0021-972X/91/7205-1008$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society
Vol. 72, No. 5 Printed in U.S.A.
Comparison of Sequential Cyproterone Acetate/Estrogen Versus Spironolactone/Oral Contraceptive in the Treatment of Hirsutism R. C. O'BRIEN, M. E. COOPER, R. M. L. MURRAY, E. SEEMAN, A. K. THOMAS, AND G. JERUMS Department of Endocrinology, Austin Hospital, Heidelberg, Victoria, Australia
treatment efficacy, the frequency with which subjects performed cosmetic measures was recorded. This fell by 38% with spironolactone and by 44.7% with CPA (P < 0.001 both drugs), and again there was no difference between the drugs. Side effects caused cessation of treatment in one subject taking CPA and two subjects taking spironolactone, and milder side effects were noted in two further subjects from each treatment group. We conclude that spironolactone and CPA, in the dosages used in this study, are effective and well tolerated agents for the treatment of hirsutism, and that neither drug demonstrates a particular advantage over the other. (J Clin Endocrinol Metab 72: 1008-1013, 1991)
ABSTRACT. The effects of the antiandrogen drugs cyproterone acetate (CPA) and spironolactone on hair growth and androgen levels were compared in a randomized study of 48 hirsute women. Twenty six subjects completed 6 months of therapy with 100 mg/day CPA and 19 subjects completed 6 months of 100 mg/day spironolactone. All except 10 subjects received concomitant estrogen therapy. Measured objectively, total hair diameter fell by 17.1% with spironolactone (P < 0.001), and by 16.8% with CPA (P < 0.001). The diameter of the hair medulla fell by 17.8% with spironolactone (P < 0.01), and by 31.7% with CPA (P < 0.001). There was no difference between the drugs in their effect on hair diameter. Plasma testosterone levels also fell significantly with both drugs. As a subjective assessment of
T
HE antiandrogen drugs cyproterone acetate (CPA) (1-4) and spironolactone (5-10) have been used extensively in the treatment of hirsutism. Both drugs appear to act primarily by binding to the androgen receptor in target tissues (11-13), and both also reduce androgen biosynthesis (13, 14). In addition CPA is strongly progestogenic, and inhibits the gonadotropin response to lowered testosterone levels (15). Spironolactone and CPA have been shown to be effective in reducing hair growth and androgen levels in hirsute women (1-6, 8-10), although not all studies have shown a beneficial effect (7, 16). The variable results may be due in part to difficulties in obtaining an accurate objective assessment of hair growth (10). Despite the widespread use of CPA and spironolactone in the treatment of female hirsutism, we are unaware of a direct objective comparison of regimens containing the two drugs. The aim of this study was to compare, in a randomized prospective trial, the effects of CPA and spironolactone on hair growth and androgen levels in hirsute women.
Subjects and Methods Fifty hirsute women, mean age 32 ± 1 yr (19-46) were recruited from patients presenting to the Austin Hospital EnReceived April 6,1990. Address requests for reprints to: Dr. R. C. O'Brien, Department of Endocrinology, Austin Hospital, Heidelberg, Victoria, Australia.
docrinology Clinic. Based on ovarian ultrasound examination and plasma gonadotropin measurements (17), eight subjects had the polycystic ovary syndrome (PCO), and 42 had idiopathic hirsutism. No subject had clitoromegaly or other evidence of severe virilization. All were using regular cosmetic measures for hirsutism, but considered this therapy unsatisfactory. Randomization was performed with subjects stratified for the presence of PCO. Twenty-seven subjects were randomized to receive CPA, and twenty-three to receive spironolactone; however, two subjects in the latter group withdrew for personal reasons before commencing therapy. Side effects caused the withdrawal of a further 2 subjects receiving spironolactone and 1 receiving CPA. The total numbers available for analysis were therefore 19 for spironolactone and 26 for CPA, and each group contained 4 subjects with PCO. Treatment Subjects received either spironolactone (Searle Laboratories, Crows Nest, NSW, Australia), 100 mg daily, or CPA (Schering Pty Ltd, Alexandria, NSW, Australia), 100 mg daily on days 5-14 of the menstrual cycle. In these doses both agents have been shown to be effective and well tolerated in the treatment of hirsutism (1, 3, 8, 18). To ensure menstrual regularity and to maintain contraception, CPA was administered with ethinyl estradiol, 30 jug daily on days 5-25. This mode of administration, known as the reverse sequential regimen, was employed to prevent the accumulation of CPA in body fat (3). Subjects
1008
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EFFECTS OF CPA VS. SPIRONOLACTONE IN HIRSUTISM receiving spironolactone were prescribed a triphasic combined oral contraceptive (Triphasil, Wyeth Pharmaceuticals, N.S.W. Australia). Four subjects in the CPA group and six in the spironolactone group did not receive estrogens, three because of previous tubal ligation and seven because of personal reasons. No subject had contra-indications to estrogen therapy. Hormone measurements Samples were taken for measurement of plasma androgens at baseline and again after 6 months of treatment. All samples were taken in the early follicular phase (day 5-10) of the menstrual cycle. Plasma testosterone, androstenedione, dihydroepiandrosterone sulfate (DHEA-S) and sex hormone binding globulin (SHBG) were measured by RIA. Serum electrolytes, urea, and creatinine and liver function tests were also measured regularly throughout the study. Hair measurements Hirsutism was assessed objectively by measuring hair shaft diameter as described by Barth et al. (10). Ten hairs were plucked from the facial area and mounted on a petroleum jelly coated slide. These samples were collected after a constant number of days following whatever cosmetic measures were used. Three measurements were performed on each hair using an eyepiece micrometer (Leitz, Wetzlar, Germany) at 100 times magnification. The hair shaft consists of a deeply pigmented medulla and a paler cortex. We found that anti-androgen therapy frequently had a preferential effect on the medullary portion of the hair (Fig. 1), and thus measurements of both total hair width and of medullary width were performed. A total of 30 readings for medullary width and for total hair width were performed in each subject, and the mean obtained. Measurements were performed by a single examiner who was unaware of the origin of the samples. To determine the reproducibility of the technique, a sample slide of 10 hairs was remeasured on 5 consecutive days. The total hair shaft diameter was 124 ± 4.2 ^m (mean ± SD), and the medullary diameter was
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34.2 ± 0.7 ^m, giving a coefficient of variation of 3.4% and 2.0%, respectively. Cosmetic measures All subjects were performing regular cosmetic measures for control of their hirsutism before the commencement of the study. Methods of depilation employed included plucking, shaving, and waxing of unwanted hair. In order to obtain a subjective indication of the severity of hirsutism, all subjects were asked to record the frequency with which they performed cosmetic measures at the beginning and at the end of the treatment period. The posttreatment frequency was then expressed as a fraction of the baseline frequency, and as percentage reduction. Thus for example, a decrease in frequency of plucking from daily to every third day would be recorded as baseline 1 and post treatment 0.33, a 67% reduction, and a change in waxing frequency from every 3 weeks to every 5 weeks would yield baseline 1 and post treatment 0.6, a 40% reduction. Statistical analysis The paired t test was used to compare changes within the groups, and comparisons between the groups were made using two-way analysis of variance with repeated measures. Changes in the frequency of cosmetic measures were analysed by the Wilcoxon test.
Results Both spironolactone and CPA significantly reduced total hair and medullary diameters (Fig. 2, Table 1). After 6 months of treatment, total hair diameter fell by 17.1 ± 3.6% with spironolactone (P < 0.001), and 16.8 ± 2.7% with CPA (P < 0.001). Medullary hair diameter fell by 17.8 ± 6.8% with spironolactone (P < 0.01), and by 31.7 ± 6.6% with CPA (P < 0.001). Thus, CPA reduced medullary diameter to a greater extent than total hair
FIG. 1. Hairs plucked from the facial area of the same subject before and after 6 months of spironolactone therapy. Note the marked reduction in the diameter and density of the medulla. (100X, magnification).
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O'BRIEN ET AL.
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Total Hair Width Spironolactone
Cyproterone Acetate 400 "I
400 n
300 -
300
200 -
200 •
100 •
100 •
um
Pre
Pre
Post
Post
Medullary Hair Width Spironolactone 120 • 100 •
JCE & M • 1991 Vol 72 • No 5
this respect it was more effective than spironolactone, which did not alter DHEA-S or androstenedione (Table 2). SHBG levels increased significantly with both treatments. There was a strong correlation between the fall in serum testosterone and the fall in total hair diameter, r = 0.49, P = 0.001 (Fig. 3). The reduction in cosmetic measures did not correlate with the reduction in hair diameter, nor with the fall in serum androgen levels. Nine subjects, four receiving spironolactone and five receiving CPA, had less than a 15% reduction in both total and medullary hair diameter. However, no factor, including basal hair diameter, hormone levels, and subject's age, was predictive of a failure to respond to therapy. The eight subjects with PCO tended to have a higher basal serum testosterone than the subjects without PCO (2.9 ± 0.2 vs. 2.3 ± 0.1; P = 0.057). Testosterone also fell to a greater extent in the PCO group (—52 ± 10% vs. -24 ± 5%; P = 0.019). There was no difference in baseline hair diameters between subjects with or without PCO. There was a trend towards a greater reduction in total hair diameter in subjects with PCO, however with the small numbers involved this failed to reach significance (-23 ± 5% vs. -16 ± 2% P = 0.2).
80 •
Effect of estrogens
60 40 20 0
Pre
Post
Pre
Post
FIG. 2. The effect of spironolactone and CPA on total and medullary hair diameter of each individual subject in the study. *, P < 0.01 vs. pre.
diameter (P < 0.5), whereas spironolactone had an equal effect on both measurements. However, there was no significant difference between the two drugs in their effects on total or medullary hair diameter. The frequency of cosmetic measures was also reduced by both drugs, and again both were equally effective (Table 1). CPA significantly reduced all androgen levels and in
Ten subjects (4 receiving CPA, 6 receiving spironolactone) did not receive estrogen therapy, the remainder being treated with ethinyl estradiol or a combination oral contraceptive. The reduction in hair diameter, cosmetic measures and androgen levels was not influenced by concomitant estrogen therapy (Table 3). Only SHBG levels were influenced by estrogens, showing a marked increase in subjects taking estrogens, but remaining unchanged in subjects not receiving estrogens. Side effects Three subjects withdrew from the study because of side effects. One subject taking CPA and ethinyl estradiol developed a marked reduction in libido and ceased therapy. Two subjects taking spironolactone and Triphasil
TABLE 1. The effect of treatment on hair width and cosmetic measures Pretreatment
Posttreatment
% Change
P value
Total Hair Diameter (jam)
S CPA
182 ± 9.2 184 ± 12.6
149 ± 9.3 152 ± 10.1
-17.1 ± 3.6 -16.8 ± 2.7
0.0004 0.0001
Medullary Diameter (jum)
S CPA
37 ± 4.3 42 ± 4.9
28 ± 3.4 27 ± 3.4
-17.8 ± 6.8 -31.7 ± 6.6
0.005 0.0001
Cosmetic Measures
S CPA
0.62 ± 0.07 0.55 ± 0.07
-38.0 ± 6.9 -44.7 ± 6.1
0.0001 0.0001
1 1
The effects of spironolactone (S) (n = 19) and CPA (n = 26) on total and medullary hair diameters, and on the frequency of cosmetic measures. P values relate to pretreatment us. posttreatment. Mean ± SEM are shown.
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EFFECTS OF CPA VS. SPIRONOLACTONE IN HIRSUTISM
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TABLE 2. Effect of treatment on serum hormone levels
Pretreatment S CPA S
Testosterone (nM) DHEA-S
CPA
(MM)
S CPA S CPA
Androstenedione (nM)
SHBG (nM)
2.3 ± 0.2 2.5 ± 0.2 8.1 ± 0.8 8.1 6.0 6.1 35.8 34.3
± ± ± ± ±
0.7 0.4 0.6 5.0 3.9
Posttreatment 1.7 1.5 8.0 6.2 4.9 3.7 87.5 96.7
± 0.2 ± 0.1 ± 0.7 ± 0.6 ± 1.0 ± 0.4 ± 15.1 ± 10.9
% Change -22.1 -34.1 7.4 -17.9 -14.9 -31.2 +193 +273
± 7.4 ± 6.0 ± 11.1 ± 9.1 ± 15.3 ± 9.5 ± 54 ± 88
P value 0.005 0.0001 0.88 0.01 0.4 0.008 0.006 0.0001
The effects of spironolactone (S) (n = 19) and CPA (n = 26) on hormone levels. P values relate to pretreatment vs. posttreatment. Mean SEM are shown.
ronolactone (transient breast tenderness — spironolactone + Triphasil, and oligomenorrhea — spironolactone alone).
1 -
a en c ra .c O
•o
o
o-
Discussion
-1 -
•
0)
c o
a>
-2-
o Spironolactone • CPA
o >
-3-
E S
\
-4-
-15
-10 -5 0 Total Hair Width Change (um)
FIG. 3. The relationship between change in serum testosterone and change in total hair diameter for the whole study group. For each individual subject, the change in total hair diameter after 6 months of treatment is shown on the x-axis and the corresponding change in serum testosterone is shown on the y-axis. R = 0.49, P = 0.001.
had to cease treatment, one because of breast tenderness and the other because of chest tightness and dyspnea. In the latter subject, there were no changes in serum electrolytes, and the relationship of the symptoms to the medication was considered doubtful. Other side effects not requiring cessation of therapy occurred in two subjects taking CPA and ethinyl estradiol (transient nausea, transient galactorrhea), and in two subjects taking spi-
CPA and spironolactone have both been shown to be effective in the treatment of hirsutism, but there are no reports of objective randomized studies directly comparing the two drugs. This study compares sequential CPA and estrogen with spironolactone combined with an oral contraceptive. These regimens were chosen because the study group were predominantly young, sexually active women, and avoidance of conception during antiandrogen therapy was a major priority. Thus, although not a direct comparison of CPA and spironolactone as single agents, the study evaluates the drugs in regimens which are clinically practical and in common use. The study confirms that both drugs were effective in the treatment of hirsutism, as measured by objective and subjective methods. There was no difference between the drugs in this respect, with total and medullary hair diameter decreasing with both regimens. The results of the present study are similar to those reported by other groups in which objective assessment of hair growth during treatment with a single antiandrogen has been used (1, 4, 7.
TABLE 3. Effect of estrogen therapy Estrogen therapy
Total Hair Width (fim) Medullary Width (^m) Testosterone (nM) SHBG (nM) Cosmetic measures
+ — + + + + -
Pretreatment 183 ± 10 192 ± 16 40 ± 4.0
38 ± 6.4 2.4 ± 0.16 2.5 ± 0.28
35 ± 3.3 37 ± 11 1 1
Posttreatment 151 ± 8 156 ± 15 27 ± 2.9
29 ± 4.5 1.6 ± 1.8 ± 105 ± 23 ± 0.57 ± 0.68 ±
0.13 0.13 8.7 7.1 0.05 0.11
% Change -16.2 -18.3 -28.5 -16.7 -29.3 -28.7 286 -16.8 -42.6
± ± ± ± ± ± ± ± ±
2.7 4.0 5.7 11.0 5.8 8.7 63.7 28.4 5.3
-32.5 ± 10.6
P value 0.001 0.004 0.06 0.001 0.001 0.02 0.001 0.14 0.001 0.02
Comparison of subjects receiving estrogen (ethinyl estradiol or triphasic contraceptive), n = 10, to subjects receiving spironolactone or CPA alone (n = 35). P values relate to pretreatment us. posttreatment. Mean ± SEM are shown.
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O'BRIEN ET AL.
10). CPA and spironolactone were similarly effective in reducing plasma testosterone. Spironolactone failed to lower DHEA sulfate, as has been previously reported (14), whereas CPA caused a significant reduction in levels of this hormone. The reduction of DHEA-S, an adrenal steroid, may be due to a glucocorticoid-like action of CPA, which results in suppression of ACTH (19). CPA may also directly inhibit adrenal steroidogenesis (20). The discrepancy between the drugs in their effect on DHEA-S was not reflected in their effect on hair diameters. Indeed, with the exception of plasma testosterone levels, which have been previously reported to correlate with hair diameter in CPA treated patients (4), we found little correlation between reduction in androgen levels and a reduction in hair diameter. Ten subjects in the study did not receive concomitant estrogen therapy. Subanalysis for each drug with or without ethinyl estradiol or a combination contraceptive resulted in insufficient numbers to enable meaningful statistical analysis. However the addition of estrogens showed no trend to enhance response to anti androgen therapy as measured by reduction in hair width or by reduction in the frequency of cosmetic measures. Estrogen therapy has a theoretical advantage in the treatment of hirsutism because estrogens increase SHBG levels, and therefore reduce free androgens. Significantly higher SHBG levels were observed in the estrogen-treated subjects, however this did not appear to confer any advantage in terms of reduction in hair growth. This finding suggests that hirsute women who have a contra-indication to estrogen therapy may still benefit from treatment with antiandrogen drugs. Both CPA and spironolactone were well tolerated in this study. Three out of 48 subjects had to cease therapy because of adverse reactions, and in only 2 of these were the side effects considered to be adverse reactions related to the medication. Loss of libido has been frequently reported as an adverse effect of antiandrogen therapy (21), and breast tenderness has been reported to occur in up to 48% of patients taking spironolactone (22), although it is also a common side effect of estrogen therapy (23). Side effects in this study were otherwise mild and did not necessitate cessation of therapy. Menstrual irregularity has been reported as a frequent side effect of spironolactone (5-7, 9-10), and CPA (24) therapy. This side effect was reduced in this study by the concomitant use of cyclical estrogen or oral contraceptive therapy. However, even in the 10 subjects who did not receive estrogens, only one experienced menstrual irregularity. This study confirms that CPA and spironolactone are effective agents in the treatment of hirsutism. These findings were based on an objective reduction in hair
JCE & M • 1991 Vol 72 • No 5
shaft diameter, and on the more subjective reduction in the frequency of cosmetic measures. The drugs were equally effective, with neither spironolactone nor CPA demonstrating a particular advantage in terms of reduction in hair growth or in frequency of side effects. The availability of CPA and spironolactone varies in different countries, and this may be a major consideration in drug choice. However at this stage it appears that either drug can provide an effective and well tolerated treatment for hirsutism.
Acknowledgments We are grateful to Dr. J. Montalto of the Steroid Laboratory, Royal Children's Hospital, Parkville Victoria, for performing plasma androstenedione measurements. References 1. Dewhurst CJ, Underhill R, Goldman S, Mansfield M. The treatment of hirsutism with Cyproterone Acetate (an anti-androgen). Br J Obstet Gynaecol. 1977;84:119-123. 2. Kuttenn F, Rigaud C, Wright F, Muavais-Jarvis P. Treatment of hirsutism by oral Cyproterone Acetate and percutaneous estradiol. J Clin Endocrinol Metab. 1980;51:1107-llll. 3. Garner PR, Chir B, Poznaski N. Treatment of severe hirsutism resulting from hyperandrogenism with the reverse sequential cyproterone acetate regimen. J Reprod Med. 1984;29:232-6. 4. Jones DB, Ibraham I, Edwards CRW. Hair growth and androgen responses in hirsute women treated with continuous cyproterone acetate and cyclical ethinyl oestradiol. Acta Endocrinologica (Copenh). 1987;116:497-501. 5. Schapiro G and Evron S. A novel use of Spironolactone: treatment of hirsutism. J Clin Endocrinol Metab. 1988;51:429-432. 6. Cumming D, Yang J, Rebar R, Yen S. Treatment of hirsutism with Spironolactone. JAMA. 1982;247:1295-8. 7. Dorrington-Ward P, McCartney ACE, Holland S, et al. The effect of Spironolactone on hirsutism and female androgen metabolism. Clin Endocrinol (Oxf). 1985;23:161-7. 8. Pittaway DE, Maxson WS, Wentz AC. Spironolactone in combination drug therapy for unresponsive hirsutism. Fertil Steril. 1985;43:878-82. 9. Evans DJ, Burke CW. Spironolactone in the treatment of idiopathic hirsutism and the polycystic ovary syndrome. JR Soc Med. 1986;79:451-3. 10. Barth JH, Cherry CA, Wojnarowaka F, Dawber RP. Spironolactone is an effective and well tolerated systemic anti-androgen therapy for hirsute women. J Clin Endocrinol Metab. 1989;68:966-70. 11. Brochovsky N. Molecular action of androgens and anti-androgens. In: Hammerstein J, Lachnit-Fixson V, Neumann F, Plewig G, eds. Androgenisation in women. Amsterdam: Excerpta Medica 7; 1980. 12. Corvol P, Michaud A, Menard J, et al. Anti-androgenic effects of Spironolactones: mechanisms of action. Endocrinology. 1975;97:52-8. 13. Mowszowicz I, Wright F, Vincens M, et al. Androgen metabolism in hirsute patients treated with cyproterone acetate. J Steroid Biochem. 1984;20:757-61. 14. Serafini P, Lobo RA. The effects of Spironolactone on adrenal steroidogenesis in hirsute women. Fertil Steril. 1985;44:595-9. 15. Jones KR, Katz M, Keyzer C, Gordon W. Effect of Cyproterone Acetate on rate of hair growth in hirsute females. Br J Dermatol. 1981;105:695-9. 16. McLellan AR, Rentoul J, MacKie R, Mclnnes GT. Lack of effects of Spironolactone on hair shaft diameter in hirsute females. Postgrad Med J. 1989;65:459-62.
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EFFECTS OF CPA VS. SPIRONOLACTONE IN HIRSUTISM 17. Young RL, Goldzieher JW. Clinical manifestations of polycystic ovarian disease. Endocrinol Metab Clin North Am. 1988;17:62135. 18. Lobo RA, Shoupe DS, Serafini P, Brinton D, Horton R. The effects of two doses of spironolactone on serum androgens and anagen hair in hirsute women. Fertil Steril. 1985;43:200-5. 19. Panesar NS, Stitch SR. Effects of cyproterone and cyproterone acetate on the biosynthesis of steroidal hormones. J Endocrinol. 1976;69:14P-15P. 20. Girard J, Baumann JB, Buhler U, et al. Cyproteroneacetate and
21. 22. 23. 24.
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ACTH adrenal function. J Clin Endocrinol Metab. 1978;47:58186. Loy R, Seibel MM. Evaluation and therapy of polycystic ovarian disease. Endocrinol Metab Clin North Am. 1988;17:785-813. Nielsen PG. Treatment of idiopathic hirsutism with spironolactone. Dermatologica. 1982;165:194-96. Dukes MNG, ed. Meyler's side effects of drugs, 11th edition. 1988; Amsterdam: Elsevier; 860-2. Miller JA, Jacobs HS. Treatment of hirsutism and acne with cyproterone acetate. Baillieres Clin Endocrinol Metab. 1986;15:373-89.
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Vol. 72, No. 5 Printed in U.S.A.
Comparison of Sequential Cyproterone Acetate/Estrogen Versus Spironolactone/Oral Contraceptive in the Treatment of Hirsutism R. C. O'BRIEN, M. E. COOPER, R. M. L. MURRAY, E. SEEMAN, A. K. THOMAS, AND G. JERUMS Department of Endocrinology, Austin Hospital, Heidelberg, Victoria, Australia
treatment efficacy, the frequency with which subjects performed cosmetic measures was recorded. This fell by 38% with spironolactone and by 44.7% with CPA (P < 0.001 both drugs), and again there was no difference between the drugs. Side effects caused cessation of treatment in one subject taking CPA and two subjects taking spironolactone, and milder side effects were noted in two further subjects from each treatment group. We conclude that spironolactone and CPA, in the dosages used in this study, are effective and well tolerated agents for the treatment of hirsutism, and that neither drug demonstrates a particular advantage over the other. (J Clin Endocrinol Metab 72: 1008-1013, 1991)
ABSTRACT. The effects of the antiandrogen drugs cyproterone acetate (CPA) and spironolactone on hair growth and androgen levels were compared in a randomized study of 48 hirsute women. Twenty six subjects completed 6 months of therapy with 100 mg/day CPA and 19 subjects completed 6 months of 100 mg/day spironolactone. All except 10 subjects received concomitant estrogen therapy. Measured objectively, total hair diameter fell by 17.1% with spironolactone (P < 0.001), and by 16.8% with CPA (P < 0.001). The diameter of the hair medulla fell by 17.8% with spironolactone (P < 0.01), and by 31.7% with CPA (P < 0.001). There was no difference between the drugs in their effect on hair diameter. Plasma testosterone levels also fell significantly with both drugs. As a subjective assessment of
T
HE antiandrogen drugs cyproterone acetate (CPA) (1-4) and spironolactone (5-10) have been used extensively in the treatment of hirsutism. Both drugs appear to act primarily by binding to the androgen receptor in target tissues (11-13), and both also reduce androgen biosynthesis (13, 14). In addition CPA is strongly progestogenic, and inhibits the gonadotropin response to lowered testosterone levels (15). Spironolactone and CPA have been shown to be effective in reducing hair growth and androgen levels in hirsute women (1-6, 8-10), although not all studies have shown a beneficial effect (7, 16). The variable results may be due in part to difficulties in obtaining an accurate objective assessment of hair growth (10). Despite the widespread use of CPA and spironolactone in the treatment of female hirsutism, we are unaware of a direct objective comparison of regimens containing the two drugs. The aim of this study was to compare, in a randomized prospective trial, the effects of CPA and spironolactone on hair growth and androgen levels in hirsute women.
Subjects and Methods Fifty hirsute women, mean age 32 ± 1 yr (19-46) were recruited from patients presenting to the Austin Hospital EnReceived April 6,1990. Address requests for reprints to: Dr. R. C. O'Brien, Department of Endocrinology, Austin Hospital, Heidelberg, Victoria, Australia.
docrinology Clinic. Based on ovarian ultrasound examination and plasma gonadotropin measurements (17), eight subjects had the polycystic ovary syndrome (PCO), and 42 had idiopathic hirsutism. No subject had clitoromegaly or other evidence of severe virilization. All were using regular cosmetic measures for hirsutism, but considered this therapy unsatisfactory. Randomization was performed with subjects stratified for the presence of PCO. Twenty-seven subjects were randomized to receive CPA, and twenty-three to receive spironolactone; however, two subjects in the latter group withdrew for personal reasons before commencing therapy. Side effects caused the withdrawal of a further 2 subjects receiving spironolactone and 1 receiving CPA. The total numbers available for analysis were therefore 19 for spironolactone and 26 for CPA, and each group contained 4 subjects with PCO. Treatment Subjects received either spironolactone (Searle Laboratories, Crows Nest, NSW, Australia), 100 mg daily, or CPA (Schering Pty Ltd, Alexandria, NSW, Australia), 100 mg daily on days 5-14 of the menstrual cycle. In these doses both agents have been shown to be effective and well tolerated in the treatment of hirsutism (1, 3, 8, 18). To ensure menstrual regularity and to maintain contraception, CPA was administered with ethinyl estradiol, 30 jug daily on days 5-25. This mode of administration, known as the reverse sequential regimen, was employed to prevent the accumulation of CPA in body fat (3). Subjects
1008
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EFFECTS OF CPA VS. SPIRONOLACTONE IN HIRSUTISM receiving spironolactone were prescribed a triphasic combined oral contraceptive (Triphasil, Wyeth Pharmaceuticals, N.S.W. Australia). Four subjects in the CPA group and six in the spironolactone group did not receive estrogens, three because of previous tubal ligation and seven because of personal reasons. No subject had contra-indications to estrogen therapy. Hormone measurements Samples were taken for measurement of plasma androgens at baseline and again after 6 months of treatment. All samples were taken in the early follicular phase (day 5-10) of the menstrual cycle. Plasma testosterone, androstenedione, dihydroepiandrosterone sulfate (DHEA-S) and sex hormone binding globulin (SHBG) were measured by RIA. Serum electrolytes, urea, and creatinine and liver function tests were also measured regularly throughout the study. Hair measurements Hirsutism was assessed objectively by measuring hair shaft diameter as described by Barth et al. (10). Ten hairs were plucked from the facial area and mounted on a petroleum jelly coated slide. These samples were collected after a constant number of days following whatever cosmetic measures were used. Three measurements were performed on each hair using an eyepiece micrometer (Leitz, Wetzlar, Germany) at 100 times magnification. The hair shaft consists of a deeply pigmented medulla and a paler cortex. We found that anti-androgen therapy frequently had a preferential effect on the medullary portion of the hair (Fig. 1), and thus measurements of both total hair width and of medullary width were performed. A total of 30 readings for medullary width and for total hair width were performed in each subject, and the mean obtained. Measurements were performed by a single examiner who was unaware of the origin of the samples. To determine the reproducibility of the technique, a sample slide of 10 hairs was remeasured on 5 consecutive days. The total hair shaft diameter was 124 ± 4.2 ^m (mean ± SD), and the medullary diameter was
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34.2 ± 0.7 ^m, giving a coefficient of variation of 3.4% and 2.0%, respectively. Cosmetic measures All subjects were performing regular cosmetic measures for control of their hirsutism before the commencement of the study. Methods of depilation employed included plucking, shaving, and waxing of unwanted hair. In order to obtain a subjective indication of the severity of hirsutism, all subjects were asked to record the frequency with which they performed cosmetic measures at the beginning and at the end of the treatment period. The posttreatment frequency was then expressed as a fraction of the baseline frequency, and as percentage reduction. Thus for example, a decrease in frequency of plucking from daily to every third day would be recorded as baseline 1 and post treatment 0.33, a 67% reduction, and a change in waxing frequency from every 3 weeks to every 5 weeks would yield baseline 1 and post treatment 0.6, a 40% reduction. Statistical analysis The paired t test was used to compare changes within the groups, and comparisons between the groups were made using two-way analysis of variance with repeated measures. Changes in the frequency of cosmetic measures were analysed by the Wilcoxon test.
Results Both spironolactone and CPA significantly reduced total hair and medullary diameters (Fig. 2, Table 1). After 6 months of treatment, total hair diameter fell by 17.1 ± 3.6% with spironolactone (P < 0.001), and 16.8 ± 2.7% with CPA (P < 0.001). Medullary hair diameter fell by 17.8 ± 6.8% with spironolactone (P < 0.01), and by 31.7 ± 6.6% with CPA (P < 0.001). Thus, CPA reduced medullary diameter to a greater extent than total hair
FIG. 1. Hairs plucked from the facial area of the same subject before and after 6 months of spironolactone therapy. Note the marked reduction in the diameter and density of the medulla. (100X, magnification).
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O'BRIEN ET AL.
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Total Hair Width Spironolactone
Cyproterone Acetate 400 "I
400 n
300 -
300
200 -
200 •
100 •
100 •
um
Pre
Pre
Post
Post
Medullary Hair Width Spironolactone 120 • 100 •
JCE & M • 1991 Vol 72 • No 5
this respect it was more effective than spironolactone, which did not alter DHEA-S or androstenedione (Table 2). SHBG levels increased significantly with both treatments. There was a strong correlation between the fall in serum testosterone and the fall in total hair diameter, r = 0.49, P = 0.001 (Fig. 3). The reduction in cosmetic measures did not correlate with the reduction in hair diameter, nor with the fall in serum androgen levels. Nine subjects, four receiving spironolactone and five receiving CPA, had less than a 15% reduction in both total and medullary hair diameter. However, no factor, including basal hair diameter, hormone levels, and subject's age, was predictive of a failure to respond to therapy. The eight subjects with PCO tended to have a higher basal serum testosterone than the subjects without PCO (2.9 ± 0.2 vs. 2.3 ± 0.1; P = 0.057). Testosterone also fell to a greater extent in the PCO group (—52 ± 10% vs. -24 ± 5%; P = 0.019). There was no difference in baseline hair diameters between subjects with or without PCO. There was a trend towards a greater reduction in total hair diameter in subjects with PCO, however with the small numbers involved this failed to reach significance (-23 ± 5% vs. -16 ± 2% P = 0.2).
80 •
Effect of estrogens
60 40 20 0
Pre
Post
Pre
Post
FIG. 2. The effect of spironolactone and CPA on total and medullary hair diameter of each individual subject in the study. *, P < 0.01 vs. pre.
diameter (P < 0.5), whereas spironolactone had an equal effect on both measurements. However, there was no significant difference between the two drugs in their effects on total or medullary hair diameter. The frequency of cosmetic measures was also reduced by both drugs, and again both were equally effective (Table 1). CPA significantly reduced all androgen levels and in
Ten subjects (4 receiving CPA, 6 receiving spironolactone) did not receive estrogen therapy, the remainder being treated with ethinyl estradiol or a combination oral contraceptive. The reduction in hair diameter, cosmetic measures and androgen levels was not influenced by concomitant estrogen therapy (Table 3). Only SHBG levels were influenced by estrogens, showing a marked increase in subjects taking estrogens, but remaining unchanged in subjects not receiving estrogens. Side effects Three subjects withdrew from the study because of side effects. One subject taking CPA and ethinyl estradiol developed a marked reduction in libido and ceased therapy. Two subjects taking spironolactone and Triphasil
TABLE 1. The effect of treatment on hair width and cosmetic measures Pretreatment
Posttreatment
% Change
P value
Total Hair Diameter (jam)
S CPA
182 ± 9.2 184 ± 12.6
149 ± 9.3 152 ± 10.1
-17.1 ± 3.6 -16.8 ± 2.7
0.0004 0.0001
Medullary Diameter (jum)
S CPA
37 ± 4.3 42 ± 4.9
28 ± 3.4 27 ± 3.4
-17.8 ± 6.8 -31.7 ± 6.6
0.005 0.0001
Cosmetic Measures
S CPA
0.62 ± 0.07 0.55 ± 0.07
-38.0 ± 6.9 -44.7 ± 6.1
0.0001 0.0001
1 1
The effects of spironolactone (S) (n = 19) and CPA (n = 26) on total and medullary hair diameters, and on the frequency of cosmetic measures. P values relate to pretreatment us. posttreatment. Mean ± SEM are shown.
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EFFECTS OF CPA VS. SPIRONOLACTONE IN HIRSUTISM
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TABLE 2. Effect of treatment on serum hormone levels
Pretreatment S CPA S
Testosterone (nM) DHEA-S
CPA
(MM)
S CPA S CPA
Androstenedione (nM)
SHBG (nM)
2.3 ± 0.2 2.5 ± 0.2 8.1 ± 0.8 8.1 6.0 6.1 35.8 34.3
± ± ± ± ±
0.7 0.4 0.6 5.0 3.9
Posttreatment 1.7 1.5 8.0 6.2 4.9 3.7 87.5 96.7
± 0.2 ± 0.1 ± 0.7 ± 0.6 ± 1.0 ± 0.4 ± 15.1 ± 10.9
% Change -22.1 -34.1 7.4 -17.9 -14.9 -31.2 +193 +273
± 7.4 ± 6.0 ± 11.1 ± 9.1 ± 15.3 ± 9.5 ± 54 ± 88
P value 0.005 0.0001 0.88 0.01 0.4 0.008 0.006 0.0001
The effects of spironolactone (S) (n = 19) and CPA (n = 26) on hormone levels. P values relate to pretreatment vs. posttreatment. Mean SEM are shown.
ronolactone (transient breast tenderness — spironolactone + Triphasil, and oligomenorrhea — spironolactone alone).
1 -
a en c ra .c O
•o
o
o-
Discussion
-1 -
•
0)
c o
a>
-2-
o Spironolactone • CPA
o >
-3-
E S
\
-4-
-15
-10 -5 0 Total Hair Width Change (um)
FIG. 3. The relationship between change in serum testosterone and change in total hair diameter for the whole study group. For each individual subject, the change in total hair diameter after 6 months of treatment is shown on the x-axis and the corresponding change in serum testosterone is shown on the y-axis. R = 0.49, P = 0.001.
had to cease treatment, one because of breast tenderness and the other because of chest tightness and dyspnea. In the latter subject, there were no changes in serum electrolytes, and the relationship of the symptoms to the medication was considered doubtful. Other side effects not requiring cessation of therapy occurred in two subjects taking CPA and ethinyl estradiol (transient nausea, transient galactorrhea), and in two subjects taking spi-
CPA and spironolactone have both been shown to be effective in the treatment of hirsutism, but there are no reports of objective randomized studies directly comparing the two drugs. This study compares sequential CPA and estrogen with spironolactone combined with an oral contraceptive. These regimens were chosen because the study group were predominantly young, sexually active women, and avoidance of conception during antiandrogen therapy was a major priority. Thus, although not a direct comparison of CPA and spironolactone as single agents, the study evaluates the drugs in regimens which are clinically practical and in common use. The study confirms that both drugs were effective in the treatment of hirsutism, as measured by objective and subjective methods. There was no difference between the drugs in this respect, with total and medullary hair diameter decreasing with both regimens. The results of the present study are similar to those reported by other groups in which objective assessment of hair growth during treatment with a single antiandrogen has been used (1, 4, 7.
TABLE 3. Effect of estrogen therapy Estrogen therapy
Total Hair Width (fim) Medullary Width (^m) Testosterone (nM) SHBG (nM) Cosmetic measures
+ — + + + + -
Pretreatment 183 ± 10 192 ± 16 40 ± 4.0
38 ± 6.4 2.4 ± 0.16 2.5 ± 0.28
35 ± 3.3 37 ± 11 1 1
Posttreatment 151 ± 8 156 ± 15 27 ± 2.9
29 ± 4.5 1.6 ± 1.8 ± 105 ± 23 ± 0.57 ± 0.68 ±
0.13 0.13 8.7 7.1 0.05 0.11
% Change -16.2 -18.3 -28.5 -16.7 -29.3 -28.7 286 -16.8 -42.6
± ± ± ± ± ± ± ± ±
2.7 4.0 5.7 11.0 5.8 8.7 63.7 28.4 5.3
-32.5 ± 10.6
P value 0.001 0.004 0.06 0.001 0.001 0.02 0.001 0.14 0.001 0.02
Comparison of subjects receiving estrogen (ethinyl estradiol or triphasic contraceptive), n = 10, to subjects receiving spironolactone or CPA alone (n = 35). P values relate to pretreatment us. posttreatment. Mean ± SEM are shown.
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O'BRIEN ET AL.
10). CPA and spironolactone were similarly effective in reducing plasma testosterone. Spironolactone failed to lower DHEA sulfate, as has been previously reported (14), whereas CPA caused a significant reduction in levels of this hormone. The reduction of DHEA-S, an adrenal steroid, may be due to a glucocorticoid-like action of CPA, which results in suppression of ACTH (19). CPA may also directly inhibit adrenal steroidogenesis (20). The discrepancy between the drugs in their effect on DHEA-S was not reflected in their effect on hair diameters. Indeed, with the exception of plasma testosterone levels, which have been previously reported to correlate with hair diameter in CPA treated patients (4), we found little correlation between reduction in androgen levels and a reduction in hair diameter. Ten subjects in the study did not receive concomitant estrogen therapy. Subanalysis for each drug with or without ethinyl estradiol or a combination contraceptive resulted in insufficient numbers to enable meaningful statistical analysis. However the addition of estrogens showed no trend to enhance response to anti androgen therapy as measured by reduction in hair width or by reduction in the frequency of cosmetic measures. Estrogen therapy has a theoretical advantage in the treatment of hirsutism because estrogens increase SHBG levels, and therefore reduce free androgens. Significantly higher SHBG levels were observed in the estrogen-treated subjects, however this did not appear to confer any advantage in terms of reduction in hair growth. This finding suggests that hirsute women who have a contra-indication to estrogen therapy may still benefit from treatment with antiandrogen drugs. Both CPA and spironolactone were well tolerated in this study. Three out of 48 subjects had to cease therapy because of adverse reactions, and in only 2 of these were the side effects considered to be adverse reactions related to the medication. Loss of libido has been frequently reported as an adverse effect of antiandrogen therapy (21), and breast tenderness has been reported to occur in up to 48% of patients taking spironolactone (22), although it is also a common side effect of estrogen therapy (23). Side effects in this study were otherwise mild and did not necessitate cessation of therapy. Menstrual irregularity has been reported as a frequent side effect of spironolactone (5-7, 9-10), and CPA (24) therapy. This side effect was reduced in this study by the concomitant use of cyclical estrogen or oral contraceptive therapy. However, even in the 10 subjects who did not receive estrogens, only one experienced menstrual irregularity. This study confirms that CPA and spironolactone are effective agents in the treatment of hirsutism. These findings were based on an objective reduction in hair
JCE & M • 1991 Vol 72 • No 5
shaft diameter, and on the more subjective reduction in the frequency of cosmetic measures. The drugs were equally effective, with neither spironolactone nor CPA demonstrating a particular advantage in terms of reduction in hair growth or in frequency of side effects. The availability of CPA and spironolactone varies in different countries, and this may be a major consideration in drug choice. However at this stage it appears that either drug can provide an effective and well tolerated treatment for hirsutism.
Acknowledgments We are grateful to Dr. J. Montalto of the Steroid Laboratory, Royal Children's Hospital, Parkville Victoria, for performing plasma androstenedione measurements. References 1. Dewhurst CJ, Underhill R, Goldman S, Mansfield M. The treatment of hirsutism with Cyproterone Acetate (an anti-androgen). Br J Obstet Gynaecol. 1977;84:119-123. 2. Kuttenn F, Rigaud C, Wright F, Muavais-Jarvis P. Treatment of hirsutism by oral Cyproterone Acetate and percutaneous estradiol. J Clin Endocrinol Metab. 1980;51:1107-llll. 3. Garner PR, Chir B, Poznaski N. Treatment of severe hirsutism resulting from hyperandrogenism with the reverse sequential cyproterone acetate regimen. J Reprod Med. 1984;29:232-6. 4. Jones DB, Ibraham I, Edwards CRW. Hair growth and androgen responses in hirsute women treated with continuous cyproterone acetate and cyclical ethinyl oestradiol. Acta Endocrinologica (Copenh). 1987;116:497-501. 5. Schapiro G and Evron S. A novel use of Spironolactone: treatment of hirsutism. J Clin Endocrinol Metab. 1988;51:429-432. 6. Cumming D, Yang J, Rebar R, Yen S. Treatment of hirsutism with Spironolactone. JAMA. 1982;247:1295-8. 7. Dorrington-Ward P, McCartney ACE, Holland S, et al. The effect of Spironolactone on hirsutism and female androgen metabolism. Clin Endocrinol (Oxf). 1985;23:161-7. 8. Pittaway DE, Maxson WS, Wentz AC. Spironolactone in combination drug therapy for unresponsive hirsutism. Fertil Steril. 1985;43:878-82. 9. Evans DJ, Burke CW. Spironolactone in the treatment of idiopathic hirsutism and the polycystic ovary syndrome. JR Soc Med. 1986;79:451-3. 10. Barth JH, Cherry CA, Wojnarowaka F, Dawber RP. Spironolactone is an effective and well tolerated systemic anti-androgen therapy for hirsute women. J Clin Endocrinol Metab. 1989;68:966-70. 11. Brochovsky N. Molecular action of androgens and anti-androgens. In: Hammerstein J, Lachnit-Fixson V, Neumann F, Plewig G, eds. Androgenisation in women. Amsterdam: Excerpta Medica 7; 1980. 12. Corvol P, Michaud A, Menard J, et al. Anti-androgenic effects of Spironolactones: mechanisms of action. Endocrinology. 1975;97:52-8. 13. Mowszowicz I, Wright F, Vincens M, et al. Androgen metabolism in hirsute patients treated with cyproterone acetate. J Steroid Biochem. 1984;20:757-61. 14. Serafini P, Lobo RA. The effects of Spironolactone on adrenal steroidogenesis in hirsute women. Fertil Steril. 1985;44:595-9. 15. Jones KR, Katz M, Keyzer C, Gordon W. Effect of Cyproterone Acetate on rate of hair growth in hirsute females. Br J Dermatol. 1981;105:695-9. 16. McLellan AR, Rentoul J, MacKie R, Mclnnes GT. Lack of effects of Spironolactone on hair shaft diameter in hirsute females. Postgrad Med J. 1989;65:459-62.
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EFFECTS OF CPA VS. SPIRONOLACTONE IN HIRSUTISM 17. Young RL, Goldzieher JW. Clinical manifestations of polycystic ovarian disease. Endocrinol Metab Clin North Am. 1988;17:62135. 18. Lobo RA, Shoupe DS, Serafini P, Brinton D, Horton R. The effects of two doses of spironolactone on serum androgens and anagen hair in hirsute women. Fertil Steril. 1985;43:200-5. 19. Panesar NS, Stitch SR. Effects of cyproterone and cyproterone acetate on the biosynthesis of steroidal hormones. J Endocrinol. 1976;69:14P-15P. 20. Girard J, Baumann JB, Buhler U, et al. Cyproteroneacetate and
21. 22. 23. 24.
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ACTH adrenal function. J Clin Endocrinol Metab. 1978;47:58186. Loy R, Seibel MM. Evaluation and therapy of polycystic ovarian disease. Endocrinol Metab Clin North Am. 1988;17:785-813. Nielsen PG. Treatment of idiopathic hirsutism with spironolactone. Dermatologica. 1982;165:194-96. Dukes MNG, ed. Meyler's side effects of drugs, 11th edition. 1988; Amsterdam: Elsevier; 860-2. Miller JA, Jacobs HS. Treatment of hirsutism and acne with cyproterone acetate. Baillieres Clin Endocrinol Metab. 1986;15:373-89.
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