containing ethinyl-oestradiol (EE) and cyproterone acetate (CPA) versus the EE-CPA pill alone on polycystic ovarian disease-related hyperandrogenisms.

The aim of this study was to compare the clinical and hormonal effects of the combination of a long-acting gonadotrophin-releasing hormone analogue (GnRH-a) plus an oral contraceptive (OC) pill containing ethinyl-oestradiol (EE) and cyproterone acetate (CPA) versus the EE-CPA pill alone in patients with polycystic ovarian disease (PCOD) and related hyperandrogenisms, in order to evaluate whether the addition of GnRH-a has any advantage. A total of 12 PCOD patients were treated with the EE-CPA pill alone for 10 consecutive cycles according to an OC standard regimen. A further 12 patients were treated with GnRH-a, one i.m. injection every 28 days for a total of eight injections, combined with the EE-CPA pill for 10 consecutive cycles. The latter was thus prolonged for two cycles more than GnRH-a. Clinical evaluations (symptoms, weight, Ferriman-Gallwey score) and hormonal and biochemical analyses were assessed before, during (at 3 or 6 months) and after treatment, either when spontaneous cycles had resumed or after 3 months of amenorrhoea. There was a significant improvement in hirsutism, and a strong reduction in gonadotrophin, oestradiol, testosterone, androstenedione and 17-OH-progesterone concentrations in both treatment groups but with no significant differences between them, except in the gonadotrophin concentrations. Cortisol and triglyceride concentrations increased during treatment in both groups. The Ferriman-Gallwey score remained significantly decreased in both groups after treatment, as did androstenedione in the GnRH-a plus EE-CPA pill group, but there were no significant differences between the two groups. No changes were observed in prolactin, dehydroepiandrosterone sulphate (DHEA-S), insulin, glycaemia and cholesterol concentrations. However, when only the obese and more hirsute patients were considered, significant differences between the two groups were found during treatment in the Ferriman-Gallwey score and the gonadotrophin and DHEA-S concentrations (which increased during treatment in obese patients with the pill alone), and after treatment in the Ferriman-Gallwey score and the concentration of 17-OH-progesterone in the more hirsute patients, with the GnRH-a plus pill group having better results. In conclusion, a cyclic prolonged treatment with OC EE-CPA pills is not improved in most PCOD patients by the addition of GnRH-a, and is complicated and expensive. However, the addition of a long-acting GnRH-a may be recommended in obese and severely hirsute patients.

Adolescent↗
PubMed1997

Gonadotrophin-releasing hormone agonist therapy for hirsutism is as effective as high dose cyproterone acetate but results in a longer remission.

Both cyproterone acetate (CPA) and the gonadotrophin-releasing hormone agonist (GnRHa) have been shown to be effective for the treatment of hirsutism. We wished to compare the effectiveness of CPA in two standard doses with GnRHa and add-back therapy and to compare the length of remission after these treatments. A total of 60 hirsute hyperandrogenic women was assigned to the following treatment groups: CPA 2 mg with 35 microg of ethinylestradiol for 21 days each month (Diane group), CPA 50 mg, days 5-15, and ethinylestradiol 50 microg, days 5-25, each month (CPA group) or Decapeptyl 3.75 mg i.m. every 28 days with the addition of conjugated oestrogen 0.625 mg, days 1-21, and medroxyprogesterone acetate 10 mg, days 12-21 (GnRHa group). Hirsutism was graded by the Ferriman-Gallwey-Lorenzo (FGL) index and anagen hair shaft diameters and serum luteinizing hormone (LH) and testosterone were assessed before and every 3 months during and after treatment. All women were treated for 1 year with 1 year follow-up. At baseline hirsutism and endocrine patterns were similar in all groups. After one year of treatment, hirsutism decreased in all groups but the changes were greater (P <0.05) in the CPA and GnRHa groups than in the Diane group. Serum LH and testosterone were lowest in the GnRHa group. After withdrawal, hirsutism increased rapidly in the Diane and CPA groups and after 6 months, FGL scores and hair shaft diameters were similar to pretreatment values. In the GnRHa group, hirsutism increased more gradually and after 1 year of withdrawal, FGL scores and hair diameters were significantly (P <0.05) less than pretreatment values. Serum LH and testosterone increased rapidly in all three groups reaching pretreatment values by 6 months. These data suggest equal efficacy of the GnRHa and the high dose CPA regimen for the treatment of hirsutism in hyperandrogenic women. GnRHa with add-back treatment appears to result in a longer remission of hirsutism in comparison with CPA.

Adult↗
PubMed2003

The risk of venous thromboembolism in women prescribed cyproterone acetate in combination with ethinyl estradiol: a nested cohort analysis and case-control study.

BACKGROUND: Cyproterone acetate combined with ethinyl estradiol (CPA/EE) is licensed in the UK for the treatment of women with acne and hirsutism and is also a treatment option for polycystic ovary syndrome (PCOS). Previous studies have demonstrated an increased risk of venous thromboembolism (VTE) associated with CPA/EE compared with conventional combined oral contraceptives (COCs). We believe the results of those studies may have been affected by residual confounding. METHODS: Using the General Practice Research Database we conducted a cohort analysis and case-control study nested within a population of women aged between 15 and 39 years with acne, hirsutism or PCOS to estimate the risk of VTE associated with CPA/EE. RESULTS: The age-adjusted incidence rate ratio for CPA/EE versus conventional COCs was 2.20 [95% confidence interval (CI) 1.35-3.58]. Using as the reference group women who were not using oral contraception, had no recent pregnancy or menopausal symptoms, the case-control analysis gave an adjusted odds ratio (OR(adj)) of 7.44 (95% CI 3.67-15.08) for CPA/EE use compared with an OR(adj) of 2.58 (95% CI 1.60-4.18) for use of conventional COCs. CONCLUSIONS: We have demonstrated an increased risk of VTE associated with the use of CPA/EE in women with acne, hirsutism or PCOS although residual confounding by indication cannot be excluded.

Acne Vulgaris↗
PubMed2002

Pathologic effects of neoadjuvant cyproterone acetate on nonneoplastic prostate, prostatic intraepithelial neoplasia, and adenocarcinoma: a detailed analysis of radical prostatectomy specimens from a randomized trial.

Neoadjuvant hormonal therapy (NHT; androgen ablation) is used prior to radical prostatectomy (RP) in an attempt to pathologically "downstage" prostatic adenocarcinoma and ultimately to improve disease-free survival. This study describes the pathologic effects of NHT with the antiandrogen cyproterone acetate, 300 mg/day for 12 weeks, on the RP specimens from men with clinically localized (stage T1 or T2) prostatic adenocarcinoma. There were 101 men in the pretreatment group (CPA) and 91 men in a control group who were treated with surgery alone. The prevalence and extent of morphologic effects were recorded for the nonneoplastic prostate, high-grade prostatic intraepithelial neoplasia, and invasive adenocarcinoma. The commonest effects on the nonneoplastic prostate were atrophy and basal cell hyperplasia and prominence. High-grade prostatic intraepithelial neoplasia was more commonly identified in the surgery alone group than the CPA group (p <0.01). In the CPA group, flat and low tufted patterns of high-grade prostatic intraepithelial neoplasia predominated. Following NHT, the adenocarcinoma showed characteristic morphologic alterations, including reduction in cytoplasmic quantity, cytoplasmic vacuolation, nuclear pyknosis, reduced gland diameter, and mucinous breakdown. In many cases there was prominence of collagenous stroma, obscuring malignant glands. Compared with the surgery alone group, the CPA group RP specimens had a significantly lower mean specimen weight (40.3 g vs 46.5 g, p = 0.025) and less tumor extent by several measures. Organ-confined tumor (stage pT2, margin negative) was found in 41.6% of the CPA group compared with 19.8% of the surgery alone group (p = 0.0017). The overall rate of margin positivity was lower in the CPA group (27.7% vs 64.8%, p = 0.001). We consider that the difference in margin positivity is the result of tumor shrinkage with a decreased likelihood of sampling in routine sections. There was no significant difference in the rate of extraprostatic extension between the two groups. There was elevation of the Gleason score in the RP specimens versus baseline biopsy in 60% of the CPA group compared with 33% of the surgery alone group (p = 0.02). The higher rate of elevation in the CPA group largely resulted from an increase in primary or secondary Gleason score 5 tumor, a morphologic artifact introduced by NHT. Because of this, we recommend not giving a Gleason grade to RP specimens following NHT. Monotherapy with CPA has similar pathologic effects on benign and malignant prostate tissue as does dual agent androgen blockade. Prolonged follow-up of these patients is required to determine if NHT with CPA leads to improved disease-free survival.

Adenocarcinoma↗
PubMed2005

Cyproterone acetate and ethinylestradiol-induced pill oesophagitis: a case report.

Although there are many cases of oesophagitis related to pill in medical literature, there are only a few reports concerning oesophagitis related to oral contraceptives, and none about cyproterone acetate and ethinylestradiol combination (Diane-35). In this report, we describe a female patient who suffered from odynophagia and retrosternal pain after taking Diane-35 for hirsutism. The endoscopic examination revealed two well-demarcated circumferential ulcers of 1 cm diameter surrounded by relatively normal mucosa in mid-oesophagus. The patient had gone to bed immediately after taking the pill. Oral intake was stopped, and intravenous fluids and omeprazole were administered as part of treatment. The patient benefited from this approach very quickly and was discharged from hospital in 5 days. The oesophagus was completely normal in control endoscopy after 2 months. Diane-35 should be added to the list of drugs causing pill oesophagitis, and physicians should inform the patients that the pills should be taken with enough water and they should not lie down right after ingesting the pills.

Adult↗
PubMedDate not supplied

The effect of cyproterone acetate on motor activity, aggression, "emotionality", body weight and testes in wild mice.

The literature reports on antiandrogenic and antigonadotropic effects of cyproterone acetate (CA) and on its inhibitory influence on the structure and function of the testis and reduction of the sexual drive in man and animals. No one has as yet been able to confirm a reduction of aggression which could be expected under CA. Isolated male wild mice received daily doses of 0.5 mg (17 mg/kg) CA subcutaneously over 32 days and were studied daily for aggressive behavior, motor activity and emotionality during the last 11 days. Aggression was reduced significantly by CA in the form of an increased latent time and continued to decrease during the test period with a reduction of fighting time and the correlated coarse motor activity. A latent period of approximately 4 weeks was determined for the aggression-inhibiting effect of CA. The detection rate was not changed under CA. It is doubted whether it is an adequate parameter of "emotionality". The overall motor activity was not reduced, so that an aggression-specific effect is assumed rather than a general reduction of drive. The body and testicular weight was reduced, the testicular tissue atrophies. Central points of attack of CA probably play a major role in the reduction of aggression.

Aggression↗
PubMedDate not supplied

The influence of human menopausal gonadotropin, natrium fluoride and cyproterone acetate on the spermatogenesis in immature rats.

Human menopausal gonadotropin (HMG), natrium fluoride (NaF) and cyproterone acetate (CYA) were applied to immature male rats between the 26th and 32nd day of life and histological examination was performed in testes of 33rd-day-old rats. HMG treatment alone slightly influenced the spermatid completion process, while NaF evidently increased frequency of occurrence of various seminiferous tubules containing spermatids. CYA alone damaged the spermatid completion process (especially the cap-phase of spermiogenesis), produced a degeneration of meiotic spermatocytes, and decreased the tubular diameter. Those changes were prevented by addition of HMG to the CYA treated animals. The results suggest a possible regulatory role of FSH at the end of the first meiosis, and, also, in the progression of spermiogenesis. The mechanism of action of NaF may be hypothetical, but it probably consists of direct action on the seminiferous epithelium level.

Animals↗
PubMedDate not supplied

Lactate dehydrogenase activity of the rat testis treated with cyproterone acetate during fetal life.

Histological changes, total LDH activity and LDH isozyme patterns of testicular tissues of rats, exposed to cyproterone acetate during fetal life, were studied at different days after birth. While such treated testes revealed all stages of spermatogenesis and normal patterns of LDH isozymes including LDH-X bands, complete loss of isozymes was discernible in the Leydig cell fraction. It is probable that this abnormality in the Leydig cell is a consequence of impairment in the hypothalamo-hypophyseal axis or due to improper scrotal development following CA exposure.

Age Factors↗
PubMedDate not supplied

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.

Cyproterone Acetate↗