STUDY Topical Cyproterone Acetate Treatment in Women With Acne A Placebo-Controlled Trial Doris M. Gruber, MD; Michael O. Sator, MD; Elmar A. Joura, MD; Eva Maria Kokoschka, MD; Georg Heinze, MSc; Johannes C. Huber, MD, PhD Objective: To evaluate the clinical and hormonal re- Results: After 3 months of therapy with topical cypro- sponse of topically applied cyproterone acetate, oral cy- terone acetate, the decrease of mean facial acne grade from proterone acetate, and placebo lotion in women with 1.57 to 0.67 was significantly better (P<.05) compared with acne. placebo (which showed a change from 1.57 to 1.25), but not compared with oral medication (1.56 to 0.75) (P >.05). Design: Placebo-controlled, randomized study. Lesion counts also decreased from 35.9 to 9.1 in the topi- cal cyproterone acetate group compared with oral medi- Setting: Patients were recruited from the Institute of En- cation (45.4 to 15.5) (P..05) and placebo (38.2 to 23.1) docrine Cosmetics, Vienna, Austria. (P,.05). After topical cyproterone acetate treatment, se- rum cyproterone acetate concentrations were 10 times lower Patients: Forty women with acne. than those found after oral cyproterone acetate intake. Interventions: Treatment with oral medication con- Conclusions: The therapeutic effect of topically ap- sisting of 0.035 mg of ethinyl estradiol and 2 mg of cy- plied cyproterone acetate for acne treatment was clearly proterone acetate (n=12), 20 mg of topical cyproterone demonstrated. Topically applied sexual steroids in com- acetate lotion (n=12), and placebo lotion (n=16) was of- bination with liposomes are as effective as oral antian- fered. Patients were assessed monthly for 3 months. drogen medication in acne treatment, while reducing the risk of adverse effects and avoiding high serum cypro- Main Outcome Measures: Clinical grading accord- terone acetate concentrations. ing to acne severity and lesion counts as well as deter- minations of serum cyproterone acetate concentrations. Arch Dermatol. 1998;134:459-463 ORMONAL approaches to because of the lack of a suitable vehicle for the treatment of acne have transdermal treatment.1,2 Cyproterone ac- been the subject of much etate is a potent steroidal antiandrogen with interest ever since the se- progestational activity. It is used alone or baceous gland was dem- in combination with ethinyl estradiol or es- Honstrated to be sensitive to androgens. The tradiol valerate in the treatment of women use of topical antiandrogens has had theo- suffering from disorders associated with an- retical appeal since the pilosebaceous unit drogenization, eg, acne or hirsutism. Cy- was found to be an androgen-dependent proterone acetate competes with dihy- structure. Unfortunately, however, this drotestosterone for the androgen receptor theory has not been translated into clinical and inhibits translocation of the hormone practice. receptor complex into the cell nucleus.3 From the Division of 17b-Estradiol and progesterone have This study was undertaken to con- Gynecological Endocrinology long been applied topically in the treat- sider once again a cyproterone acetate for- and Reproductive Medicine ment of acne. The reasons for using topi- mulation delivered to the skin surface, thus (Drs Gruber, Sator, and cal rather than oral therapy include the approaching the target cell topically and by- Huber), Department of avoidance of hepatic metabolism, the re- passing the enterohepatic circulation. The Gynecology and Obstetrics, duced risk of systemic adverse effects, the aim of this open, placebo-controlled study Division of Gynecology ability to combat acne in both female and was to compare the effectiveness of topi- (Dr Joura), Department of Dermatology (Dr Kokoschka), male patients, and the lack of a contracep- cal cyproterone acetate, an oral formula- and Department of Computer tive effect in women. It is known that cy- tion containing 0.035 mg of ethinyl estra- Sciences (Mr Heinze), General proterone acetate is effective when given diol and 2 mg of cyproterone acetate Hospital, University of Vienna, orally. However, trials using topical cypro- (Dianemite, Schering, Vienna, Austria), and Vienna, Austria. terone acetate have not proved successful a placebo preparation in women with mod- ARCH DERMATOL / VOL 134, APR 1998 459 ©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 PATIENTS AND METHODS TOPICAL APPLICATION OF CYPROTERONE ACETATE Forty-five women aged between 26 and 38 years (mean age, The application system was similar to that used for topical 30.3 years) with moderate to severe acne who consulted 17b-estradiol and topical 17a-dihydrotestosterone stud- the endocrinology outpatient department for a hormonal ies. Pharmacokinetic details for these steroidal substances evaluation and treatment of their acne were enrolled in this have been described previously.5,6 Because cyproterone ac- 3-month trial. etate is a lipophilic steroid, a similar absorption rate was Informed consent was obtained from all the patients, assumed. The daily transdermal cyproterone acetate dos- and the study was approved by the local ethics committee. age was 20 mg, based on a similar formulation combining Patients with medical contraindications to the therapy or soybean oil, eilecithin, glycerol, and oleic acid. unwilling to smoke less than 5 cigarettes daily were not in- Liposomes were used to improve the transdermal pen- cluded in the study. Patients were required to use barrier etration of the antiandrogen. Topical application of cypro- contraception during the treatment period. All acne medi- terone acetate in patients with acne had been attempted be- cation had been stopped 6 weeks before the commence- fore, but the clinical results were discouraging. ment of the study. During the initial visit, the patients were randomly as- SERUM CYPROTERONE ACETATE LEVELS signed to 1 of the 3 treatment groups. One group (n=12) received an oral contraceptive regimen for 3 months, with Serum levels of cyproterone acetate were determined in 5 administration of a daily dose of 0.035 mg of ethinyl estra- patients in the topical cyproterone acetate group both be- diol and 2 mg of cyproterone acetate for the first 21 days of fore treatment and 3 months after study entry, with blood the menstrual cycle, followed by a 7-day pill-free interval. samples taken exactly 45 minutes after the last topical cy- The first treatment cycle started on the first day of men- proterone acetate application. Baseline serum cyproter- strual bleeding. The second group (n=12) used a topical cy- one acetate concentrations were below the detection limit. proterone acetate lotion, with treatment starting on the first Serum cyproterone acetate levels were measured by radio- day of menstrual bleeding and being taken continuously for immunoassay, by a dextran-coated charcoal method. Ali- 3 months. The topical lotion was self-applied once daily in quots of serum (0.1 mL) were diluted with physiological the evening, to the face only, with a calibrated pipette. The saline to a final volume of 0.5 mL. After extraction with daily amount of cyproterone acetate liposome lotion used 2.5 mL of diethyl ether, the ether phase was separated and was 10 mL, containing 20 mg of cyproterone acetate. Lipo- fully evaporated, and the residue was reconstituted with some lotion consisted of soybean oil, eilecithin, glycerol, and 0.8 mL of an assay buffer. This solution was incubated with oleic acid (Leopold Pharma, Graz, Austria). 0.1 mL of tritiated cyproterone acetate (specific activity, The third group (n=16) used a placebo liposome lo- 0.84 GBq/mg; Schering AG, Berlin, Germany) and 0.1 mL tion containing soybean oil, eilecithin, glycerol, and oleic of antiserum (batch C003, Schering AG) at 4°C for 16 hours, acid without the active substance; it was applied as in the mixed with 0.2 mL of dextran-coated charcoal, and vor- topical cyproterone acetate group. texed. After 15 minutes at 4°C, the mixture was centri- Acne severity on the face was graded according to the fuged. The supernatants were decanted into liquid scintil- method of Burke and Cunliffe,4 with the individual scores lation vials and mixed with 4.5 mL of scintillation cocktail. added up to yield a total result. Four sites on the face (chin, The radioactivity was measured on a scintillation counter. forehead, and left and right cheeks) were graded. The mean To obtain the standard curves, 1 mg of cyproterone ac- value from this grading was used for further calculations. etate was dissolved in methanol and diluted with assay In addition, numbers of macules, papules, pustules, nod- buffer, yielding final concentrations ranging from 39 to ules, and cysts on the face were counted by the same der- 10 000 pg/mL. In addition, a drug-free sample (0 pg/mL) matologist (E.M.K.) at each visit. Lesion counts were de- was used. Calibration and samples were analyzed in du- fined as the total of comedones and inflammatory lesions. plicates. A spline function was used for the evaluation of Only 3 of the patients had few inflammatory lesions, and the data. The interassay and intra-assay coefficients ranged their counts were thus added to the noninflammatory le- from 5.0% to 13.0%. The mean blank value for blank con- sions. Acne on other parts of the body was not evaluated trol samples was found to be 28 pg/mL. in this study. Assessments were done during the midpoint of the menstrual cycle, ie, between days 10 and 19, with STATISTICAL METHODS day 1 being defined as the first day of menstrual bleeding. Before commencement of the trial, all patients underwent Overall significance of the group effect was evaluated by analy- 2 baseline examinations performed 1 week apart. Progress sis of variance. Pairwise comparisons between groups were assessments were made midway through the first, second, made by Student t tests for mean comparison.