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BACKGROUND: Hirsutism is a distressing and relatively common endocrine problem in women which may prove difficult to manage. Cyproterone acetate, an anti-androgen, is frequently used to treat hirsutism, usually in combination with ethinyl estradiol. OBJECTIVES: The objective of this review was to investigate the effectiveness of cyproterone acetate alone, or in combination with ethinyl estradiol, in reducing hair growth in women with hirsutism secondary to ovarian hyperandrogenism. SEARCH STRATEGY: The Cochrane Menstrual Disorders and Subfertility Group trials register was searched (last search - 4 June 2002). The Cochrane Menstrual Disorders and Subfertility Group register is based on regular searches of MEDLINE (1966 to 2002), EMBASE (1980 to 2002), CINAHL (1982 to 2002), PsycINFO (1987 to 2002) and CENTRAL (Issue 2, 2002 of the Cochrane Library) the handsearching of several journals and conference proceedings, and searches of several key grey literature sources. All publications of randomised controlled trials of cyproterone acetate with or without estrogen versus placebo or other drug therapies for hirsutism were identified. SELECTION CRITERIA: All randomised controlled studies comparing:- cyproterone acetate to placebo- cyproterone acetate with ethinyl estradiol to placebo- cyproterone acetate with ethinyl estradiol to cyproterone acetate alone- cyproterone acetate (with or without estradiol) to other medical therapies for treatment of hirsutism. DATA COLLECTION AND ANALYSIS: Eleven studies were identified which fulfilled the inclusion criteria. Nine randomised studies were included in the review, and two were excluded because of insufficient information. Only one study had more than 100 women included in the analysis. The major outcomes included: subjective improvement in hirsutism, changes in Ferriman Gallwey scores, changes in linear hair growth and hair shaft diameter, alterations in endocrine parameters, side effects to treatment, withdrawals during therapy MAIN RESULTS: There were no clinical trials comparing cyproterone acetate alone with placebo. There was one small study comparing cyproterone acetate in combination with ethinyl estradiol to placebo. In this study there was a significant subjective reduction in hair growth with cyproterone acetate therapy, although the confidence limits were large. There were no studies comparing cyproterone acetate alone with cyproterone acetate in combination with ethinyl estradiol to treat hirsutism. In studies where cyproterone acetate was compared to other drug modalities (ketoconazole, spironolactone, flutamide, finasteride, GnRH analogues) no difference in clinical outcome was noted. There were, however, endocrinological differences in androgen and estrogen levels between different drug therapies. There were insufficient data to assess differences in side effects between women treated with cyproterone acetate and other medical therapy. REVIEWER'S CONCLUSIONS: Cyproterone acetate combined with estradiol results in a subjective improvement in hirsutism compared to placebo. Clinical differences in outcome between cyproterone acetate and other medical therapies were not demonstrated in the studies included in this review. This may be because of the small size of the studies, lack of standardized assessment and lack of objective determinants of improvement in hirsutism. The endocrinological effects of the different drug therapies reflect the mode of action. Larger carefully designed studies are needed to compare efficacy and safety profiles between drug therapies for hirsutism.
OBJECTIVE: To evaluate the clinical and hormonal response of topically applied cyproterone acetate, oral cyproterone acetate, and placebo lotion in women with acne. DESIGN: Placebo-controlled, randomized study. SETTING: Patients were recruited from the Institute of Endocrine Cosmetics, Vienna, Austria. PATIENTS: Forty women with acne. INTERVENTIONS: Treatment with oral medication consisting of 0.035 mg of ethinyl estradiol and 2 mg of cyproterone acetate (n=12), 20 mg of topical cyproterone acetate lotion (n=12), and placebo lotion (n=16) was offered. Patients were assessed monthly for 3 months. MAIN OUTCOME MEASURES: Clinical grading according to acne severity and lesion counts as well as determinations of serum cyproterone acetate concentrations. RESULTS: After 3 months of therapy with topical cyproterone acetate, the decrease of mean facial acne grade from 1.57 to 0.67 was significantly better (P<.05) compared with placebo (which showed a change from 1.57 to 1.25), but not compared with oral medication (1.56 to 0.75) (P>.05). Lesion counts also decreased from 35.9 to 9.1 in the topical cyproterone acetate group compared with oral medication (45.4 to 15.5) (P>.05) and placebo (38.2 to 23.1) (P<.05). After topical cyproterone acetate treatment, serum cyproterone acetate concentrations were 10 times lower than those found after oral cyproterone acetate intake. CONCLUSIONS: The therapeutic effect of topically applied cyproterone acetate for acne treatment was clearly demonstrated. Topically applied sexual steroids in combination with liposomes are as effective as oral antiandrogen medication in acne treatment, while reducing the risk of adverse effects and avoiding high serum cyproterone acetate concentrations.
BACKGROUND/AIMS: Hepatocellular carcinoma possesses androgen receptor but its true role is not known. This study aimed to investigate the effect of an anti-androgen cyproterone acetate on the growth of androgen receptor-positive hepatocellular carcinoma. METHODS: Androgen receptor-positive human hepatocellular carcinoma cells (KYN-1/SM-10) were subcutaneously transplanted into male nude mice. When the tumor size was about 10 mm, animals were subcutaneously administered cyproterone acetate (0.1 mg/day and 0.8 mg/day) or solvent alone for 21 days. Animals were serially sacrificed for measurements of testicular weight, tumor size, and cytosolic and nuclear androgen receptor levels in tumor. Proliferating cell nuclear antigen, transforming growth factor-alpha, and transforming growth factor-beta 1 in tumor were investigated immunohistochemically, using monoclonal antibodies. Apoptotic activity was also studied by the in situ DNA nick end labeling method. RESULTS: Cyproterone acetate depressed testicular weight, suppressed tumor growth, and decreased both cytosolic-androgen receptor and nuclear-androgen receptor levels dose-dependently. Numbers of proliferating cell nuclear antigen-positive cells were decreased transiently with the low dose but continuously with the high dose of cyproterone acetate. Transforming growth factor-alpha expression was not influenced by cyproterone acetate, but the high dose of cyproterone acetate induced higher expression of transforming growth factor-beta 1, associated with increased numbers of apoptotic tumor cells, peaking on day 3. CONCLUSIONS: The inhibition of growth of androgen receptor-positive hepatocellular carcinoma with cyproterone acetate in male nude mice could be due to G1-phase cell cycle arrest, and to some extent apoptosis induced by increased synthesis of transforming growth factor-beta 1 in tumor, caused by the direct action of cyproterone acetate through androgen receptors, as well as decreased testosterone levels in blood due to cyproterone acetate-induced testicular atrophy.
Cyproterone acetate, a widely used synthetic progestagen with antiandrogenic activity, is known for years to produce liver tumours in rats, with a higher incidence in females. This effect was attributed to a rodent-specific tumour promoting mode of action based on the detection of a strong hepato-mitogenic activity of cyproterone acetate. However, more recent studies have demonstrated that cyproterone acetate is sex-specifically activated to (a) DNA-damaging intermediate(s) in the liver of female rats which result in the formation of DNA adducts, induction of DNA repair, and increased levels of micronuclei and gene mutations. Consistent with a sex-specific genotoxicity, cyproterone acetate showed a tumour-initiating potential in a liver foci assay with female rats but not with male rats. Most important, cyproterone acetate was found to induce formation of DNA adducts in primary cultures of human hepatocytes indicating that human liver cells have the capacity to activate cyproterone acetate to genotoxic intermediates. However, the overall assessment of the preclinical data presented in this review suggests that induction of liver tumours in female rats most probably depends on both, genotoxic and mitogenic effects which would suggest a non-linear mode of action with regard to tumour formation. With the exception of DNA adduct formation all other adverse effects induced by cyproterone acetate in rat liver, including gene mutations and liver tumours, can be detected at very high dose levels only. Hence, a cancer risk estimate based on a simple linear extrapolation from high dose to low exposure conditions of recommended clinical use would be questionable. Human data from pharmacoepidemiological studies that specifically addressed the question of possible liver cancer risk in patients treated with cyproterone acetate do in principle support this interpretation. In agreement with these considerations the regulatory authorities of the European Union came to the common conclusion that a possible cancer risk associated with the clinical use of cyproterone acetate, if any, appears to be low and the risk-benefit ratios for the currently authorised indications remain favourable.
The effects of estradiol-17 beta on androgen uptake, metabolism and binding were studied in rat epididymis in vivo in comparison with cyproterone acetate. Steroids (250 ug/100 g body weight) were injected 5 min prior to 3H-testosterone in castrate rats. Estradiol-17 beta inhibited 3H-testosterone uptake into epididymal cytosol by 58% as compared to 38% by cyproterone acetate. 3H-Testosterone uptake into epididymal nuclei was inhibited 95% by estradiol-17 beta and 83% by cyproterone acetate. Total bound radioactivity in cytosol fractions was reduced to a greater extent by estradiol-17 beta than cyproterone acetate when either 3H-testosterone or 3H-dihydrotestosterone was injected. Binding of 3H-dihydrotestosterone to nuclear receptors was completely abolished by estradiol-17 beta; whereas approximately 20% binding remained in the nuclear extract after cyproterone acetate treatment. Metabolism of 3H-testosterone in vivo was also altered by estradiol-17 beta, resulting in diminished conversion to 3H-dihydrotestosterone. Cyproterone acetate, on the other hand, did not affect 3H-testosterone metabolism. Estradiol-17 beta and cyproterone acetate inhibited in vitro binding of 3H-dihydrotestosterone to the intracellular cytoplasmic receptor, but not the intraluminal androgen binding protein (ABP). These data suggest that estradiol-17 beta may have a more potent antiandrogenic effect on the epididymis than cyproterone acetate due to inhibition of 5 alpha reduction of testosterone as well as binding to the androgen receptor.
In the study reported here the ovulation inhibition dose for cyproterone acetate was determined. Experiments showed that the ovulation inhibition dose is 1 mg of cyproterone acetate, administered daily. Results proved that the cyproterone acetate dose cannot be reduced when cyproterone acetate is combined with ethinyl estradiol. However, the objective of this study was to determine whether it is possible to reduce the estrogen dose to 35 micrograms when the common combination of 2 mg cyproterone acetate and ethinyl estradiol is being used. After a control menstruation cycle, 2 mg cyproterone acetate and 35 micrograms ethinyl estradiol were administered daily to six women with normal menstruation. Drug administration began on Day 5 and ended on Day 25. During the control cycle, the first treatment cycle, and the third treatment cycle, LH, FSH, 17 beta estradiol, progesterone, testosterone, prolactin, and SHGB were examined daily. Cervix score and karyopyknosis index were determined at the same time. In addition, antithrombin III was examined during the control cycle and during the third treatment cycle. Present results show that ovulation inhibition is possible with dose reduction of ethinyl estradiol to 35 micrograms, combined with 2 mg of cyproterone acetate. Increase in SHBG and reduction in testosterone serum level point to an additional antiandrogenic effect of cyproterone acetate, aside from its cellular effect. The combined preparation discussed here does not bring about any changes in antithrombin III values. Results permit the conclusion that ovulation inhibition is insured with a reduction of the daily estrogen dose from 50 micrograms to 35 micrograms.
Since the recent introduction of a drug regimen containing 2 mg of the antiandrogen cyproterone acetate and 50 micrograms ethinyl-oestradiol (Diane; oestrogen-cyproterone acetate) several uncontrolled reports have extolled the benefits of this drug. Double blind studies, however, are lacking. Sixty two patients with moderate or moderately severe acne were therefore included in a double blind trial of treatment for six months comparing tetracycline alone, oestrogen-cyproterone acetate alone, and a combination of these agents. Sebum excretion rates and bacterial counts were measured before, during, and after treatment, at the same time as a clinical assessment was made. At six months the acne (as assessed by overall grade) had improved by 68% in the antibiotic treated group and by 74% in the oestrogen-cyproterone treated group. The group given a combination of both agents improved by 82%, which was significantly better (p less than 0.025) than the improvement in the tetracycline treated patients. No significant difference was found between the groups given oestrogen-cyproterone alone and the combined treatment. The sebum excretion rate was suppressed by 25% in the patients in both groups receiving oestrogen-cyproterone but not in the group given antibiotics alone. Oestrogen-cyproterone acetate is as effective as antibiotics in treating acne in women, and adding antibiotics offers no advantage over using oestrogen-cyproterone on its own, although in this study the combination was more effective than tetracycline alone at six months.