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Spontaneous gonadotrophin pulsatility and ovarian morphology in girls with central precocious puberty treated with cyproterone acetate.

We have studied four girls with central precocious puberty treated with cyproterone acetate for a mean of 3.6 years (range 1.5-6.3 years). Pelvic ultrasound assessment demonstrated suppression of the ovarian morphology of central precocious puberty despite the presence of spontaneous pulsatile gonadotrophin secretion at night. We suggest that the previously reported effects on gonadotrophin secretion induced by cyproterone acetate therapy, administered in recommended doses, are minor and that the predominant effect of cyproterone acetate in the treatment of girls with central precocious puberty is direct inhibition of ovarian steroidogenesis.

Child↗

Effects of minoxidil 2% vs. cyproterone acetate treatment on female androgenetic alopecia: a controlled, 12-month randomized trial.

BACKGROUND: Hormone studies have demonstrated the androgen-dependent character of female androgenetic alopecia, but there have been few controlled studies of therapies for alopecia in women. OBJECTIVES: To compare topical minoxidil 2% and cyproterone acetate in the treatment of female alopecia. METHODS: Sixty-six women with female-pattern alopecia were randomly assigned for 12 cycles into two groups, 33 received two local applications (2 mL day-1) of topical minoxidil 2% plus combined oral contraceptive and 33 received cyproterone acetate 52 mg day-1 plus ethinyl oestradiol 35 microg for 20 of every 28 days. RESULTS: A mean reduction of 2.4 +/- 6.2 per 0.36 cm2 in hairs of diameter > 40 microm was observed in the cyproterone acetate group (P = 0.05) and a mean increase of 6.5 +/- 9 per 0.36 cm2 in the minoxidil group (P < 0.001). Comparison of the total number of hairs at 12 months and the body mass index (BMI) revealed a borderline positive correlation in the cyproterone acetate group (r = 0.39, P = 0.06) and a negative correlation in the minoxidil group (r = -0.42, P < 0.05). No significant difference was observed in the total number of hairs among cyproterone acetate patients according to the presence or absence of other symptoms of hyperandrogenism, whereas in the minoxidil group, the total number of new hairs was higher in patients with isolated alopecia (Delta = 8.1; P < 0.05). Variations in scalp seborrhoea were significant in both groups, but the result was better (for acne and hirsutism as well) in the cyproterone acetate group than in the minoxidil group (P < 0.001). CONCLUSIONS: Minoxidil treatment was more effective in the absence of other signs of hyperandrogenism, hyperseborrhoea, and menstrual cycle modifications when the BMI was low, and when nothing argued in favour of biochemical hyperandrogenism. Cyproterone acetate treatment was more effective when other signs were present and when the BMI was elevated, factors that favoured a diagnosis of biochemical hyperandrogenism.

Administration, Topical↗

Metabolism and mode of action of androgens in target tissues of male rats. V. Uptake and metabolism of cyproterone acetate and its influence on the uptake and metabolism of testosterone and 5alpha-dihydrotestosterone in target organs and peripheral tissues.

In order to get more information on the mode of action of anti-androgens, two series with low but biologically active doses of cyproterone acetate were started. In the first experiments 12 mug of [3H]cyproterone acetate was injected intravenously into adult rats castrated 3 days before treatment. Thirty min after injection the radioactivity uptake in the target organs and other tissues was measured. The metabolites were separated by thin layer chromatography. A large pool of radioactivity could be shown in the liver. Thin layer chromatography revealed that in this pool cyproterone acetate had been converted by more than 80% to one metabolite. In blood plasma, too, the metabolite accounted for the major part of radioactivity. When compared to skeletal muscle, the prostate, seminal vesicles, and m. bulbocavernosus and m. levator ani accumulated more radioactivity. Within 30 min unchanged cyproterone acetate was retained selectively thus showing its relative high affinity to target organs. In a second experimental series, adult castrated male rats were given 10 mug of cyproterone acetate intravenously 30 min before the injection of [3H]testosterone or [3H]5alpha-dihydrotestosterone. Under this condition androgen uptake in target tissues was reduced to about 70% of the control values. The data parallel the results of in vivo studies on cytosol receptor displacement of androgens by cyproterone acetate. In agreement with previous investigators no significant influence of the anti-androgen on androgen metabolism was observed. The importance of the findings concerning the mode of anti-androgen action is discussed.

Adipose Tissue↗

The combination of cyproterone acetate and low dose diethylstilbestrol in the treatment of advanced prostatic carcinoma.

Cyproterone acetate is a steroidal antiandrogen with weak progestational activity that results in the partial suppression of pituitary gonadotropin. We demonstrate that the associated decrease in serum testosterone is more complete and prolonged if cyproterone acetate (200 mg. daily) is combined with a low dose of diethylstilbestrol (0.1 mg. daily). The effectiveness of the combination in the treatment of prostatic carcinoma was investigated in 51 patients with stage D2 malignancy. From an initial concentration of 360 +/- 23 ng. per dl. (mean +/- standard error), serum testosterone decreased to 56 +/- 5 ng. per dl. after 1 week and reached a plateau of approximately 30 ng. per dl. after 2 months. This was accompanied by a decrease in serum prostatic acid phosphatase from a mean starting concentration of 43 +/- 11 ng. per ml. to a low of 3 +/- 1 ng. per ml. at 12 months; the proportion of normal values increased from 10 to 80 per cent. A complete response was observed in 7 patients (13 per cent), partial response in 35 (69 per cent) and stable disease in 8 (16 per cent), yielding an over-all objective response rate of 98 per cent (1980 National Prostatic Cancer Project criteria). The actuarial median time to progression was 17 months and the median survival time was 23.5 months. In 26 patients who subsequently had signs of progressive carcinoma the relapse rate in bone (85 per cent) far exceeded that in nonskeletal sites (23 per cent). The incidence of cardiovascular toxicity was 12 per cent. These results indicate that cyproterone acetate and low dose diethylstilbestrol may be co-administered to achieve a synergistic and potent androgen withdrawal effect in the treatment of advanced prostatic carcinoma.

Acid Phosphatase↗

The effects of cyproterone acetate on the elements in the intraluminal fluids of the testis and epididymis of the rat.

Spermatozoal maturation and the integrity of the epididymis are dependent on the action of androgen. Micropuncture techniques and electron probe microanalysis were used to investigate the effect of cyproterone acetate on the concentrations of seven elements in intraluminal fluids of the testis, rete testis, and epididymis. After 4 weeks of treatment with cyproterone acetate, the sodium concentration rose in the corpus epididymidis (74.4 +/- 5.4 to 102 +/- 6 mmol/L, p less than 0.01). The concentration of potassium rose in seminiferous tubular fluid (33.9 +/- 2.7 to 49.4 +/- 4.4 mmol/L, p less than 0.01) and caput epididymidal fluid (15.9 +/- 1.4 to 25.7 +/- 0.9 mmol/L, p less than 0.01) after 8 weeks of cyproterone acetate treatment. The chloride concentration rose in the caput (23.7 +/- 0.8 to 65.4 +/- 12.5 mmol/L, p less than 0.01) and distal cauda (39.4 +/- 4.6 to 74.7 +/- 10.8 mmol/L, p less than 0.01) epididymidis after 8 weeks of treatment. Cyproterone acetate had no effect on the concentrations of phosphorus, calcium, and magnesium. The sulfur concentration rose in seminiferous tubular fluid (4.3 +/- 0.3 to 7.3 +/- 0.3 mmol/L, p less than 0.01) and distal cauda fluid (5.3 +/- 0.5 to 14.0 +/- 1.6 mmol/L, p less than 0.01) after 8 weeks of treatment with cyproterone acetate. Four weeks of treatment also increased the sulfur concentration in the distal cauda (6.8 +/- 1.6 to 13.4 +/- 1.5 mmol/L, p less than 0.01). Cyproterone acetate treatment did not affect the concentration of any element in rete testis fluid or serum.

Animals↗

Cyproterone acetate versus a continuous monophasic oral contraceptive in the treatment of recurrent pelvic pain after conservative surgery for symptomatic endometriosis.

OBJECTIVE: To evaluate the efficacy and safety of cyproterone acetate versus an oral contraceptive in the treatment of endometriosis-associated recurrent pelvic pain. DESIGN: Randomized controlled trial. SETTING: Academic center. PATIENT(S): Ninety women with recurrent moderate or severe pelvic pain after conservative surgery for symptomatic endometriosis. INTERVENTION(S): Six months of continuous treatment with oral cyproterone acetate, 12.5 mg/d, or an oral contraceptive containing ethinyl estradiol, 0.02 mg, and desogestrel, 0.15 mg. MAIN OUTCOME MEASURE(S): Degree of satisfaction with therapy. RESULT(S): Six patients in the cyproterone acetate arm and nine in the oral contraceptive arm withdrew because of side effects (n = 9), treatment inefficacy (n = 4), or loss to follow-up (n = 2). At 6 months, dysmenorrhea, deep dyspareunia, and nonmenstrual pelvic pain scores were substantially reduced, and significant improvements were observed in health-related quality-of-life, psychiatric profile, and sexual satisfaction; no major between-group differences were seen. Subjective and metabolic side effects were limited. According to an intention-to-treat analysis, 33 of 45 (73%) of patients in the cyproterone acetate group and 30 of 45 (67%) in the oral contraceptive group were satisfied with the treatment received. CONCLUSIONS: Both cyproterone acetate and a continuous monophasic oral contraceptive were effective, safe, and inexpensive therapy for recurrent pain after conservative surgery for endometriosis.

Adult↗

Acute hepatitis induced by cyproterone acetate.

OBJECTIVE: To report a case of acute hepatitis resulting from the use of cyproterone acetate, an adjuvant treatment for prostate cancer. CASE SUMMARY: An 87 year-old white man, admitted to surgery for prostate cancer, received cyproterone acetate 300 mg/d orally and developed acute hepatitis, which initially was diagnosed clinically. A liver biopsy showed changes suggestive of acute cholestatic hepatitis. Cyprotorone was stopped immediately, and the patient was subsequently treated with corticosteroids. He then improved rapidly. DISCUSSION: Cyproterone acetate is thought to be well tolerated, but some authors have reported severe hepatic reactions, in particular acute hepatitis, fatal fulminant hepatic failure, and hepatocellular carcinoma. The above-mentioned hepatotoxicity represents an idiosyncratic drug reaction, probably due to the hepatomitogen action of cyproterone, causing an increase of hepatocytes expressing placental glutathione S-transferase, which are considered preneoplastic elements. CONCLUSION: This case suggests the possibility of hepatotoxicity from cyproterone.

Adenocarcinoma↗

[The effectiveness of oral cyproterone acetate in combination with ethinylestradiol in acne tarda of the facial type].

BACKGROUND: Cyproterone acetate is a potent antiandrogen with strong progestational activity. In combination with ethinyloestradiol, it has been shown to be of clinical benefit to women displaying signs of androgenization, such as acne, seborrhoea and hirsutism. In addition, this combined oestrogen/progestogen preparation provides effective contraceptive protection. OBJECTIVE: The aim of this open-label, multicentre study was to determine the efficacy and tolerability of a preparation containing cyproterone acetate and ethinyloestradiol in women with various grades of facial acne. PATIENTS: A total of 890 women aged from 15 to 50 years with grade I-IV facial acne according to the classification of Plewig and Kligman, participated in the study. METHODS: Patients received six cycles of a preparation containing 2 mg cyproterone acetate and 0.035 mg ethinyloestradiol (EE/CPA). Changes from baseline counts of individual acne lesions (open and closed comedones, papules, pustules, nodes and cysts) were monitored together with the simultaneous presence of seborrhoea and hirsutic signs. Reductions in the number of all and individual lesions were classified as: 75-100%, "very good"; 50-75%, "good"; 25-50%, "moderate"; < or = 25%, "absence of therapeutic effect". Body weight and blood pressure were recorded throughout the study. Adverse events and reasons for premature withdrawal from treatment were documented. RESULTS: A "good" or "very good" therapeutic response (i.e. reduction in the total lesion count of > 50%) was seen in 82.8% (95% CI 80.1-85.5) of patients after six cycles of EE/CPA. A similar response was achieved in the different grades of acne with a significant decrease in the number of all lesions throughout the study (p < 0.05). A greater than 50% reduction in open and closed comedones, papules, pustules, nodes and cysts was observed in 75.6%, 80.0%, 88.4% and 85.1% of patients, respectively. By the end of the study, 64.3% of women displayed a lower grade of acne and only 4.9% experienced exacerbation of the condition. EE/CPA was well tolerated, with only 3.4% of patients discontinuing treatment because of adverse events. The majority of events were described as mild, and their incidence declined as the study progressed. No clinically significant changes in blood pressure and body weight were recorded. CONCLUSION: EE/CPA is an effective treatment for acne of all grades and all types of lesion. The preparation is well tolerated and would appear to be an appropriate treatment for women with these symptoms of androgenization.

Acne Vulgaris↗

Transfer of cyproterone acetate to the milk of lactating women.

Cyproterone acetate (CPA) was administered in a dose of 50 mg to 6 lactating women delivered by caesarean section. All women had to discontinue breast feeding the day before treatment. Prior to, and 3 and 9 hours after ingestion of the drug, plasma and milk specimens were taken. Total daily milk volume was recorded. Concentration of CPA in plasma and milk was determined by RIA. The plasma levels of CPA were in the range of 65 - 450 ng/ml at 3 h and 76 - 270 ng/ml after 9 hours. The respective concentrations in milk were 16 - 260 ng/ml (3 h) and 55 - 130 ng/ml (9 h). The plasma/milk ratio of drug concentration varied between 1.1 and 9.3 (3 h) and 0.6 and 2.9 (9 h). The mean of all values amounted to 2.8 +/- 2.3. Taking into account a daily milk production of 1050 +/- 230 ml, 0.2% of the dose administered (range: 0.06 - 0.41 % of dose) would have been transferred to the newborn. Use of the CPA-containing oral contraceptive DIANER (2 mg of CPA + 50 microgram of ethinyl estradiol) by nursing women would therefore result in the transfer of 1 microgram/kg to the child.

Adult↗

Treatment of endometriosis with cyproterone acetate. Preliminary report.

The objective of this work was to evaluate the effectiveness of cyproterone acetate for the treatment of endometriosis. Seven patients with dysmenorrhea due to endometriosis and idiopathic hirsutism were included. Endometriosis was laparoscopically classified as minimal in two cases, mild in two, moderate in two and severe in one patient. Cyproterone acetate was initiated at a daily dose of 10 mg orally for 20 days, followed by 10 days without medication. This sequence was repeated over a period of 6 months. Dysmenorrhea improved in all study subjects. Menstrual disorders were observed in all women, with oligomenorrhea in six patients and spotting in one. At the end of treatment, a second look laparascopy revealed minimal endometriosis in five patients and no evidence of the disease in the other two cases. Hirsutism was slightly reduced in two patients and without changes in the other five. These preliminary data disclose the possible therapeutic use of cyproterone acetate in endometriosis.

Administration, Oral↗

Effect of cyproterone acetate on the action and metabolism of testosterone in the mouse kidney.

Cyproterone acetate given alone or in combination with testosterone propionate or 5alpha-dihydrotestosterone to castrated male mice does not exhibit an antiandrogenic action on the kidney. It functions rather as a slightly renotropic hormone, even potentiating the renotropic activity of androgens. The administered amount of cyproterone acetate to intact males or castrates supplemented with androgens, however, decreased dramatically the weight of seminal vesicles and of spleen. Cyproterone acetate treatment of the animals influences in vitro the testosterone to androstenedione conversion but not the activity of 5alpha-reductase in the mouse kidney slices.

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

Cyproterone acetate for severe hirsutism: results of a double-blind dose-ranging study.

OBJECTIVE: The objective was to determine if cyproterone acetate (CPA) therapy for hirsute women demonstrated a dose response. DESIGN: A double-blind dose-ranging study of the effect of 3 doses of cyproterone acetate for a period of 12 months. PATIENTS: Twenty-one hirsute women received the Dianette contraceptive pill (35 micrograms ethinyl oestradiol + 2 mg CPA, Schering Healthcare, UK), 20 received Dianette plus 20 mg CPA and 19 received Dianette plus 100 mg CPA: supplementary CPA was administered on days 1-10 of the birth control pill cycle as described by Hammerstein. MEASUREMENTS: Hair growth was measured using the clinical scale of Ferriman and Gallwey and by direct measurement of hair shaft diameter and linear growth of hair on the face, forearm, abdomen and thigh. RESULTS: Thirty-eight women completed 12 months therapy, eight withdrew due to side-effects and 14 were lost to follow-up. All three dose schedules produced significant reductions in clinical hair growth scores. This reduction was seen after 6 months with Dianette alone (P less than 0.005) and after 3 months with both the higher doses (P less than 0.01). There were no significant differences between the effect of different doses at any of the three-monthly time points. Hair diameter measurements were reduced by all doses after 12 months: face by 27*, 37, 37%*, forearm 5, 10, 8%*, abdomen 22*, 39*, 33%*, thigh 12, 24*, 30%* (median reductions (*P less than 0.01) for Dianette, D + 20 mg CPA and D + 100 mg CPA respectively). There were no significant reductions in daily linear growth rates. A comparison of the percentage reduction in hair shaft diameter at each site demonstrated no significant difference between doses, although the reductions by the three doses on the forearm, abdomen and thigh suggested a trend towards a dose response. CONCLUSIONS: We conclude that cyproterone acetate 2 mg daily appears to be as effective as higher doses in the therapy of hirsute women.

Adolescent↗

Testosterone-induced DNA synthesis in cultured rat ventral prostate. I. Effects of cyproterone acetate.

Testosterone-induced DNA synthesis in cultured rat ventral prostate was evaluated as an in vitro model for screening the direct effects of anticancer agents on prostatic growth. Optimal conditions for this bioassay, particularly the concentration of testosterone, were established using the inhibitory effects of cyproterone acetate on testosterone-induced 125iododeoxyuridine (I-UdR) uptake as an index of DNA synthesis inhibition. Using 4 X 10(-7) M testosterone, only the highest concentration (X 10(-5) M) of cyproterone acetate inhibited I-UdR uptake and histological observations indicated that this was due to a non-specific cytotoxic effect. In contrast, cyproterone acetate had a dose-dependent inhibitory effect on the proliferative response to 4 X 10(-9) M testosterone. Cyproterone acetate (4 X 10(-7) M) combined with 4 X 10(-9) M testosterone exerted an inhibitory effect on I-UdR uptake and caused epithelial atrophy indicative of androgen deprivation. The results are consistent with similar in vivo studies and confirm the hypothesis that cyproterone acetate acts by directly antagonising testosterone action at the target tissue level. Thus, this in vitro method provides a useful model for screening the direct effects of antiprostatic drugs.

Androgen Antagonists↗

Plasma levels of active ingredients after single and repeated administration of a new oral contraceptive containing 2 mg of cyproterone acetate and 50 micrograms of ethinyl estradiol (DIANE) to five young women.

Peripheral plasma from five young women was analyzed for cyproterone acetate and ethinyl estradiol during a period of 96 hours duration after single oral intake of a coated tablet of DIANE (2 mg of cyproterone acetate + 50 micrograms of ethinyl estradiol), and during a treatment cycle of 21 days during which the formulation was given daily. Radioimmunoassays were utilized for quantifications. A maximum concentration of 11.0 +/- 3.4 ng of cyproterone acetate/ml plasma was found 1.6 +/- 0.6 hours after a single administration of DIANE. Postmaximal disposition took place in two phases with half-lives of 1.9 +/- 0.6 hours and 2.2 +/- 0.2 days. The maximum level of 0.08 +/- 0.03 ng of ethinyl estradiol/ml plasma was found 1.6 +/- 0.6 hours after such single administration. Following commencement of a daily oral intake of DIANE a steady state was reached by the 5th to 8th days, during which 24 hours after each dose cyproterone acetate concentrations were found to be 2.4 +/- 0.7 times higher than at the corresponding time after a single administration. Accordingly, after the first third of the 21 day treatment cycle an almost constant plasma level was reached indicating an equilibrium of intake and elimination. Except for a change in the mean terminal half life after multiple dosing, there was evidently no change in the kinetics of cyproterone acetate. No pointers to an accumulation of ethinyl estradiol upon daily administration of DIANE could be found.

Adult↗

Effect of estradiol valerate alone or in association with cyproterone acetate upon vascular function of postmenopausal women at increased risk for cardiovascular disease.

OBJECTIVES: a large body of evidence has been accumulated suggesting that impairment of vascular endothelial function is an initial step in the development of atherosclerosis. Recent studies have shown that estrogen replacement therapy in postmenopausal women (PMW) improves endothelium-dependent, flow-mediated dilatation (FMD) while the cyclical adjunct of a progestin may reverse this effect. METHODS: the purpose of this study was to evaluate endothelium-dependent, FMD in the brachial artery and the plasma levels of Endothelin-1 in menopausal females treated with estradiol valerate with and without cyclical cyproterone acetate in 20 PMW (mean age 64+/-6 years) with more than one risk factor for coronary artery disease. After a baseline evaluation, PMW entered a double-blinded, placebo controlled single cross-over study and were randomized to receive either estradiol valerate (2 mg) for 21 days or estradiol valerate (2 mg) for 11 days and estradiol valerate (2 mg) and cyproterone acetate (1 mg) for 10 days. Patients were crossed-over the complementary treatment 7 days after completing the first treatment phase. The study of forearm blood flow was repeated at the end of each treatment period. RESULTS: estradiol valerate significantly increased FMD as compared with baseline (12+/-3 vs. 7+/-4%, P<0.01) the adjunct of cyproterone acetate did not affect the effect of estradiol valerate upon FMD (12+/-3 vs. 11+/-4%, P=NS). Similarly reactive hyperemic flow increased after estradiol valerate alone (24%) or in association with cyproterone acetate (24%) compared with baseline. Plasma levels of Endothelin-1 were significantly reduced by estradiol valerate alone or in association with cyproterone acetate. CONCLUSIONS: in conclusion hormone replacement therapy with estradiol valerate and cyproterone acetate improves endothelial function and reduces plasma levels of Endothelin-1 in PMW at risk of coronary artery disease. These effects may be relevant for cardioprotection.

Brachial Artery↗

Cyproterone acetate monotherapy in advanced prostatic carcinoma.

Cyproterone acetate was given as monotherapy to 18 patients with advanced prostatic carcinoma at a weekly dose of 300 mg. Progression was observed in all of the patients; median time to progression was 35 months and median survival time was 48 months. Partial response, stabilization, progression and exitus rates by years also showed favourable results, as compared with other forms of therapy in advanced prostatic carcinoma.

Aged↗

Efficacy of low-dose oral contraceptives containing levonorgestrel, gestoden and cyproterone acetate.

The efficacy of low-dose oral contraceptives containing 30 micrograms or 35 micrograms ethinyl estradiol in combination with Levonorgestrel, gestoden (delta 15-Levonorgestrel) and cyproterone acetate was studied. Borderline doses for inhibition of ovulation were found to be approximately 50 micrograms for Levonorgestrel, 40 micrograms for gestoden and 1 mg for cyproterone acetate. These results were derived from the assay of luteinizing hormone, follicle-stimulating hormone, 17 beta-estradiol and progesterone serum levels during the daily treatment of a total of 47 female volunteers from day 5 through day 25 of their cycles. A combination of 30 micrograms ethinyl estradiol plus 75 micrograms Levonorgestrel or 75 micrograms gestoden resulted in complete inhibition of ovulation in each of the 20 subjects studied. Monitoring of hormone serum levels in 6 female volunteers with normal cycles during the administration of 35 micrograms ethinyl estradiol plus 2 mg cyproterone acetate showed inhibition of ovulation in all subjects studied during the first and third therapy cycle. One subject exhibited follicular maturation during the third treatment cycle as judged from the patterns of 17 beta-estradiol serum levels. Present data suggest that low-dose oral contraceptives containing Levonorgestrel, gestoden and cyproterone acetate are highly efficient in providing great contraceptive safety and do not support the previous notion that the kind of progestagen used is relevant for the degree of central inhibition.

Adolescent↗

Initiation of enzyme-altered foci by the synthetic steroid cyproterone acetate in rat liver foci bioassay.

Cyproterone acetate (CPA) is a synthetic steroid which is used in oral contraceptive and anti-androgen formulations. It has previously been classified as a tumor promoter in rat liver. Recent studies have shown that CPA induces DNA repair synthesis in isolated hepatocytes, and this implies that CPA is genotoxic. We studied the initiating activity of CPA in vivo by means of a rat liver foci bioassay, using weanling female Sprague-Dawley rats. The results show that CPA induces adenosine-triphosphatase-deficient and gamma-glutamyltranspeptidase-positive putative preneoplastic foci in a dose-dependent manner. This indicates that CPA has not only promoting but also initiating activity and may therefore act as a complete carcinogen in rat liver.

Adenosine Triphosphatases↗