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.     

Antiandrogen withdrawal syndrome with cyproterone acetate

OBJECTIVES: To determine whether the antiandrogen withdrawal syndrome occurs with the steroidal antiandrogen cyproterone acetate. METHODS: Cyproterone acetate was withheld in 12 patients with progressing androgen-independent metastatic prostate cancer. Eight patients had been receiving cyproterone acetate concomitant with androgen ablation, and in 4 patients it was prescribed after failure of androgen suppression. Time to response and to disease progression were defined by serum prostate-specific antigen (PSA) levels and imaging studies. RESULTS: PSA levels decreased in 5 of the 1 2 patients; in 4 of them (33%), the decrease exceeded 50%. The decline lasted a median of 24 weeks (range 9 to 37.8). All 5 patients had received initial concomitant exposure to androgen ablation and cyproterone acetate. CONCLUSIONS: We recommend that the steroidal antiandrogen cyproterone acetate be added to the list of agents capable of inducing antiandrogen withdrawal syndrome.     

Bioavailability and pharmacokinetics of cyproterone acetate after oral administration of 2.0 mg cyproterone acetate in combination with 50 micrograms ethinyloestradiol to 6 young women

The bioavailability and pharmokinetics of cyproterone acetate (CA) were studied in 6 healthy young women. The subjects received a single oral dose of 2 mg carbon-14-CA plus 50 mcg tritiated-ethinyl estradiol. Matimum plasma levels of CA were observed about 4 hours after administration. During the 4-10 hours following administration, carbon-14-CA in plasma disappeared with a half-life of 3 + or -1.6 hours. The half-life for the subsequent phase of disposition was 1.7 + or -.5 days. The apparent volume of distribution for CA was 1300 + or -580 liters. Although plasma equivalents of carbon-14-CA had higher absolute values, the course of their distribution was similar to those concentrations for the unchanged drug. 88 + or -11% of the dose was recovered and 30.4 + or -7.3 excreted in urine. The concentration of the primary metabolite of CA in plasma showed a decline which paralleled the terminal disposition phase of CA; the elmination half-life being 1.8 + or -.1 days. The apparent distribution volume for the primary metabolite was 95 + or -25 liters. CA, in comparison with its primary metabolite, had 10 times the apparent distribution volume. Approximately 90% of CA was present at all times following administration. In terms of total activity, the proportion of CA in plasma remained constant 1/2 day after administration. It is suggested that the transfer of CA from tissues determines the rate of metabolization of CA and the excretion of metabolites.     

Effects of cyproterone acetate on reproductive functions in normal human males

The effects of cyproterone acetate (CA) on reproductive functions in normal human males were studied. 6 volunteers received 5 or 10 mg CA over a 20-week period. The treatment caused a gradual decrease in the number of spermatozoa and their motility, and an increase in the percentage of nonmotile, abnormal, and immature sperms. There was also a marked inhibition of sperm transport of motile sperm through cervical mucus, as determined by Kremer's test. Semen levels of acid phosphatase, sialic acid, and glycerylphosphorylcholine progressively decreased, though semen levels of fructose were not markedly altered. There were no marked changes in levels of SGOT, SGPT, serum alkaline phosphatase, blood urea, and hematocrit values. The possible mode of action of CA and its potential as a male contraceptive agent are discussed.     

Low dose of cyproterone acetate and testosterone enanthate for contraception in men

After a control phase, 10 normal men received cyproterone acetate (CPA) at a dose of 25 mg/day (CPA-25; n=5) or 12.5 mg/day (CPA-12.5; n=5) plus testosterone enanthate (TE) 100 mg/week, for 16 weeks. Throughout the study sperm counts were performed every 2 weeks, and luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, biochemical and haematological tests were performed every 4 weeks. All five men in group CPA-25 and three men in group CPA-12.5 achieved azoospermia. One man in group CPA-25 was azoospermic by week 12 of hormone administration, but had a sperm count of 0.1 x 10(6)/ml at week 16. Time to azoospermia was 9.0+/-1.3 and 8.7+/-0.7 weeks in groups CPA-25 and CPA-12.5 respectively. Gonadotrophins were decreased by week 4 of hormone administration, remained around the minimum detectability of the assay for the duration of hormone administration and returned to baseline after stopping hormone administration. Testosterone values did not change. No change in any biochemical parameters was found. Haematological parameters were decreased at week 16 of hormone administration and returned to baseline after stopping hormone administration. In conclusion, these results suggest that an hormonal regimen consisting of testosterone plus a progestin with anti-androgenic properties holds promise as an effective, safe and reversible male contraceptive.     

Dosing-induced stress causes hepatocyte apoptosis in rats primed by the rodent nongenotoxic hepatocarcinogen cyproterone acetate

It has been proposed that several nongenotoxic compounds act as hepatocarcinogens by suppressing the apoptosis that would normally act to remove damaged or potentially initiated cells from the liver. During our investigations of this hypothesis using a widely applied protocol, we have found that the stress induced by the process of gavage dosing can induce massive apoptosis in livers uniquely primed by withdrawal of the hepatomitogen cyproterone acetate from the hyperplastic rat liver. This effect of gavage dosing was not seen in livers of naive animals. Apoptosis was measured by both in situ end labeling (ISEL) of the DNA damage associated with programmed cell death and conventional hematoxylin and eosin (H&E) staining of apoptotic morphology. Apoptotic rates measured by H&E increased significantly from 0.005 +/- 0.010% on Day 11 to 0.657 +/- 0.315% of hepatocytes on Day 15, 4 days after cessation of 10 days dosing with CPA (120 mg/kg). The readministration of CPA suppressed > 89% of this Day 15 apoptosis. However, the readministration of vehicle alone (corn oil) caused a 390% increase in apoptosis to 2.56 +/- 1.31% of hepatocytes. Similar results were obtained using ISEL. Measurements of liver to body weight ratios and total DNA per liver reflected these changes in cell loss by apoptosis. In a second experiment, CPA was administered for 10 days as before then animals were subjected to readministration of CPA in corn oil, CPA in saline, corn oil, saline, or sham dosed. Again, apoptosis was dramatically suppressed by the readministration of CPA in either vehicle but was dramatically increased to around 2% of hepatocytes in all other groups, including the sham dosed group. Data on food consumption provided no evidence for a reduction in food intake as a causative agent but rather pointed to a less efficient usage of food in the stressed animals. The ability of stress to induce liver apoptosis should be borne in mind in the design and interpretation of future toxicological studies aimed at understanding the putative suppression of apoptosis by liver nongenotoxic carcinogens and other toxicants.     

Release of microquantities of cyproterone acetate from subcutaneous silastic capsules: failure to produce an antifertility effect

Plasma testosterone profiles were determined by taking frequent blood samples at intervals from birth to 21 months of age from rams reared in isolation, in an all-male group and in a mixed-sex group. The testosterone pattern was not modified by these different social environments. The ability of the ram to copulate when first exposed to an oestrous ewe, apparently a maturational process, was also independent of social rearing. At birth plasma testosterone levels were detectable but low, they were higher at 10 and 16 weeks of age and showed a marked rise by 26 weeks, coincident with the time of puberty. Depressive effects of season on testosterone profiles occurred during the 2nd year of life but not the 1st year.     

Formation of DNA adducts by cyproterone acetate and some structural analogues in primary cultures of human hepatocytes

To compare inductively coupled plasma mass spectrometry (ICP-MS) and graphite furnace atomic absorption spectometry (GF-AAS) as the method for determining lead and cadmium in the human diet and blood, 418 diet homogenate samples and the same number of blood samples were collected from Chinese and Japanese women and were analyzed by the two methods. The results showed that our ICP-MS method is precise and accurate, being comparable to the GF-AAS method established previously. The ICP-MS method is simple and fast spending only one-tenth of the time necessary for GF-AAS and allows simultaneous analyses of lead and cadmium with low detection limits. When applied to actual sample analysis, however, ICP-MS results tend to be 10-20% lower than GF-AAS results in the analysis of lead in the diet and blood and cadmium in blood. This is possibly due to some interference in ICP-MS and matrix of samples. As the ICP-MS results could be mathematically corrected to be equivalent to the GF-AAS results, we conclude that this ICP-MS method can be used as a routine analytical method for the determination of lead and cadmium in human diet and blood samples.     

Endometrial effects during hormone replacement therapy with a sequential oestradiol valerate/cyproterone acetate preparation

Different stages of thymus morphogenesis and thymocyte differentiation have been studied at the ultrastructural level in the lizard, Chalcides ocellatus. On stage 36 of embryonic development, the thymus primordium was composed principally of undifferentiated epithelial cells and some lymphoid stem-cells. From stage 37 to 38, the lymphoid stem-cells differentiate into lymphoblasts and then transform into typical lymphocytes. A clasmotosis phenomenon seems to be involved in this transformation. In the developing cortical regions, lymphoblasts accumulated rapidly, stretching the epithelial cells which become stellate in shape. From stage 39 to 40, a phase of intense proliferation occurs and numerous lymphocytes die in the thymic tissue and are phagocytosed by macrophages. On stage 41, the presence of interdigitating cells in the medullary area completed cortico-medullary differentiation. On neonatal and juvenile lizards, small cortical thymocytes differentiated and the thymus possessed all characteristic of an adult thymus. Thus, at birth, the histogenesis of the lizard thymus was achieved and the only further modification consisted in a gain of weight.     

Effect of cyproterone acetate on the testis and epididymis of the lizard, Psammophilus dorsalis (gray)

The effect of cytproterone acetate (CPA) on the testis and epididymis of the lizard, Psammophilus dorsalis has been studied. Treatment with CPA affects spermatogensis and steroid metabolism in the testis. It also causes regression of the epididymis and a decrease in steroidogenic enzyme activity.     

Pharmacokinetics of cyproterone acetate in normal subjects after i.m. and oral application (author's transl)

Sixteen volunteers were given cyproterone acetate-2'-14C (6-chloro-17-hydroxy-1alpha,2alpha-methylene-pregna-4,6-diene-3,20-dione acetate; Androcur?) in single doses of between 2 and 12 mg i.m. and p.o. in 19 investigations. The plasma radioactivity was then determined at suitable intervals. Urine and faeces were collected quantitatively for 12 days. After oral administration the highest concentrations in plasma were found 1--4 h after administration. The mean amounts were 2--3% of the administered dose in the plasma volume. Plasma concentrations of more than half the highest values were measured for a period of 2--8 h. Cyproterone acetate was eliminated from the body with a half-life of about 1 1/2 days for men and about 2 days for women. After oral administration in single doses of 2--12 mg the compound was almost completely absorbed.     

Effects of cyproterone acetate on FSH and testosterone influenced spermatogenesis, steroidogenesis and epididymis in the Indian wall lizard, Hemidactylus flaviviridis (Ruppell)

The effects of FSH, testosterone and either cyproterone acetate (CPA) alone or in combination with FSH or testosterone on testis and epididymis in male lizards were studied histologically and histochemically during recrudescent phase to find out whether the onset of spermatogenesis is androgen dependent or FSH dependent. The testes of control lizards consisted of mainly spermatogonia, a few primary spermatocytes and secondary spermatocytes rarely. The interstitial or Leydig cells were atrophied. FSH treatment induced spermatogenic activity substantially as indicated by increase in number of primary and secondary spermatocytes and transformation of secondary spermatocytes into spermatids and into spermatozoa in a few cases. Besides, steroidogenic activity was also remarkably stimulated as evidences by considerable depletion of sudanophilic lipid and an increase in Delta5-3beta-hydroxysteroid dehydrogenase enzyme activity in Leydig cells. However, testosterone treatment resulted in the inhibition of spermatogenesis. A significant inhibition of spermatogenesis was noted in lizards treated either with CPA alone or in combination with FSH. The inhibitory effect of CPA on spermatogenesis was increased when it was given in combination with testosterone. The results indicate that onset of spermatogenic activity is dependent on FSH (or FSH-like protein), but not on the androgen. The ductus epididymidis in control lizards was regressed with low cuboidal epithelium. The lumen of the tubules was totally devoid of secretory material and spermatozoa. FSH treatment induced a marked hypertrophy in epididymidis. The lumen became filled with secretory material mixed with spermatozoa. The hypertrophy in epididymidis was also recorded after the treatment with testosterone, but the degree of induction was not to that extent as noted in FSH treated ones. However, CPA injected either with FSH or with testosterone resulted in the profound atrophy in epididymidis.     

Serum concentrations of type I and III procollagen propeptides in healthy children and girls with central precocious puberty during treatment with gonadotropin-releasing hormone analog and cyproterone acetate

Serum levels of type I and III procollagen propeptides (s-PICP and s-PIIINP) were measured in 466 healthy school children and in 23 girls with central precocious puberty (CPP) during GnRH analog and cyproterone acetate therapy, using two commercially available RIAs. In normal children, s-PICP and s-PIIINP changed significantly with age and pubertal development stages. For s-PIIINP, a peak was seen at 12 yr for girls and 13 yr for boys; no peak could be discerned for s-PICP. The prepubertal (Tanner stage 1) s-PICP value (mean +/- SD) for girls was 374 +/- 132 micrograms/L, the midpubertal value (stage 3) was 442 +/- 135 micrograms/L, and the postpubertal value (stage 5) was 203 +/- 103 micrograms/L. The mean s-PIIINP levels for girls were 9.1 +/- 2.4, 15.0 +/- 4.3, and 6.8 +/- 3.1 micrograms/L, respectively. For boys, levels were 362 +/- 119, 544 +/- 138, and 359 +/- 256 micrograms/L for s-PICP and 8.5 +/- 2.2, 14.5 +/- 5.0, and 8.6 +/- 3.8 micrograms/L for s-PIIINP (P < 0.001 for both propeptides in both boys and girls). There was, however, a large variation in normal values for both propeptides within the age groups and pubertal stages. There was a significant correlation of s-PICP and s-PIIINP levels to height velocity in girls (r = 0.35; P < 0.001 and r = 0.33; P < 0.001, respectively), while in boys, only s-PIIINP showed significant correlation to height velocity (r = 0.40; P < 0.001). In untreated girls with CPP, serum levels of s-PIIINP were elevated [PIIINP SD score (SDS), 2.13]. Levels of s-PICP were normal (PICP SDS, 0.39). Levels of both propeptides decreased within 2 months after initiation of therapy and remained below initial values (P < 0.01). The decrease in s-PIIINP after 2 months of therapy showed a significant correlation with the fall in height velocity SDS for chronological age after 6 months of therapy (r = 0.64; P < 0.01). We conclude that s-PIIINP and, to a lesser degree, s-PICP reflect growth in normal children, but due to the large variation, both propeptides seem unsuitable as markers for screening of growth disorders in children.     

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

This study examined how cyclophosphamide (CP)-induced cystitis related manifestations (bladder inflammation and behavioral impairment) differed in female and male Sprague-Dawley rats. Under transient halothane-O2-N2O gas anesthesia, a single dose of CP was injected (100 mg/kg i.p. in 1 ml saline) and the animal's behaviors analyzed for a period of 4 h using a protocol that permits quantitative analysis of behavioral impairment. The rats were then sacrificed and their bladders removed for histological quantification of inflammation. All CP-injected, but not control rats, exhibited a range of impairment behaviors that increased rapidly over a period of 2 h, gradually reaching plateau levels over the next 2 h. Female rats initially developed behavioral responses faster than male rats, but reached the same mean peak values overall as males. No sex differences were observed in CP-induced bladder inflammation. Influences of time-of-day and estrous stage were further examined in females. Time-of-day had no effect on the degree of bladder inflammation. Although there were also no significant time-of-day differences in behavioral impairments, impairment scores from 90 min after the injection consistently tended to be lower for rats injected 5 h versus 9 h after lights on. Overall, the effects of estrous stage were also insignificant. However, a subset of rats who were in the estrous stage of their cycle early in the morning of the experimental day developed the most severe degree of bladder inflammation, but failed to develop the severe behavioral impairments shown by all the other rats. These results show that there are seemingly only minor sex differences in the overall behavioral and inflammatory consequences of CP injections, as evidenced by similar final degrees of behavioral impairment and inflammation. These results also suggest, however, that there are sex differences in the etiology of the disease process. These differences are evidenced by the more rapid development of behavioral symptoms in females and the susceptibility of some of those having shown morning estrous smears to develop very severe bladder inflammation in absence of corresponding behavioral impairment. The multiple influences of sex and estrous condition on CP-induced cystitis related manifestations observed here underline the complexity of the etiological factors associated with the cystitis disease process.     

转炉炉壳热应力分析

根据实际转炉建立实体模型。以有限元为手段,考虑了炉衬和炉壳材料的物性参数随温度变化的特点和炉衬与炉壳之间膨胀间隙,计算了转炉炉壳在温度载荷和炉衬膨胀压力同时作用下的热应力。所得结果可为转炉炉壳设计提供依据。     

焦炭热性能指标意义浅析

通过对焦炭在高炉内的历程及其变化规律的剖析,阐述焦炭热性能指标的意义,形象地把焦炭在高炉内的损耗分为三部分(M1,M2,M3)。指出M2对焦比及焦炭价格有一定的指导作用。     

Results of treatment of cancer of the cardia

Cancer of the cardia is traditionally discussed with cardiac cancer of the lower portion of the esophagus and upper gastric cancer invading the esophagus, and the specific characteristics of cancer of the cardia have never been clearly defined. We reviewed the outcome of 172 patients with adenocarcinoma of the cardia who had undergone radical surgery between 1949 and 1994 in the Division of Gastrointestinal Surgery of the Cancer Institute Hospital. The centers of the tumors were located within 2 cm above and below the boundary between the esophagus and the stomach, and their longitudinal diameter was less than 8 cm. We divided the patients into an early period (1949-1979; n = 79) and a late period (1980-1994; n = 93), and focused on the historical transition. There were no differences in patient gender or histology between the two periods. However, the late period was associated with fewer cases of esophageal invasion and shorter longitudinal diameter, as the age of the population advanced. The number of advanced cancers such as the localized and infiltrative type had decreased, and early cancer and early clinical stage had become more common, but despite the fact that the number of early cancers had increased, extended dissection, such as thoracic and paraaortic lymph node dissection, was performed more frequently. By clinical stage, the long-term outcome markedly improved in Stage I patient in the late period, and tended to improve in Stage II and III patients. This appears to have been attributable to the prevention of micrometastasis by extended dissection, although the number of early cancers is another major potential cause. There were no differences in the outcome of Stage IV patients between the two periods, and further advances in multimodality therapy must be awaited. The range of resection is basically proximal gastrectomy, and if there are adequate indications, the prognosis is favorable. In view of the status of lymphatic flow and lymph node metastasis, and long-term results, lateroaortic lymph node dissection is important. Since the number of early cancer patients has been increasing, if intraabdominal recurrence is prevented, intrathoracic lymph node dissection will contribute greatly to the outcome of such patients.     

The effect of amount of possession of the trait of hostility on accuracy of perception of hostility in others.

Some theories of personality hold that an individual's perception of others is influenced by his own personality characteristics; more specifically, that a trait of low social value will be projected more into others, and that insight into the possession of these characteristics reduces this distortion. These 2 hypotheses were tested by having a group of college students rate each other (including themselves) on degree of friendliness or hostility. Agreement with group rating about self yielded the insight score. In general, the hypotheses were supported; the "friendly" Ss were most accurate in their perception of others, and insight was positively associated with accurate perception. From Psyc Abstracts 36:04:4HL16M. (PsycINFO Database Record (c) 2010 APA, all rights reserved)