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Clinical efficacy and safety of cyproterone acetate in severe hirsutism: results of a multicentered Canadian study*†
Vol. 46, No.6, December 1986 Printed in U.SA.
FERTIT..ITY AND STERILITY Copyright c 1986 The American Fertility Society
Clinical efficacy and safety of cyproterone acetate in severe hirsutism: results of a multicentered Canadian study*t
Serge Belisle, M.D.:!: Edgar J. Love, Ph.D.§ University of Sherbrooke, School of Medicine, Sherbrooke, Quebec, and University of Calgary, School of Medicine, Calgary, Alberta, Canada
We compared the efficacy and safety of cyproterone acetate (Shering AC, Berlin, FRG) at a low (Diane, 2 mg) or a high dose (Androcur, 100 mg) in the treatment of 158 patients with severe hirsutism. At baseline, no difference was observed in mean hirsutism total index (19.5 Diane versus 20.1 Androcur) or distribution (facial, bust, or abdomen). By the end of the study, patient loss in Diane and Androcur groups was 29.1% and 27.8%, respectively, and the mean percent difference in the scoring index was as follows: total, 24.6 Diane versus 30.8 Androcur, P < 0.05; facial, 30.1 Diane versus 33.0 Androcur, P < 0.10; bust, 12.1 Diane versus 312 Androcur, P < 0.02; and abdomen, 20.1 Diane versus 312 Androcur, P < 0.02. Except for breast tenderness (Diane> Androcur), amenorrhea, and weight gain, (Androcur > Diane), the incidence of side effects was comparable in both groups. Fertil Steril46:1015, 1986
Antiandrogens have been introduced into the treatment of hirsutism because of their ability to prevent androgens from expressing their activity at target sites (for review, see Biffignandi et al. 1 ). The antiandrogen cyproterone acetate (CPA) was
Received May 7, 1986; revised and accepted August 14, 1986. *Sponsored by the Canadian Fertility Research Association and funded by a grant-in-aid from Berlen Laboratories Limited, Canada. tThe following collaborators participated in this study: Peter Garner, M.D., University of Ottawa; Barbara Cruckshank, M.D., University of Western Ontario; Youssef Ainmelk, M.D., University of Sherbrooke; Togas Tulandi, M.D., McGill University; Nacia Faure, M.D., Laval University; Arthur Leader, M.D., University of Calgary; Timothy Rowe, M.D., University of British Columbia; and Jerald Bain, M.D., University of Toronto. :j:Reprint requests: Dr. Serge Belisle, Department ofObstetrics and Gynecology, Centre Hospitalier Universitaire, 3001 12th Avenue North, Sherbrooke, Quebec, JIH 5N4, Canada. §Department of Community Health Sciences, University of Calgary, School of Medicine. Vol. 46, No.6, December 1986
first used clinically by Hammerstein and Cupceancu. 2 It is a hydroxyprogesterone derivative that blocks the effects of bioactive androgens at the receptor level. It has also marked progestational activity, as well as mild antigonadotropic and glucocorticoid-like action. 3 , 4 Extended clinical trials using CPA in androgenized women were conducted in several European countries. 5 -8 Recruited in these studies were mostly women with signs of androgenization, such as acne, seborrhea, and milder forms of hirsutism, who were given a progestogen-estrogen combination therapy consisting of 2 mg of CPA and 0.05 mg of ethinylestradiol (EE 2 ) (Diane, Shering AC, Berlin, FRG). Overall, the results showed significant improvement in mild hirsutism after 6 to 9 months of treatment with Diane. However, much less success was observed in moderate to severe hirsutism, where uncontrolled studies suggested that a higher dose of CPA should be considered. 1 , 6, 8-11 The objective of this research, therefore, was to compare the efficacy and safety of a low and a
Belisle and Love Cyproterone acetate in severe hirsutism
1015
high dose of CPA in patients with severe forms of hirsutism, in a randomized and double-blind study. MATERIALS AND METHODS SUBJECTS
The research project was approved by the Human Ethics Committee of each of the eight participating centers. Women with severe hirsutism of nontumoral origin, with or without menstrual disorders, were recruited from the following Canadian university centers: Sherbrooke (Quebec), Laval (Quebec), McGill (Quebec), Ottawa (Ontario), Toronto (Ontario), Western Ontario (Ontario), Calgary (Alberta), and British Columbia. The inclusion criteria were (1) severe hirsutism (Le., patients who presented with the chief complaint of excessive hair growth and who, after appropriate clinical and paraclinical investigation, required systemic therapy for such a condition); (2) clinical grading of body hair growth> 14, according to the index of Ferriman and Gallway12; (3) age between 18 and 40 years; and (4) ability to give consent to therapy and to remain in the study for 12 months. Excluded from the study were patients (1) with ovarian and adrenal tumors; (2) on hormonal medications within 60 days of enrollment period; (3) receiving other types of prescribed medication; and (4) with absolute contraindications to steroids. No other form of ancil·lary therapy of hirsutism, except shaving during the first month, was allowed during the study period. One hundred seventy-one women were initially recruited into the study. Thirteen of these women were subsequently excluded for reasons unrelated to the medication and due to the following: age < 18 years or > 40 years (n = 3); total hirsutism score < 14 (n = 6); ovarian cyst(s) noted on enrollment (n = 2); or failure to take the drugs assigned (n = 2).
taken in conjunction with Diane from days 5 to 15 of each cycle, according to the reverse sequential regimen of Hammerstein and Cupceancu. 2 The drugs were handed to the subjects at each of the clinical follow-up visits 1, 3, 6, 9, and 12 months after starting Diane, where the following were also recorded: evaluation of general complaints as well as of specific endocrine and menstrual problems, assessment of the number of tablets taken and/or missed, weight and blood pressure recordings, and grading of hirsutism according to the index score of Ferriman and Gallway.12 Endocrine studies, consisting of plasma total and free testosterone (T), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), androstenedione (A), as well as dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), were done between 8:00 A.M. and 10:00 A.M. prior to therapy and repeated at 6 to 9 months of study prior to the start of a new cycle of medication. EXPRESSION OF RESULTS
Plasma androgens, gonadotropins, and PRL were assayed at one center, according to radioimmunoassay methods previously published. 13 Samples from each subject were assayed simultaneously to minimize assay variations, which never exceeded 10%. All clinical data were forwarded to the Department of Community Health Sciences of the University of Calgary (Dr. Love) for statistical evaluation. The relative difference in the hirsutism score, whether total, facial, bust, or abdominal, was calculated as follows: Difference between hirsutism score at selected month and baseline score
x 100
Baseline hirsutism score
Determination of the levels of significance was done using a paired t-test for the laboratory findings and corrected chi-square analysis for the clinical data.
EXPERIMENTAL DESIGN
After signing the appropriate consent, each subject was given a progestogen-estrogen combination drug containing 2 mg of CPA and 0.05 mg ofEE 2 (Diane) to be taken daily from days 5 to 25 of each month for 12 months. They were then randomized and double-blindly assigned to either a placebo or Androcur (100 mg of CPA) to be 1016
Belisle and Love Cyproterone acetate in severe hirsutism
RESULTS
There was no significant aHterence between the Diane and Androcur groups at the beginning of the study, with respect to the following variables: age, race, gravidity, parity, number of previous abortions, body weight, mean blood pressure, presence and length of menstrual cycle, preFertility and Sterility
women who terminated the study prematurely were depression, weight increase, headaches, decreased libido, and fatigue.
Table 1. Premature Termination of Patients Enrolled in Study of Treatment of Hirsutism Androcur % No.
Diane
Reason
No.
%
Adverse eft'ectsa Patient-relatedb Physician-related Preterm (> 4 weeks from end of study) Loss to follow-up
10179 2179 9179 0/79
12.7 2.5 11.4 0.0
12/79 4179 4/79 2/79
15.2 5.1 5.1 2.5
2179
2.5
0/79
0.0
Total
29/79
29.1
22179
27.8
SAFETY OF CYPROTERONE ACETATE
aAlone or in combination with other reasons. bNoncompliance, moving from area, wishes pregnancy, states no longer needs therapy, wishes cosmetic therapy.
vious and type of hormonal therapy (within 2 years), and previous and type of cosmetic therapy. The mean baseline total and specific body distributions of hirsutism for each study group were: Diane-total, 19.5; facial, 5.8; thorax, 1.6; abdomen, 4.7; and Androcur-total, 20.1; facial, 6.0; thorax, 1.8; abdomen, 5.0. Sixty-seven and ninetenths percent of the subjects in the Diane study group and 65.4% of those in the Androcur group showed a total scoring index that ranged between 15 and 22. PREMATURE TERMINATIONS
Of the 79 women entered into each of the study groups, 29.1% of the patients in the Diane group and 27.8% of those in the Androcur group had left the study before its 12-month completion. As shown in Table 1, more of the women in the Androcur group left the study because of patientrelated factors or preterm termination at the investigator's choice, whereas more of the patients in the Diane group left the study because of physician-related factors or loss of follow-up. The most common adverse effects experienced by the
For both study groups, the cumulative incidence of adverse effects (since the previous visit) was studied at each month offollow-up. We found no significant difference in the incidence of the following adverse effects at any month of followup evaluation between the Diane and Androcur groups: menometrorrhagia (mean incidence, 9.9%); acne (6.5%); decreased libido (9.5%); edema (9.3%); nausea (17.5%); vomiting (4.8%); headache (20.3%); and depression (12.7%). In contrast, as illustrated in Table 2, in the Diane group, the incidence of breast tenderness at 3 and 9 months of follow-up study was significantly greater than in the Androcur group. On the other hand, the incidence of the two following complications was significantly greater at selected months in the Androcur group: amenorrhea, at 1, 3, and 6 months, and weight gain, at 6, 9, and 12 months. Among a list of "other complaints," which represented symptoms not specifically solicited at the follow-up visit, the one of greatest importance over the duration of the study was fatigue, the mean frequency of which was 2.5% in the Diane group and 6.7% in the Androcur group (P < 0.05, results not shown).
EFFICACY OF THERAPY
The results are summarized in Table 3. Table 4 compares plasma androgens, gonadotropins, and PRL concentrations before therapy and at 6 to 9 months of therapy in these same subjects. With respect to the total hirsutism score (Table 3), 70%
Table 2. Cumulative Incidence of Breast Tenderness, Amenorrhea, and Weight Gain in Women Treated for Hirsutism with Diane and Androcur, by Month of Follow-up Study Month of follow-up 1 3 6 9 12
Breast tenderness Andocur Diane No. % No. % 27/71 32/69 18/64 14/59 7/56
38.0 46.4 28.2 23.7 12.5
20176 12/73 17/68 4/59 2/56
26.3 16.4b 25.0 6.8 c 3.6
Amenorrhea Androcur Diane No. No. % % 3/71 0/69 0/64 2/59 1156
4.2 0.0 0.0 3.4 1.8
24176 20173 10/68 9/59 3/56
32.6 b 27.4 b 14.7d 15.3 5.4
Weight gainG No.
Diane Mean
71, 79 64 59 56
1.0 1.7 1.2 0.5 1.1
±
± ± ± ± ±
SEM
No.
0.45 0.66 0.74 1.14 1.47
76 73 68 59 56
Androcur Mean ± SEM 0.4 1.1 2.2 3.4 6.3
± ± ± ± ±
0.43 c 0.59 0.85c 1.04d 2.36d
aRelative percent gain in body weight from baseline. SEM, standard error of the mean. bp < 0.001. cp < 0.05. dp < 0.01. Vol. 46, No.6, December 1986
Belisle and Love Cyproterone acetate in severe hirsutism
1017
Table 3. Relative Difference in Hirsutism Scores in Women Treated for Hirsutism with Diane and with Androcur by Month of Follow-up Study Index of hirsutism Total Diane Androcur P valued Facial Diane Androcur P value Bust Diane Androcur P value Abdomen Diane Androcur P value
%
1 month
Relative decrease in scoring index per specific visit (mean ± SE) 3 months 6 months 9 months
12 months
0.1 ± 0.92 (n = 71) 0.3 ± 1.32 (n = 76) > 0.10
4.3 ± 1.44a (n = 69) 14.0 ± 1.51 b (n = 64) 19.6 ± 1.67 b (n = 69) 24.6 ± 1.91 b (n = 56) 10.7 ± 2.02b (n = 73) 21.8 ± 2.09 b (n = 68) 16.8 ± 2.02b (n = 59) 30.8 ± 1.94b (n = 56) < 0.01 < 0.05 < 0.02 < 0.01
0.1 ± 1.64 (n = 71) 0.2 ± 2.08 (n = 76) > 0.10
8.6 ± 2.30 b (n = 69) 15.7 ± 2.55 b (n = 64) 24.0 ± 2.92b (n = 60) 30.1 ± 2.82b (n = 56) 15.4 ± 2.85 b (n = 73) 25.8 ± 2.98 b (n = 68) 27.9 ± 3.34 b (n = 59) 33.0 ± 3.29 b (n = 56) > 0.10 > 0.10 > 0.10 < 0.01
3.3 ± 3.06 (n = 71) 3.7 ± 3.39 (n = 76) > 0.10
5.0 ± 3.68 (n = 69) 10.0 ± 3.30 a (n = 64) 9.3 ± 4.34c (n = 60) 12.1 ± 4.25a (n = 56) 9.1 ± 2.68 b (n = 73) 21.1 ± 3.25 b (n = 68) 25.4 ± 3.50 b (n = 59) 31.2 ± 2.66 b (n = 56) < 0.01 < 0.02 < 0.10 < 0.02
0.1 ± 1.96 (n = 71) 2.1 ± 2.38 (n = 76) > 0.10
1.3 ± 2.59 (n = 69) 12.7 ± 2.94 b (n = 64) 14.8 ± 3.17 b (n = 60) 20.1 ± 3.57 b (n = 65) 6.2 ± 2.64c (n = 73) 20.6 ± 2.92b (n = 68) 26.0 ± 2.81 b (n = 59) 31.2 ± 2.66 b (n = 56) > 0.10 < 0.01 < 0.02 > 0.10
Values significantly different from hirsutism score at baseline. ap < 0.01. bp < 0.001. cp < 0.05. dDifferences between Diane and Androcur in treated subjects (n).
to 80% of the subjects showed a decrease in their grading index, compared with baseline score. This relative difference from the baseline index was significantly different in both the Diane and the Androcur group by the third month of followup study, although it was greater in the Androcur group than in the Diane group. This difference in drug effects persisted throughout the study thereafter. Thus, by the 12th month offollow-up study, 28 patients (48.3%) in the Androcur group presented a total hirsutism score < 14, 10 of whom showed complete normalization of their index (Le., < 10). In contrast, in the Diane study group, 18 patients (27.2%) showed a regression in their total score to < 14, and only 3 subjects normalized their hirsutism index (P < 0.002, Androcur versus Diane). When facial and abdominal distributions of hirsutism were graded, a similar trend of improvement was observed in both study groups, although with some variations at specific followup visits. Thus with respect to facial hirsutism, the relative difference from baseline hirsutism was significantly different by the third month in both the Diane and Androcur groups. However, the difference between study groups was significant only at the sixth month of follow-up. On the other hand, for bust and abdominal hirsutism scores, whereas the differences from baseline scores were significant beginning at the third follow-up month in the Androcur group, those in the Diane group were significantly different from 1018
baseline only after the sixth month. Consequently, the Androcur group showed a greater effect than the Diane group by the 6th month of followup study for bust hirsutism score but only at the 9- and 12-month visits for the abdominal index. As illustrated in Table 4, these clinical improvements were paralleled by significant decreases in circulating plasma FSH, LH, and free T in both study groups, without significant changes in the Table 4. Plasma Androgens, Gonadotropins, and PRL Before Therapy and After 6 to 9 Months of Therapy for Hirsutism with Diane and Androcur Plasma deterrninationsa
Baseline mean ± SEM
FSH (mIU/ml) LH (mIU/ml) PRL (ng/ml) T (ng/dl) Free T (%) A (ng/ml) DHEA (ng/ml) DHEA-S (fJ-g/ml)
7.6 22.7 7.3 88.4 2.54 3.7 8.1 2.8
± 3.5 ± 5.8 b ± 4.6 ± 45.7 b ± 0.82b ± 1.1 ± 2.1 ± 1.6
S to 9 months
of therapy
mean ± SErn
4.1 6.9 8.3 44.5 1.64 2.1 7.7 2.7
± 1.9c ± 4.8d ± 5.2 23.0 0.52c 0.52c 1.9 ± 1.9
± ± ± ±
aPlasma hormone concentrations were analyzed separately before therapy and at 6 to 9 months of follow-up for both the Diane and the Androcur study groups. They were then pooled and analyzed as a single treated group, because no drug difference was observed. b Above-normal plasma hormone concentration. cValues at 6 to 9 months significantly different from baseline value, P < 0.05. dValues at 6 to 9 months significantly different from baseline value, P < 0.01.
Belisle and Love Cyproterone acetate in severe hirsutism
Fertility and Sterility
concentrations of PRL, total T, A, DHEA, or DHEA-S. No difference was observed, however, in the induction of these endocrine changes between the Diane and Androcur groups. DISCUSSION
More information is still needed on the pharmacologic approach of severe hirsutism with antiandrogens. The recent availability of CPA for medical use in Canada prompted this doubleblind and randomized study. Our main findings show that CPA significantly reduced severe hirsutism at both low (Diane) and high (Androcur) doses and that the therapeutic effects are greater with Androcur. Furthermore, with the exception of amenorrhea, breast tenderness, and weight gain, our results demonstrate a similar incidence of adverse effects with both drug regimens. With respect to total body hair distribution, our study demonstrates a significant improvement by CPA, as attested by the criteria of Ferriman and Gallway.l2 By the 9th to the 12th month of therapy, 70% to 80% of our subjects showed significant reduction in their hirsutism. However, this therapeutic effect was more pronounced at each specific follow-up visit in the Androcur group, where 20% of our treated subjects showed complete normalization in their scoring index by the end of the study. Few studies exist comparing the effects of CPA at various doses in hirsute women. Our results agree with those of Biffignandi et al.,1 who showed maximal therapeutic effects in 93.5% of hirsute patients treated with 50 to 100 mg of CPA for 6 to 9 months. Our results also agree with those of uncontrolled studies with a limited number of subjects, by Dewhurst et al. 8 and Garner and Poznanski,9 who used a fixed dose of 100 mg of CPA, but disagree with those of Hammerstein et al.,6 who observed complete disappearance of hirsutism in 60% to 80% of their 600 hirsute subjects after a similar therapy. Other than variation in patient sensitivity to CPA, we have no readily available explanation for this latter discordance. Our study is the first to correlate excessive hair growth distribution at specific body areas with various doses of CPA in a randomized protocol. We observed important differences in both the sequence of clinical improvements and the concentration of CPA needed to exert this effect. For both the bust and abdominal hirsutism scores, the differences from baseline index were significant Vol. 46, No.6, December 1986
by the third month in the Androcur study group but only by the sixth month of therapy in the Diane group. This is in contrast to that observed for facial hair growth, where by the third month the relative difference from baseline facial hirsutism score was significantly different in both the Diane and Androcur groups. Furthermore, greater therapeutic effect with Androcur was manifested by the sixth month of therapy for thoracic hair, by the ninth month for the abdomen, but only at the 6-month follow-up for facial hirsutism. These variations in drug responses cannot be explained by heterogeneity in our subjects, because the randomization resulted in two comparable study groups. Rather, considering that our two groups of hirsute patients showed a similar endocrine profile before therapy and at 6 to 9 months of therapy with both doses of CPA, these results suggest that at least at these specific points of study, the therapeutic effects of CPA in hirsutism were mediated primarily through its peripheral anti androgenic effects at the target cells,4 which does vary in sensitivity to circulating bioactive androgens. l4 Seasonal variability in hair growth and the limitations of the scoring index may also explain part of these discrepancies. The system is unable to take into account hair that is finer and paler and, in some cases, more sparse. Moreover, on the face, there can be a marked reduction in the area involved with no change in score. Finally, the Ferriman and Gallway index l2 does not take into account seborrhea and acne, which respond most rapidly and completely to CPA, even at low doses. 6 Fatigue, often combined with lassitude, edema, and loss of libido, are the adverse reactions most often complained about during CPA therapy.6, 7 Our results agree with these findings: these were the most common adverse effects, noted by the 28% to 30% of subjects who discontinued the study prematurely. Although the former three symptoms are attributable to the progestational activity of CPA, 11 the opposite appears to be true for the loss of libido, which mostly relates to the anti androgenic properties of CPA. However, in contrast to the observations of othersl who used similar doses of CPA, we found no difference between drugs in the cumulative incidence of these adverse effects among patients who completed the study. The increased incidence of acne in both study groups was unexpected, but current data exist to show that CPA also possesses mild intrinsic androgenic activity.l5 For those patients who
Belisle and Love Cyproterone acetate in severe hirsutism
1019
completed the study protocol, we observed that the incidence of amenorrhea, weight gain, and breast tenderness was two to three times higher than in most reports. 6, 7 Whereas the first two adverse effects were greater in the Androcur group than in the Diane group, the reverse was true for breast discomfort. Furthermore, we found that the incidence of amenorrhea was highest during the first 3 to 6 months of therapy and decreased thereafter, but weight and breast tenderness either increased or remained consistently elevated throughout the study period. We have no ready explanations for these observations, and no consistent pattern was observed when they were correlated with the menstrual history and weight of the subjects before therapy. The absence of pregnancy in both study groups attests to the in vivo antigonadotropic effect of our drug regimen, a finding that has not been consistently observed in prior studies. 16, 17 This is further enhanced by our observed decrease in circulating plasma FSH and LH after 6 to 9 months of therapy with CPA. Acute administration of 100 j.Lg of LH-releasing hormone to five of these patients (results not shown) suggested a reduced pituitary response in LH and FSH, compared with baseline response. CPA at both doses did not affect baseline PRL or the total circulating plasma T concentration, but the free T levels decreased by one-half. This would result from the increased levels in T-binding globulin by estrogens, 7 because CPA consistently increased the metabolic clearance rate of T in hirsute patients,18, 19 while decreasing its production rates. Plasma A, DHEA, and DHEA-S were unchanged under therapy, in contrast to the glucocorticoid activity reported for CPA by others in both humans 7 and animals. 15 Taken together, our results would therefore suggest that the endocrine mechanisms by which CPA acted in our group of hirsute patients are severalfold and include competition with bioactive androgens at the target cell level, decrease in androgen input to the target cell, and reduction in androgen production through its anti gonadotropic effects. REFERENCES 1. Biffignandi P, Massuchetti C, Molinatti GM: Female hirsutism: pathophysiological considerations and therapeutic implications. Endocr Rev 5:498, 1984 2. Hammerstein J, Cupceancu B: Behandlung des hirsutismus cyproterone acetat. Dtsch Med Wochenschr 94:829, 1969 Translated to German Med Monthly 14:599, 1969
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3. Neumann F,Schleusener A, Albring M: Pharmacology of antiandrogens. An Androgenization in Women, Edited by J Hammerstein, V Lachnit-Fixson, F Newmann, C Plewig. Amsterdam, Exerpta Medica, 1980, p 147 4. Newmann F, von Berswordt-Wallrabe R, Eiger W, Steinbeck H, Han JD, Kramer M: Aspects of androgen dependent events as studied by antiandrogens. Recent Prog Horm Res 26:337, 1970 5. Ismail AAA, Davidson DW, Souka AR, Barnes EW, Irvine WJ, Kilimnik H, Vanderbeeken Y: The evaluation of the role of androgens in hirsutism and the use of a new antiandrogen cyproterone acetate for therapy. J Clin Endocrinol Metab 39:81, 1974 6. Hammerstein J, Meckies J, Leo-Rossberg I, Moltz L, Zielske F: Use of cyproterone acetate in the treatment of acne, hirsutism and virilism. J Steroid Biochem 6:827, 1975 7. Gaspard UJ, Ramus MA, Soyeur-Broux M, Chantraine R, Duvivier J: Clinical, endocrinological and metabolic evaluation of women treated for acne by a combination of cyproterone acetate and ethmylestradiol (Diane). In Combined Antiandrogen-Estrogen Therapy in Dermatology: Proceedings of the Diane Symposium. Amsterdam, Excerpta Medica, 1980, p 75 8. Dewhurst CJ, Underhill R, Goldman S, Mansfield M: The treatment of hirsutism with cyproterone acetate (an antiandrogen). Br J Obstet Gynaecol 84:119, 1977 9. Garner PR, Poznanski N: Treatment of severe hirsutism resulting from hyperandrogenism with the reverse sequential cyproterone acetate regimen. J Reprod Med 29:232, 1984 10. Humpe M, Wendy H, Dogs G: Plasmaspiegel und pharmakokinetik von cyproteronacetat nagh oraler applikation als 50mgm: tablette bei 5 Mannern. Arzneimittelforsch 28:319, 1978 11. Neumann F: Anti-androgens. In Advances in Gynaecological Endocrinology, Edited by HS Jacobs. London, Royal College of Obstetricians and Gynaecologists, 1978, p 335 12. Ferriman D, Gallway JD: Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 21:1440, 1961 13. Belisle S, Menard J: Adrenal androgen production in hyperprolactinemic states. Fertil Steril 33:396, 1980 14. Serafini P, Ablan F, Lobo RA: 5 reductase activity in the genital skin of hirsute women. J Clin Endocrinol Metab 60:349, 1985 15. Poyet P, Labrie F: Comparison of the antiandrogenic/androgenic activities of fiutamide, cyproterone acetate and megestrol acetate. Mol Cell Endocrinol 42:283, 1985 16. Brotherton J, Barnard G: Some aspects of cyproterone acetate on levels of other steroid hormones in man. J Reprod Fertil 36:373, 1974 17. Knuth VA, Hano R, Nieschlag E: Effect of fiutamide or cyproterone acetate on pituitary and testicular hormones in normal men. J Clin Endocrinol Metab 59:963, 1984 18. Mowszowicz I, Bieber DE, Chung KW, Bullock L, Bardin CW: Synandrogenic and anti androgenic effect of progestins: comparison with nonprogestational antiandrogens. Endocrinology 95:1589, 1974 19. Mowszowicz I, Wright F, Vincens M, Rigaud C, Mahoul K, Mavier P, Guillemant S, Kutten F, Mauvais-Jarvis P: Androgen metabolism in hirsute patients treated with cyproterone acetate. J Steroid Biochem 20:757, 1984
Belisle and Love Cyproterone acetate in severe hirsutism
Fertility and Sterility
FERTIT..ITY AND STERILITY Copyright c 1986 The American Fertility Society
Clinical efficacy and safety of cyproterone acetate in severe hirsutism: results of a multicentered Canadian study*t
Serge Belisle, M.D.:!: Edgar J. Love, Ph.D.§ University of Sherbrooke, School of Medicine, Sherbrooke, Quebec, and University of Calgary, School of Medicine, Calgary, Alberta, Canada
We compared the efficacy and safety of cyproterone acetate (Shering AC, Berlin, FRG) at a low (Diane, 2 mg) or a high dose (Androcur, 100 mg) in the treatment of 158 patients with severe hirsutism. At baseline, no difference was observed in mean hirsutism total index (19.5 Diane versus 20.1 Androcur) or distribution (facial, bust, or abdomen). By the end of the study, patient loss in Diane and Androcur groups was 29.1% and 27.8%, respectively, and the mean percent difference in the scoring index was as follows: total, 24.6 Diane versus 30.8 Androcur, P < 0.05; facial, 30.1 Diane versus 33.0 Androcur, P < 0.10; bust, 12.1 Diane versus 312 Androcur, P < 0.02; and abdomen, 20.1 Diane versus 312 Androcur, P < 0.02. Except for breast tenderness (Diane> Androcur), amenorrhea, and weight gain, (Androcur > Diane), the incidence of side effects was comparable in both groups. Fertil Steril46:1015, 1986
Antiandrogens have been introduced into the treatment of hirsutism because of their ability to prevent androgens from expressing their activity at target sites (for review, see Biffignandi et al. 1 ). The antiandrogen cyproterone acetate (CPA) was
Received May 7, 1986; revised and accepted August 14, 1986. *Sponsored by the Canadian Fertility Research Association and funded by a grant-in-aid from Berlen Laboratories Limited, Canada. tThe following collaborators participated in this study: Peter Garner, M.D., University of Ottawa; Barbara Cruckshank, M.D., University of Western Ontario; Youssef Ainmelk, M.D., University of Sherbrooke; Togas Tulandi, M.D., McGill University; Nacia Faure, M.D., Laval University; Arthur Leader, M.D., University of Calgary; Timothy Rowe, M.D., University of British Columbia; and Jerald Bain, M.D., University of Toronto. :j:Reprint requests: Dr. Serge Belisle, Department ofObstetrics and Gynecology, Centre Hospitalier Universitaire, 3001 12th Avenue North, Sherbrooke, Quebec, JIH 5N4, Canada. §Department of Community Health Sciences, University of Calgary, School of Medicine. Vol. 46, No.6, December 1986
first used clinically by Hammerstein and Cupceancu. 2 It is a hydroxyprogesterone derivative that blocks the effects of bioactive androgens at the receptor level. It has also marked progestational activity, as well as mild antigonadotropic and glucocorticoid-like action. 3 , 4 Extended clinical trials using CPA in androgenized women were conducted in several European countries. 5 -8 Recruited in these studies were mostly women with signs of androgenization, such as acne, seborrhea, and milder forms of hirsutism, who were given a progestogen-estrogen combination therapy consisting of 2 mg of CPA and 0.05 mg of ethinylestradiol (EE 2 ) (Diane, Shering AC, Berlin, FRG). Overall, the results showed significant improvement in mild hirsutism after 6 to 9 months of treatment with Diane. However, much less success was observed in moderate to severe hirsutism, where uncontrolled studies suggested that a higher dose of CPA should be considered. 1 , 6, 8-11 The objective of this research, therefore, was to compare the efficacy and safety of a low and a
Belisle and Love Cyproterone acetate in severe hirsutism
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high dose of CPA in patients with severe forms of hirsutism, in a randomized and double-blind study. MATERIALS AND METHODS SUBJECTS
The research project was approved by the Human Ethics Committee of each of the eight participating centers. Women with severe hirsutism of nontumoral origin, with or without menstrual disorders, were recruited from the following Canadian university centers: Sherbrooke (Quebec), Laval (Quebec), McGill (Quebec), Ottawa (Ontario), Toronto (Ontario), Western Ontario (Ontario), Calgary (Alberta), and British Columbia. The inclusion criteria were (1) severe hirsutism (Le., patients who presented with the chief complaint of excessive hair growth and who, after appropriate clinical and paraclinical investigation, required systemic therapy for such a condition); (2) clinical grading of body hair growth> 14, according to the index of Ferriman and Gallway12; (3) age between 18 and 40 years; and (4) ability to give consent to therapy and to remain in the study for 12 months. Excluded from the study were patients (1) with ovarian and adrenal tumors; (2) on hormonal medications within 60 days of enrollment period; (3) receiving other types of prescribed medication; and (4) with absolute contraindications to steroids. No other form of ancil·lary therapy of hirsutism, except shaving during the first month, was allowed during the study period. One hundred seventy-one women were initially recruited into the study. Thirteen of these women were subsequently excluded for reasons unrelated to the medication and due to the following: age < 18 years or > 40 years (n = 3); total hirsutism score < 14 (n = 6); ovarian cyst(s) noted on enrollment (n = 2); or failure to take the drugs assigned (n = 2).
taken in conjunction with Diane from days 5 to 15 of each cycle, according to the reverse sequential regimen of Hammerstein and Cupceancu. 2 The drugs were handed to the subjects at each of the clinical follow-up visits 1, 3, 6, 9, and 12 months after starting Diane, where the following were also recorded: evaluation of general complaints as well as of specific endocrine and menstrual problems, assessment of the number of tablets taken and/or missed, weight and blood pressure recordings, and grading of hirsutism according to the index score of Ferriman and Gallway.12 Endocrine studies, consisting of plasma total and free testosterone (T), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), androstenedione (A), as well as dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), were done between 8:00 A.M. and 10:00 A.M. prior to therapy and repeated at 6 to 9 months of study prior to the start of a new cycle of medication. EXPRESSION OF RESULTS
Plasma androgens, gonadotropins, and PRL were assayed at one center, according to radioimmunoassay methods previously published. 13 Samples from each subject were assayed simultaneously to minimize assay variations, which never exceeded 10%. All clinical data were forwarded to the Department of Community Health Sciences of the University of Calgary (Dr. Love) for statistical evaluation. The relative difference in the hirsutism score, whether total, facial, bust, or abdominal, was calculated as follows: Difference between hirsutism score at selected month and baseline score
x 100
Baseline hirsutism score
Determination of the levels of significance was done using a paired t-test for the laboratory findings and corrected chi-square analysis for the clinical data.
EXPERIMENTAL DESIGN
After signing the appropriate consent, each subject was given a progestogen-estrogen combination drug containing 2 mg of CPA and 0.05 mg ofEE 2 (Diane) to be taken daily from days 5 to 25 of each month for 12 months. They were then randomized and double-blindly assigned to either a placebo or Androcur (100 mg of CPA) to be 1016
Belisle and Love Cyproterone acetate in severe hirsutism
RESULTS
There was no significant aHterence between the Diane and Androcur groups at the beginning of the study, with respect to the following variables: age, race, gravidity, parity, number of previous abortions, body weight, mean blood pressure, presence and length of menstrual cycle, preFertility and Sterility
women who terminated the study prematurely were depression, weight increase, headaches, decreased libido, and fatigue.
Table 1. Premature Termination of Patients Enrolled in Study of Treatment of Hirsutism Androcur % No.
Diane
Reason
No.
%
Adverse eft'ectsa Patient-relatedb Physician-related Preterm (> 4 weeks from end of study) Loss to follow-up
10179 2179 9179 0/79
12.7 2.5 11.4 0.0
12/79 4179 4/79 2/79
15.2 5.1 5.1 2.5
2179
2.5
0/79
0.0
Total
29/79
29.1
22179
27.8
SAFETY OF CYPROTERONE ACETATE
aAlone or in combination with other reasons. bNoncompliance, moving from area, wishes pregnancy, states no longer needs therapy, wishes cosmetic therapy.
vious and type of hormonal therapy (within 2 years), and previous and type of cosmetic therapy. The mean baseline total and specific body distributions of hirsutism for each study group were: Diane-total, 19.5; facial, 5.8; thorax, 1.6; abdomen, 4.7; and Androcur-total, 20.1; facial, 6.0; thorax, 1.8; abdomen, 5.0. Sixty-seven and ninetenths percent of the subjects in the Diane study group and 65.4% of those in the Androcur group showed a total scoring index that ranged between 15 and 22. PREMATURE TERMINATIONS
Of the 79 women entered into each of the study groups, 29.1% of the patients in the Diane group and 27.8% of those in the Androcur group had left the study before its 12-month completion. As shown in Table 1, more of the women in the Androcur group left the study because of patientrelated factors or preterm termination at the investigator's choice, whereas more of the patients in the Diane group left the study because of physician-related factors or loss of follow-up. The most common adverse effects experienced by the
For both study groups, the cumulative incidence of adverse effects (since the previous visit) was studied at each month offollow-up. We found no significant difference in the incidence of the following adverse effects at any month of followup evaluation between the Diane and Androcur groups: menometrorrhagia (mean incidence, 9.9%); acne (6.5%); decreased libido (9.5%); edema (9.3%); nausea (17.5%); vomiting (4.8%); headache (20.3%); and depression (12.7%). In contrast, as illustrated in Table 2, in the Diane group, the incidence of breast tenderness at 3 and 9 months of follow-up study was significantly greater than in the Androcur group. On the other hand, the incidence of the two following complications was significantly greater at selected months in the Androcur group: amenorrhea, at 1, 3, and 6 months, and weight gain, at 6, 9, and 12 months. Among a list of "other complaints," which represented symptoms not specifically solicited at the follow-up visit, the one of greatest importance over the duration of the study was fatigue, the mean frequency of which was 2.5% in the Diane group and 6.7% in the Androcur group (P < 0.05, results not shown).
EFFICACY OF THERAPY
The results are summarized in Table 3. Table 4 compares plasma androgens, gonadotropins, and PRL concentrations before therapy and at 6 to 9 months of therapy in these same subjects. With respect to the total hirsutism score (Table 3), 70%
Table 2. Cumulative Incidence of Breast Tenderness, Amenorrhea, and Weight Gain in Women Treated for Hirsutism with Diane and Androcur, by Month of Follow-up Study Month of follow-up 1 3 6 9 12
Breast tenderness Andocur Diane No. % No. % 27/71 32/69 18/64 14/59 7/56
38.0 46.4 28.2 23.7 12.5
20176 12/73 17/68 4/59 2/56
26.3 16.4b 25.0 6.8 c 3.6
Amenorrhea Androcur Diane No. No. % % 3/71 0/69 0/64 2/59 1156
4.2 0.0 0.0 3.4 1.8
24176 20173 10/68 9/59 3/56
32.6 b 27.4 b 14.7d 15.3 5.4
Weight gainG No.
Diane Mean
71, 79 64 59 56
1.0 1.7 1.2 0.5 1.1
±
± ± ± ± ±
SEM
No.
0.45 0.66 0.74 1.14 1.47
76 73 68 59 56
Androcur Mean ± SEM 0.4 1.1 2.2 3.4 6.3
± ± ± ± ±
0.43 c 0.59 0.85c 1.04d 2.36d
aRelative percent gain in body weight from baseline. SEM, standard error of the mean. bp < 0.001. cp < 0.05. dp < 0.01. Vol. 46, No.6, December 1986
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Table 3. Relative Difference in Hirsutism Scores in Women Treated for Hirsutism with Diane and with Androcur by Month of Follow-up Study Index of hirsutism Total Diane Androcur P valued Facial Diane Androcur P value Bust Diane Androcur P value Abdomen Diane Androcur P value
%
1 month
Relative decrease in scoring index per specific visit (mean ± SE) 3 months 6 months 9 months
12 months
0.1 ± 0.92 (n = 71) 0.3 ± 1.32 (n = 76) > 0.10
4.3 ± 1.44a (n = 69) 14.0 ± 1.51 b (n = 64) 19.6 ± 1.67 b (n = 69) 24.6 ± 1.91 b (n = 56) 10.7 ± 2.02b (n = 73) 21.8 ± 2.09 b (n = 68) 16.8 ± 2.02b (n = 59) 30.8 ± 1.94b (n = 56) < 0.01 < 0.05 < 0.02 < 0.01
0.1 ± 1.64 (n = 71) 0.2 ± 2.08 (n = 76) > 0.10
8.6 ± 2.30 b (n = 69) 15.7 ± 2.55 b (n = 64) 24.0 ± 2.92b (n = 60) 30.1 ± 2.82b (n = 56) 15.4 ± 2.85 b (n = 73) 25.8 ± 2.98 b (n = 68) 27.9 ± 3.34 b (n = 59) 33.0 ± 3.29 b (n = 56) > 0.10 > 0.10 > 0.10 < 0.01
3.3 ± 3.06 (n = 71) 3.7 ± 3.39 (n = 76) > 0.10
5.0 ± 3.68 (n = 69) 10.0 ± 3.30 a (n = 64) 9.3 ± 4.34c (n = 60) 12.1 ± 4.25a (n = 56) 9.1 ± 2.68 b (n = 73) 21.1 ± 3.25 b (n = 68) 25.4 ± 3.50 b (n = 59) 31.2 ± 2.66 b (n = 56) < 0.01 < 0.02 < 0.10 < 0.02
0.1 ± 1.96 (n = 71) 2.1 ± 2.38 (n = 76) > 0.10
1.3 ± 2.59 (n = 69) 12.7 ± 2.94 b (n = 64) 14.8 ± 3.17 b (n = 60) 20.1 ± 3.57 b (n = 65) 6.2 ± 2.64c (n = 73) 20.6 ± 2.92b (n = 68) 26.0 ± 2.81 b (n = 59) 31.2 ± 2.66 b (n = 56) > 0.10 < 0.01 < 0.02 > 0.10
Values significantly different from hirsutism score at baseline. ap < 0.01. bp < 0.001. cp < 0.05. dDifferences between Diane and Androcur in treated subjects (n).
to 80% of the subjects showed a decrease in their grading index, compared with baseline score. This relative difference from the baseline index was significantly different in both the Diane and the Androcur group by the third month of followup study, although it was greater in the Androcur group than in the Diane group. This difference in drug effects persisted throughout the study thereafter. Thus, by the 12th month offollow-up study, 28 patients (48.3%) in the Androcur group presented a total hirsutism score < 14, 10 of whom showed complete normalization of their index (Le., < 10). In contrast, in the Diane study group, 18 patients (27.2%) showed a regression in their total score to < 14, and only 3 subjects normalized their hirsutism index (P < 0.002, Androcur versus Diane). When facial and abdominal distributions of hirsutism were graded, a similar trend of improvement was observed in both study groups, although with some variations at specific followup visits. Thus with respect to facial hirsutism, the relative difference from baseline hirsutism was significantly different by the third month in both the Diane and Androcur groups. However, the difference between study groups was significant only at the sixth month of follow-up. On the other hand, for bust and abdominal hirsutism scores, whereas the differences from baseline scores were significant beginning at the third follow-up month in the Androcur group, those in the Diane group were significantly different from 1018
baseline only after the sixth month. Consequently, the Androcur group showed a greater effect than the Diane group by the 6th month of followup study for bust hirsutism score but only at the 9- and 12-month visits for the abdominal index. As illustrated in Table 4, these clinical improvements were paralleled by significant decreases in circulating plasma FSH, LH, and free T in both study groups, without significant changes in the Table 4. Plasma Androgens, Gonadotropins, and PRL Before Therapy and After 6 to 9 Months of Therapy for Hirsutism with Diane and Androcur Plasma deterrninationsa
Baseline mean ± SEM
FSH (mIU/ml) LH (mIU/ml) PRL (ng/ml) T (ng/dl) Free T (%) A (ng/ml) DHEA (ng/ml) DHEA-S (fJ-g/ml)
7.6 22.7 7.3 88.4 2.54 3.7 8.1 2.8
± 3.5 ± 5.8 b ± 4.6 ± 45.7 b ± 0.82b ± 1.1 ± 2.1 ± 1.6
S to 9 months
of therapy
mean ± SErn
4.1 6.9 8.3 44.5 1.64 2.1 7.7 2.7
± 1.9c ± 4.8d ± 5.2 23.0 0.52c 0.52c 1.9 ± 1.9
± ± ± ±
aPlasma hormone concentrations were analyzed separately before therapy and at 6 to 9 months of follow-up for both the Diane and the Androcur study groups. They were then pooled and analyzed as a single treated group, because no drug difference was observed. b Above-normal plasma hormone concentration. cValues at 6 to 9 months significantly different from baseline value, P < 0.05. dValues at 6 to 9 months significantly different from baseline value, P < 0.01.
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concentrations of PRL, total T, A, DHEA, or DHEA-S. No difference was observed, however, in the induction of these endocrine changes between the Diane and Androcur groups. DISCUSSION
More information is still needed on the pharmacologic approach of severe hirsutism with antiandrogens. The recent availability of CPA for medical use in Canada prompted this doubleblind and randomized study. Our main findings show that CPA significantly reduced severe hirsutism at both low (Diane) and high (Androcur) doses and that the therapeutic effects are greater with Androcur. Furthermore, with the exception of amenorrhea, breast tenderness, and weight gain, our results demonstrate a similar incidence of adverse effects with both drug regimens. With respect to total body hair distribution, our study demonstrates a significant improvement by CPA, as attested by the criteria of Ferriman and Gallway.l2 By the 9th to the 12th month of therapy, 70% to 80% of our subjects showed significant reduction in their hirsutism. However, this therapeutic effect was more pronounced at each specific follow-up visit in the Androcur group, where 20% of our treated subjects showed complete normalization in their scoring index by the end of the study. Few studies exist comparing the effects of CPA at various doses in hirsute women. Our results agree with those of Biffignandi et al.,1 who showed maximal therapeutic effects in 93.5% of hirsute patients treated with 50 to 100 mg of CPA for 6 to 9 months. Our results also agree with those of uncontrolled studies with a limited number of subjects, by Dewhurst et al. 8 and Garner and Poznanski,9 who used a fixed dose of 100 mg of CPA, but disagree with those of Hammerstein et al.,6 who observed complete disappearance of hirsutism in 60% to 80% of their 600 hirsute subjects after a similar therapy. Other than variation in patient sensitivity to CPA, we have no readily available explanation for this latter discordance. Our study is the first to correlate excessive hair growth distribution at specific body areas with various doses of CPA in a randomized protocol. We observed important differences in both the sequence of clinical improvements and the concentration of CPA needed to exert this effect. For both the bust and abdominal hirsutism scores, the differences from baseline index were significant Vol. 46, No.6, December 1986
by the third month in the Androcur study group but only by the sixth month of therapy in the Diane group. This is in contrast to that observed for facial hair growth, where by the third month the relative difference from baseline facial hirsutism score was significantly different in both the Diane and Androcur groups. Furthermore, greater therapeutic effect with Androcur was manifested by the sixth month of therapy for thoracic hair, by the ninth month for the abdomen, but only at the 6-month follow-up for facial hirsutism. These variations in drug responses cannot be explained by heterogeneity in our subjects, because the randomization resulted in two comparable study groups. Rather, considering that our two groups of hirsute patients showed a similar endocrine profile before therapy and at 6 to 9 months of therapy with both doses of CPA, these results suggest that at least at these specific points of study, the therapeutic effects of CPA in hirsutism were mediated primarily through its peripheral anti androgenic effects at the target cells,4 which does vary in sensitivity to circulating bioactive androgens. l4 Seasonal variability in hair growth and the limitations of the scoring index may also explain part of these discrepancies. The system is unable to take into account hair that is finer and paler and, in some cases, more sparse. Moreover, on the face, there can be a marked reduction in the area involved with no change in score. Finally, the Ferriman and Gallway index l2 does not take into account seborrhea and acne, which respond most rapidly and completely to CPA, even at low doses. 6 Fatigue, often combined with lassitude, edema, and loss of libido, are the adverse reactions most often complained about during CPA therapy.6, 7 Our results agree with these findings: these were the most common adverse effects, noted by the 28% to 30% of subjects who discontinued the study prematurely. Although the former three symptoms are attributable to the progestational activity of CPA, 11 the opposite appears to be true for the loss of libido, which mostly relates to the anti androgenic properties of CPA. However, in contrast to the observations of othersl who used similar doses of CPA, we found no difference between drugs in the cumulative incidence of these adverse effects among patients who completed the study. The increased incidence of acne in both study groups was unexpected, but current data exist to show that CPA also possesses mild intrinsic androgenic activity.l5 For those patients who
Belisle and Love Cyproterone acetate in severe hirsutism
1019
completed the study protocol, we observed that the incidence of amenorrhea, weight gain, and breast tenderness was two to three times higher than in most reports. 6, 7 Whereas the first two adverse effects were greater in the Androcur group than in the Diane group, the reverse was true for breast discomfort. Furthermore, we found that the incidence of amenorrhea was highest during the first 3 to 6 months of therapy and decreased thereafter, but weight and breast tenderness either increased or remained consistently elevated throughout the study period. We have no ready explanations for these observations, and no consistent pattern was observed when they were correlated with the menstrual history and weight of the subjects before therapy. The absence of pregnancy in both study groups attests to the in vivo antigonadotropic effect of our drug regimen, a finding that has not been consistently observed in prior studies. 16, 17 This is further enhanced by our observed decrease in circulating plasma FSH and LH after 6 to 9 months of therapy with CPA. Acute administration of 100 j.Lg of LH-releasing hormone to five of these patients (results not shown) suggested a reduced pituitary response in LH and FSH, compared with baseline response. CPA at both doses did not affect baseline PRL or the total circulating plasma T concentration, but the free T levels decreased by one-half. This would result from the increased levels in T-binding globulin by estrogens, 7 because CPA consistently increased the metabolic clearance rate of T in hirsute patients,18, 19 while decreasing its production rates. Plasma A, DHEA, and DHEA-S were unchanged under therapy, in contrast to the glucocorticoid activity reported for CPA by others in both humans 7 and animals. 15 Taken together, our results would therefore suggest that the endocrine mechanisms by which CPA acted in our group of hirsute patients are severalfold and include competition with bioactive androgens at the target cell level, decrease in androgen input to the target cell, and reduction in androgen production through its anti gonadotropic effects. REFERENCES 1. Biffignandi P, Massuchetti C, Molinatti GM: Female hirsutism: pathophysiological considerations and therapeutic implications. Endocr Rev 5:498, 1984 2. Hammerstein J, Cupceancu B: Behandlung des hirsutismus cyproterone acetat. Dtsch Med Wochenschr 94:829, 1969 Translated to German Med Monthly 14:599, 1969
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3. Neumann F,Schleusener A, Albring M: Pharmacology of antiandrogens. An Androgenization in Women, Edited by J Hammerstein, V Lachnit-Fixson, F Newmann, C Plewig. Amsterdam, Exerpta Medica, 1980, p 147 4. Newmann F, von Berswordt-Wallrabe R, Eiger W, Steinbeck H, Han JD, Kramer M: Aspects of androgen dependent events as studied by antiandrogens. Recent Prog Horm Res 26:337, 1970 5. Ismail AAA, Davidson DW, Souka AR, Barnes EW, Irvine WJ, Kilimnik H, Vanderbeeken Y: The evaluation of the role of androgens in hirsutism and the use of a new antiandrogen cyproterone acetate for therapy. J Clin Endocrinol Metab 39:81, 1974 6. Hammerstein J, Meckies J, Leo-Rossberg I, Moltz L, Zielske F: Use of cyproterone acetate in the treatment of acne, hirsutism and virilism. J Steroid Biochem 6:827, 1975 7. Gaspard UJ, Ramus MA, Soyeur-Broux M, Chantraine R, Duvivier J: Clinical, endocrinological and metabolic evaluation of women treated for acne by a combination of cyproterone acetate and ethmylestradiol (Diane). In Combined Antiandrogen-Estrogen Therapy in Dermatology: Proceedings of the Diane Symposium. Amsterdam, Excerpta Medica, 1980, p 75 8. Dewhurst CJ, Underhill R, Goldman S, Mansfield M: The treatment of hirsutism with cyproterone acetate (an antiandrogen). Br J Obstet Gynaecol 84:119, 1977 9. Garner PR, Poznanski N: Treatment of severe hirsutism resulting from hyperandrogenism with the reverse sequential cyproterone acetate regimen. J Reprod Med 29:232, 1984 10. Humpe M, Wendy H, Dogs G: Plasmaspiegel und pharmakokinetik von cyproteronacetat nagh oraler applikation als 50mgm: tablette bei 5 Mannern. Arzneimittelforsch 28:319, 1978 11. Neumann F: Anti-androgens. In Advances in Gynaecological Endocrinology, Edited by HS Jacobs. London, Royal College of Obstetricians and Gynaecologists, 1978, p 335 12. Ferriman D, Gallway JD: Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 21:1440, 1961 13. Belisle S, Menard J: Adrenal androgen production in hyperprolactinemic states. Fertil Steril 33:396, 1980 14. Serafini P, Ablan F, Lobo RA: 5 reductase activity in the genital skin of hirsute women. J Clin Endocrinol Metab 60:349, 1985 15. Poyet P, Labrie F: Comparison of the antiandrogenic/androgenic activities of fiutamide, cyproterone acetate and megestrol acetate. Mol Cell Endocrinol 42:283, 1985 16. Brotherton J, Barnard G: Some aspects of cyproterone acetate on levels of other steroid hormones in man. J Reprod Fertil 36:373, 1974 17. Knuth VA, Hano R, Nieschlag E: Effect of fiutamide or cyproterone acetate on pituitary and testicular hormones in normal men. J Clin Endocrinol Metab 59:963, 1984 18. Mowszowicz I, Bieber DE, Chung KW, Bullock L, Bardin CW: Synandrogenic and anti androgenic effect of progestins: comparison with nonprogestational antiandrogens. Endocrinology 95:1589, 1974 19. Mowszowicz I, Wright F, Vincens M, Rigaud C, Mahoul K, Mavier P, Guillemant S, Kutten F, Mauvais-Jarvis P: Androgen metabolism in hirsute patients treated with cyproterone acetate. J Steroid Biochem 20:757, 1984
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