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Comparison of finasteride and flutamide in the treatment of idiopathic hirsutism
FERTILITY AND STERILITYt VOL. 72, NO. 1, JULY 1999 Copyright ©1999 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.
Comparison of finasteride and flutamide in the treatment of idiopathic hirsutism Leopoldo Falsetti, M.D., and Alessandro Gambera, M.D. Department of Gynecological Endocrinology, University of Brescia, Brescia, Italy
Objective: To compare the effectiveness of finasteride and flutamide in the treatment of idiopathic hirsutism. Design: Randomized study. Setting: Department of Gynecological Endocrinology, University of Brescia, Italy. Patient(s): Forty-six women with idiopathic hirsutism were selected. Intervention(s): Patients were assigned randomly to receive 5 mg of finasteride once daily or 250 mg of flutamide twice daily for 12 consecutive months. Main Outcome Measure(s): Hirsutism was evaluated at 6 and 12 months of therapy by measuring the Ferriman-Gallwey score and the terminal-hair diameters (mm) taken from different body areas. Blood samples were taken and side effects were monitored during the treatment. Result(s): Both finasteride and flutamide induced a statistically significant decrease in hirsutism scores and hair diameters at the end of 12 months. Finasteride reduced the Ferriman-Gallwey score by 20.5% at 6 months and by 34.2% at 12 months, and hair diameter by 18.9%–23.6% at 6 months and by 29.6%–37.9% at 12 months. Flutamide reduced the Ferriman-Gallwey score by 26.6% at 6 months and by 50.9% at 12 months, and hair diameter by 22.3%–28.2% at 6 months and by 47.7%–56.5% at 12 months. Flutamide did not induce hormonal variations, whereas finasteride increased T levels by 60% and decreased 3a-androstanediol glucuronide by 69.5% at 12 months. Conclusion(s): Both drugs were effective in the treatment of idiopathic hirsutism, but flutamide was more effective than finasteride. (Fertil Sterilt 1999;72:41– 6. ©1999 by American Society for Reproductive Medicine.) Key Words: Finasteride, flutamide, idiopathic hirsutism
Hirsutism in a woman with regular ovulatory menstrual cycles and normal serum androgen levels is usually defined as idiopathic hirsutism. Idiopathic hirsutism affects 10%–15% of hirsute women (1, 2). Patients with idiopathic hirsutism have increased sensitivity of the pilosebaceous unit to androgens. Increased 5a-reductase enzyme activity, converting T to dihydrotestosterone in the hair follicle, is considered the major mechanism underlying abnormal skin sensitivity to androgens (3). Received November 16, 1998; revised and accepted February 11, 1999. Reprint requests: Leopoldo Falsetti, M.D., Via Tirandi, 13-Scala F, 25128 Brescia, Italy. 0015-0282/99/$20.00 PII S0015-0282(99)00183-1
Numerous studies have documented an increase in 5a-reductase activity in the pubic skin of hirsute patients, even in idiopathic hirsutism (3, 4). The activity of 5a-reductase, and consequently the formation of dihydrotestosterone and 5a-reductase metabolites such as 3a-androstanediol glucuronide (5, 6), can be regulated by an increase in the circulating androgenic precursors, the insulin/insulin-like
growth factor-1 system, and genetic factors (7, 8). Therefore, 5a-reductase is a key step in hirsutism. Two genes encoding for 5a-reductase enzymes have been cloned recently. They are called 5a-reductase type 1 and type 2. Studies using specific inhibitors of 5a-reductase type 1 and type 2 (finasteride) showed that 5a-reductase type 2 enzymatic activity is predominant in urogenital sinus (including prostate and genital skin), whereas 5a-reductase type 1 is predominant in the pubic skin of normal women and hirsute patients (9). The distribution and role of type 1 are less clear. It has been cloned independently from scalp skin (10) and is present in nonsex skin such as the forearm and chest (11). Finasteride, a member of the 4-azasteroid family of compounds, is a strong inhibitor of 5a-reductase type 2 activity and is used for the 41
treatment of benign prostatic hyperplasia. The dihydrotestosterone concentration falls by 60%– 80% in men treated with a dose of 5–400 mg (12). The decrease in serum dihydrotestosterone is accompanied by a reduction in 3a-androstanediol glucuronide and a rise in plasma T concentration. However, finasteride has greater affinity for 5a-reductase type 2 at the dose used clinically (5 mg/d) than type 1, but the specificity of the two isoenzymes is incomplete (13).
from each body area at their cutaneous base. Each hair was then fixed on a slide with a transparent resin that solidifies with air and was covered with another slide. Hair was measured with a micrometer, applied to an optical microscope (310 magnification), at the constant distance of 0.8 mm from the base. Measurement of the hair diameter from each body area, expressed in micrometers (mm), represented the means 6 SD of the measurements of three hairs.
Flutamide (aaa-trifluoro-2-methyl-41-nitro-m-propionotoluidide) is a nonsteroidal selective antiandrogen with no progestogenic, glucocorticoid, androgenic, estrogenic, or antigonadotropic action used in the treatment of prostatic carcinoma and evaluated recently in hirsute women. After oral administration, flutamide is broken down rapidly into numerous plasma metabolites, among which is 2-hydroxyflutamide, the main one responsible for the drug’s antiandrogenic activity (14). Hydroxyflutamide acts as a competitive inhibitor of the cytoplasmic and nuclear binding of androgens to the receptor. Serious liver toxicity from flutamide is uncommon with a standard regimen of 750 –1,500 mg/d, with an estimated incidence ranging from 0.36% to 5% (15). The drug does not cause menstrual irregularity.
Other Evaluations
Because of the potential teratogenicity of both drugs (ambiguous genitalia in the male fetus), adequate contraception is mandatory and pregnancy must not be attempted until $3 months after cessation of therapy. The aim of this randomized study was to compare the effectiveness of finasteride and flutamide in idiopathic hirsutism.
MATERIALS AND METHODS Patients Forty-six women with idiopathic hirsutism, between 18 and 29 years of age, were included in our randomized study. All patients gave written informed consent to participate in the study. No patient had used any medication in the previous 6 months. All subjects were selected according to the following criteria: hirsutism, regular ovulatory menstrual cycles, normal serum androgen levels, LH:FSH ratio ,1, and normal serum sex hormone-binding globulin (SHBG) and 17a-hydroxyprogesterone (17-OHP) both in basal conditions and after the ACTH stimulation test performed during the follicular phase of the cycle. Ovulatory cycles were documented by midluteal-phase plasma P levels (.4 ng/mL).
Evaluation of Hirsutism Hirsutism was always evaluated by a single examiner with the Ferriman-Gallwey score (16) and with measurement of the hair diameter. Women with a Ferriman-Gallwey score $8 were included in this study. Terminal hairs were taken from four different parts of the body: face (chin), abdomen (immediately below the umbilicus), anterior mid-thigh, and forearm. Three hairs were cut 42
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Finasteride and flutamide
At 6 and 12 months of treatment, all patients underwent hirsutism evaluation with the Ferriman-Gallwey score and measurement of the hair diameter, hematochemical examinations (hemochrome, glycemia, azotemia, creatinemia, electrophoretic protidogram, total and fractionated bilirubinemia, transaminases, and alkaline phosphatase), and hormonal assays including SHBG, LH, FSH, 17-OHP, androstenedione (A), total T and free T, DHEAS, 3a-androstanediol glucuronide, and fasting insulin. Hormonal assays were assessed for 2 consecutive days at 8:00 AM in the early follicular phase of the menstrual cycle. During therapy, all hirsute women had an interview every 3 months to establish the course of the menstrual cycles and side effects. Patients were advised to avoid pregnancy during treatment because of possible feminization of a male fetus. Sexually active women were advised to use contraception barrier methods (condoms) during the study. Patients were randomly assigned in a 1:1 ratio to receive either 5 mg of finasteride (Prostide; Sigma Tau, Milan, Italy) once daily or 250 mg of flutamide (Eulexin; ScheringPlough, Milan, Italy) twice daily for 12 months. The control group to measure the vellus hair diameter consisted of 20 women with a mean (6SD) age of 24.2 6 3.2 years and a mean body mass index of 22.3 6 2.8 kg/m2. These women had regular cycles, normal serum androgen levels, and no androgenic symptoms. Control women also underwent hormone assays in the early follicular phase of the menstrual cycle. The study protocol was approved by the clinical research ethics committee of the University of Brescia.
Hormone Assays Serum LH, FSH, and SHBG levels were determined by an immunoradiometric assay method (Radim; Pomezia, Rome, Italy). The remaining hormones were tested using commercial RIA kits: for 17-OHP, A, T, and free T, Diagnostic Products Corporation (Los Angeles, CA); for DHEAS, Immunotech (Marseille, France); for insulin, Medgenix (Brussels, Belgium); and for 3a-androstanediol glucuronide, Diagnostic Systems Laboratories (Webster, TX).
Statistical Analysis
All values were expressed as means 6 SD. Student’s paired t-tests were used to compare mean hormone levels before and after treatment. The percentages of change in Vol. 72, No. 1, July 1999
TABLE 1 Basal serum hormone levels in patients with idiopathic hirsutism and in the control group. Hormone level LH (mIU/mL) FSH (mIU/mL) 17-OHP (ng/mL) A (ng/mL) T (ng/mL) Free T (pg/mL) DHEAS (mg/mL) 3a-diolG (ng/mL) Insulin (mU/mL) SHBG (nmol/L)
Idiopathic hirsutism (n 5 46)
Controls (n 5 20)
3.8 6 1.4 5.5 6 1.6 0.7 6 0.2 2.0 6 0.4 0.5 6 0.1 1.9 6 0.6 2.1 6 0.8 6.0 6 1.1* 5.0 6 2.1 46.0 6 6.5
3.6 6 0.9 5.8 6 1.3 0.6 6 0.4 1.9 6 0.4 0.4 6 0.1 1.8 6 0.6 1.8 6 0.5 1.5 6 0.5 5.1 6 1.1 47.0 6 9.6
Note: Values are means 6 SD. 3a-diolG 5 3a-androstanediol glucuronide. * P,.001, idiopathic hirsutism versus controls.
hirsutism scores between treatments were tested with oneway analysis of variance. Statistical analysis of hair diameters was performed with use of the Wilcoxon signed-rank test.
RESULTS The mean (6SD) patient age was 22.1 6 6.1 and 22.5 6 5.4 years, and the mean (6SD) body mass index was 22.7 6 3.1 and 22.2 6 3.3 kg/m2 for the finasteride and flutamide treatment groups, respectively. Table 1 shows the basal endocrine profiles of patients with idiopathic hirsutism. No statistically significant differences were seen compared with the control group, except for serum levels of 3a-androstanediol glucuronide, which were significantly higher in idiopathic hirsutism (6.0 6 1.1 versus 1.5 6 0.5 ng/mL). In women with idiopathic hirsutism, the mean basal overall Ferriman-Gallwey score was 16.7 6 3.2, and hair diameters were 51.2 6 5.0 mm in the face, 74.0 6 5.6 mm in the abdomen, 73.1 6 4.9 mm in the thigh, and 49.0 6 4.7 mm in the forearm (Table 2). Statistical analysis indicated that in patients with idiopathic hirsutism, the hair diameters in each area of the body were significantly higher than those of the control group. Table 3 shows the basal hormone levels before and after 6 and 12 months of treatment with finasteride and flutamide. Finasteride produced a statistically significant increase in T at 6 months (0.7 6 0.1 ng/mL) and at 12 months (0.8 6 0.2 ng/mL) and an equally significant reduction in 3a-androstanediol glucuronide at 6 months (2.4 6 0.8 ng/mL) and at 12 months (1.8 6 0.4 ng/mL). Flutamide did not change the hormone profile. The Ferriman-Gallwey scores for hirsutism after 6 and 12 months of treatment with finasteride and flutamide are shown in Table 4. The Ferriman-Gallwey score decreased FERTILITY & STERILITYt
significantly in both treatment groups. Finasteride decreased the Ferriman-Gallwey score by 20.5% at 6 months (from 16.1 6 3.8 to 12.8 6 3.4) and by 34.2% at 12 months (from 16.1 6 3.8 to 10.6 6 3.1). Flutamide decreased the score by 26.6% at 6 months (from 17.3 6 3.1 to 12.7 6 2.8) and by 50.9% at 12 months (from 17.3 6 3.1 to 8.5 6 3.3). The percentage change in the Ferriman-Gallwey score with flutamide was significantly higher than that with finasteride at the end of 12 months of treatment. Table 5 shows the hair diameters in the basal condition and after treatment with finasteride and flutamide. Both drugs significantly decreased hair diameters at 6 and 12 months. Finasteride reduced hair diameters by 18.9%–23.6% at 6 months and by 29.6%–37.9% at 12 months; flutamide by 22.3%–28.2% at 6 months and by 47.7%–56.5% at 12 months. Hairs in the abdomen were the most sensitive to both drugs, decreasing by 23.6% at 6 months and by 37.9% at 12 months with finasteride and by 28.2% at 6 months and by 56.5% at 12 months with flutamide. Hairs in the forearm were the least sensitive to treatment (18.9% at 6 months and 29.6% at 12 months with finasteride; 22.3% at 6 months and 47.7% at 12 months with flutamide). The decrease in facial hair at 6 and 12 months (21.8% and 36.3%, respectively, with finasteride; 27.5% and 54.0% with flutamide) was always greater than that of the thigh (19.7% and 33.7% with finasteride; 23.4% and 51.3% with flutamide). Flutamide was significantly more active than finasteride in decreasing hair diameters at 12 months. During therapy with both antiandrogens, changes in the menstrual cycle were not observed. All patients in the finasteride group completed the study, and side effects were moderate: headache in 3 patients (13%), dry skin in 5 (21.7%), and reduction in libido in 2 (8.7%). This drug did not modify hematochemical variables. Two women (8.7%) in the flutamide group dropped out of the study at 7 months: one (4.3%) because of nausea and vomiting and another (4.3%) because of high transaminase levels. In the remaining 21 patients, flutamide caused a
TABLE 2 Basal hair diameters (mm) in patients with idiopathic hirsutism and in controls. Site Face Abdomen Thigh Forearm
Idiopathic hirsutism (n 5 46)
Controls (n 5 20)
51.2 6 5.0* 74.0 6 5.6* 73.1 6 4.9* 49.0 6 4.7*
27.6 6 1.6 35.2 6 5.1 33.0 6 5.3 26.6 6 3.5
Note: Values are means 6 SD. * P,.001, idiopathic hirsutism versus controls.
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TABLE 3 Serum hormone levels with finasteride and flutamide treatment. Finasteride Hormone level LH (mIU/mL) FSH (mIU/mL) 17-OHP (ng/mL) A (ng/mL) T (ng/mL) Free T (pg/mL) DHEAS (mg/mL) 3a-diolG (ng/mL) Insulin (mU/mL) SHBG (nmol/L)
Flutamide
Baseline
6 mo
12 mo
Baseline
6 mo
12 mo*
3.5 6 1.5 5.1 6 1.6 0.7 6 0.2 2.0 6 0.3 0.5 6 0.1 1.9 6 0.5 2.1 6 0.6 5.9 6 1.2 5.0 6 2.1 45.3 6 6.1
3.6 6 0.9 5.3 6 0.8 0.8 6 0.3 2.2 6 0.6 0.7 6 0.1† 2.1 6 0.5 2.0 6 0.6 2.4 6 0.8† 5.2 6 1.8 43.3 6 5.3
3.7 6 1.2 5.2 6 1.1 0.8 6 0.2 2.3 6 0.5 0.8 6 0.2† 2.2 6 0.4 1.9 6 0.7 1.8 6 0.4† 5.1 6 1.6 43.1 6 5.9
4.1 6 1.2 5.9 6 2.1 0.6 6 0.3 1.9 6 0.4 0.5 6 0.2 1.8 6 0.5 2.2 6 0.7 6.1 6 1.1 5.2 6 2.2 46.5 6 7.0
4.3 6 1.3 6.0 6 2.2 0.7 6 0.2 1.8 6 0.4 0.4 6 0.2 2.0 6 0.4 2.0 6 0.8 5.8 6 1.4 5.3 6 1.2 47.0 6 7.8
4.2 6 1.7 5.8 6 2.0 0.7 6 0.2 1.7 6 0.5 0.4 6 0.1 1.7 6 0.5 2.0 6 0.9 5.7 6 1.4 5.2 6 1.6 46.0 6 8.2
Note: Values are means 6 SD. 3a-diolG 5 3a-androstanediol glucuronide. * Twelve-month values refer to 21 patients in the flutamide group. † P,.001, 6 and 12 months versus baseline.
reduction in libido in 3 patients (14.3%), gastrointestinal disorders in 3 (14.3%), and dry skin in 13 (62%). Dry skin appeared after 2 months of therapy.
DISCUSSION This randomized study has shown that both finasteride and flutamide are effective in women with idiopathic hirsutism. Flutamide was more effective than finasteride for hirsutism and seborrhea. In fact, flutamide reduced the Ferriman-Gallwey score by 50.9%, the hair diameter by 47.7%– 56.5%, and sebum production in 62% of women; results with finasteride were 34.2%, 29.6%–37.9%, and 21.7%, respectively. Our hormone results demonstrated that finasteride, a 5areductase type 2 selective inhibitor, increased serum levels of T by 40% at 6 months and by 60% at 12 months, and reduced 3a-androstanediol glucuronide by 59.3% at 6 months and by 69.5% at 12 months. Flutamide did not change the basal hormone profile. Decreasing 3a-androstanediol glucuronide, a dihydrotestosterone metabolite, with finasteride confirms its peripheral origin as well as the hyperfunction of 5a-reductase in idiopathic hirsutism and the importance of dihydrotestosterone for hair growth. We noted no important side effects or changes in hematochemical variables in the finasteride group, and all patients completed the study. Flutamide, on the other hand, induced high transaminase levels in 1 patient (4.3%) and nausea and vomiting in 1 (4.3%), and so 21 patients completed the study. Therefore, flutamide presents a higher risk-benefit ratio than finasteride, and its chronic administration requires repeated monitoring of liver function. Our study also showed concordance in the hirsutism evaluation between the Ferriman-Gallwey score (subjective 44
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evaluation) and the hair-diameter measurement (objective evaluation). In the literature, the results of these antiandrogens on idiopathic hirsutism are controversial. Nearly all investigators calculated the Ferriman-Gallwey score, a semiquantitative estimation of hirsutism that does not represent an objective measurement of hair growth and is operator dependent. Ciotta et al. (17) administered 7.5 mg/d of finasteride in 9 women with idiopathic hirsutism and noticed a reduction in the Ferriman-Gallwey score by 26% after 6 months and by 47% after 9 months of therapy. Tolino et al. (18) reported that finasteride at 5 mg/d caused a 60% decrease in the Ferriman-Gallwey score in 10 patients with idiopathic hirsutism at 6 months. Moghetti et al. (19) reported a 47.2% reduction in the Ferriman-Gallwey score of 12 patients with idiopathic hirsutism at 6 months. Castello et al. (20) showed that the mean Ferriman-Gallwey score was lowered by 63% after 12 months of finasteride therapy in 14 patients with mild idiopathic hirsutism. Wong et al. (21) and Erenus et al.
TABLE 4 Ferriman-Gallwey scores and changes with finasteride and flutamide treatment. Treatment
Baseline
6 mo
Change (%)
12 mo*
Change (%)
Finasteride Flutamide
16.1 6 3.8 17.3 6 3.1
12.8 6 3.4† 12.7 6 2.8†
20.5 26.6
10.6 6 3.1† 8.5 6 3.3†‡
34.2 50.9
Note: Values are means 6 SD, except as noted. * Twelve-month values refer to 21 patients in the flutamide group. † P,.001, finasteride and flutamide at 6 and 12 months versus baseline. ‡ P,.01, flutamide versus finasteride at 12 months.
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TABLE 5 Hair diameters (mm) and changes with finasteride and flutamide treatment. Finasteride Site Face Change Abdomen Change Thigh Change Forearm Change
(%) (%) (%) (%)
Flutamide
Baseline
6 mo
12 mo
Baseline
6 mo
12 mo*
51.0 6 5.0 — 74.1 6 5.6 — 73.0 6 4.9 — 48.7 6 4.8 —
39.9 6 4.2† 21.8 56.6 6 5.3† 23.6 58.6 6 4.1† 19.7 39.5 6 3.8† 18.9
32.5 6 4.3† 36.3 45.4 6 4.2† 37.9 48.4 6 4.0† 33.7 34.3 6 3.5† 29.6
51.6 6 5.2 — 73.8 6 6.0 — 73.5 6 4.7 — 49.2 6 5.1 —
37.4 6 4.4† 27.5 53.0 6 5.1† 28.2 56.3 6 4.0† 23.4 38.2 6 4.3† 22.3
23.7 6 3.9†‡ 54.0 32.1 6 4.7†‡ 56.5 35.8 6 3.1†‡ 51.3 25.7 6 4.9†‡ 47.7
Note: Values are means 6 SD, except as noted. * Twelve-month values refer to 21 patients in the flutamide group. † P,.001, finasteride and flutamide at 6 and 12 months versus baseline. ‡ P,.01, flutamide versus finasteride at 12 months.
(22) compared finasteride (5 mg/d) with spironolactone in 2 and 7 women with idiopathic hirsutism, respectively. They reported a decrease in the Ferriman-Gallwey score with finasteride by 11% at 6 months (21) and by 15.1% at 9 months (22). Most investigators reported an increase in T by 40%–70% and a decrease in 3a-androstanediol glucuronide by 56%– 81% with finasteride.
Flutamide, on the other hand, is more effective than finasteride on hirsutism and seborrhea/acne because it is able to block the peripheral receptors of both T and dihydrotestosterone by competition. Imperato-McGinley (27) showed that sebum production was depressed in subjects with complete insensitivity to androgens but not in those with congenital deficiency of 5a-reductase.
Other investigators studied the effects of flutamide on idiopathic hirsutism. Couzinet et al. (23) administered 500 mg/d of flutamide in 10 women with idiopathic hirsutism for 12 months and observed a reduction in the Ferriman-Gallwey score by 69.5%. Erenus et al. (24) studied the same number of patients and dosage of flutamide and found a decrease in the Ferriman-Gallwey score by 39.5% after 6 months and by 46.4% after 9 months of therapy. Moghetti et al. (25), using 375 mg/d of flutamide for 12 months, reported a decrease in the Ferriman-Gallwey score after 8 months of treatment by 55% and after 12 months by 71%. Grigoriou et al. (26) treated 11 women with idiopathic hirsutism with flutamide (500 mg/d) for 9 months, and the Ferriman-Gallwey score decreased by 30.1%. Unlike us, some investigators reported a statistically significant decrease in T and DHEAS after flutamide treatment (25).
On the basis of our results, it is evident that finasteride and flutamide must be given continuously and for a long time. However, chronic use of these antiandrogens can induce numerous problems related to contraception, the risk of pregnancy, and the need for repeated monitoring of liver function in patients receiving flutamide treatment. For these reasons, we believe that in sexually active women, it is necessary to administer these antiandrogens with an oral contraceptive.
The lesser effectiveness of finasteride in comparison with flutamide on hirsutism and seborrhea could be due to various factors: [1] The increase in T per se could have a direct effect on target tissues; [2] finasteride has a limited action on 5a-reductase type 1, which is theoretically more involved in hirsutism, although no studies have defined the isoform of 5a-reductase that increases in hirsutism (9); and [3] finasteride may be unable to decrease dihydrotestosterone production under a threshold value that is ineffective on the pilosebaceous apparatus. Our study in fact documents a decreased but persistent secretion of 3a-androstanediol glucuronide after 12 months of therapy with finasteride. FERTILITY & STERILITYt
Despite the high risk/benefit ratio, we believe that at present, flutamide is more effective for the treatment of idiopathic hirsutism. In the future, the use of specific 5areductase type 1 inhibitors could improve the treatment of idiopathic hirsutism. References 1. Barbieri RL. Hyperandrogenic disorders. Clin Obstet Gynecol 1990; 33:640 –54. 2. Knochenhauer ES, Azziz R. Advances in the diagnosis and treatment of the hirsute patient. Curr Opin Obstet Gynecol 1995;7:344 –50. 3. Serafini PC, Lobo RA. Increased 5a-reductase activity in idiopathic hirsutism. Fertil Steril 1985;43:74 – 8. 4. Serafini PC, Ablan F, Lobo RA. 5a-reductase activity in the genital skin of hirsute women. J Clin Endocrinol Metab 1985;60:349 –55. 5. Horton R. Dihydrotestosterone is a peripheral paracrine hormone. J Androl 1992;13:23–7. 6. Greep N, Hoopes M, Horton R. Androstanediol glucuronide plasma clearance and production rates in normal and hirsute women. J Clin Endocrinol Metab 1986;62:22–7. 7. Lobo RA. Hirsutism in polycystic ovary syndrome: current concepts. Clin Obstet Gynecol 1991;34:817–25. 8. George FW, Russel DW, Wilson JD. Feed-forward control of prostatic growth: dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5a-reductase. Proc Natl Acad Sci USA 1991;88: 8044 –7.
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9. Mestayer CH, Berthaut I, Portois MC, Wright F, Kuttenn F, Mowszowicz I, et al. Predominant expression of 5a-reductase type 1 in pubic skin from normal subjects and hirsute patients. J Clin Endocrinol Metab 1996;81:1989 –93. 10. Harris G, Azzolina B, Baginsky W. Identification and selective inhibition of an isozyme of steroid 5a-reductase in human scalp. Proc Natl Acad Sci USA 1992;89:10787–91. 11. Thigpen AE, Silver RI, Guileyardo JM, Casey ML, McConnell JD, Russell DW. Tissue distribution and ontogeny of steroid 5a-reductase isozyme expression. J Clin Invest 1993;92:903–10. 12. Royer S, Rittmaster RS. Finasteride. N Engl J Med 1994;330:120 –5. 13. Dallob AL, Sadick NS, Unger W, Lipert S, Geissler LA, Gregoire SL, et al. The effect of finasteride, a 5a-reductase inhibitor, on scalp skin testosterone and dihydrotestosterone concentrations in patients with male pattern baldness. J Clin Endocrinol Metab 1994;79: 703– 6. 14. Brogden RN, Clissold SP. Flutamide: a preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in advanced prostatic cancer. Drugs 1989;38:185–203. 15. Crownover RL, Holland J, Chen A, Krieg R, Young BK, Roack M III, et al. Flutamide induced liver toxicity including fatal hepatic necrosis. Int J Radiat Oncol Biol Phys 1996;34:911–5. 16. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961;21:1440 – 8. 17. Ciotta L, Cianci A, Calogero A, Palumbo MA, Marletta E, Sciuto A, et al. Clinical and endocrine effects of finasteride, a 5a-reductase inhibitor in women with idiopathic hirsutism. Fertil Steril 1995;64:299 –306. 18. Tolino A, Petrone A, Sarnacchiaro F, Cirillo D, Ronsini S, Lombardi G, et al. Finasteride in the treatment of hirsutism: new therapeutic perspectives. Fertil Steril 1996;66:61–5. 19. Moghetti P, Castello R, Magmani CM, Tosi F, Negri C, Armanini D, et al. Clinical and hormonal effects of the 5-alpha reductase inhibitor
46
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20.
21.
22. 23. 24. 25.
26.
27.
finasteride in idiopathic hirsutism. J Clin Endocrinol Metab 1994;79: 1115–21. Castello R, Tosi F, Perrone F, Negri C, Muggeo M, Moghetti P. Outcome of long-term treatment with the 5-alpha reductase inhibitor finasteride in idiopathic hirsutism. Clinical and hormonal effects during a 1 year course of therapy and 1 year follow up. Fertil Steril 1996;66: 734 – 40. Wong IL, Morris RS, Chang L, Spahn M, Stanczyk FZ, Lobo R. A prospective randomized trial comparing finasteride to spironolactone in the treatment of hirsute women. J Clin Endocrinol Metab 1995;80: 233– 8. Erenus M, Yu¨celten D, Durmusoglu F, Gu¨bu¨rz O. Comparison of finasteride versus spironolactone in the treatment of idiopathic hirsutism. Fertil Steril 1997;68:1000 –3. Couzinet B, Pholsena M, Young J, Schaison G. The impact of a pure anti-androgen (flutamide) on LH, FSH, androgens and clinical status in idiopathic hirsutism. Clin Endocrinol (Oxf) 1993;39:157– 62. Erenus M, Gu¨bu¨rz O, Durmusoglu F, Demircay Z, Pekin S. Comparison of the efficacy of spironolactone versus flutamide in the treatment of hirsutism. Fertil Steril 1994;61:613– 6. Moghetti P, Castello R, Negri C, Magmani CM, Fontanarosa MC, Armanini D, et al. Flutamide in the treatment of hirsutism: long-term clinical effects, endocrine changes and androgen receptor behavior. Fertil Steril 1995;64:511–7. Grigoriou O, Papadias C, Konidaris S, Antoniou G, Karakitsos P, Giannikos L. Comparison of flutamide and cyproterone acetate in the treatment of hirsutism: a randomized controlled trial. Gynecol Endocrinol 1996;10:119 –23. Imperato-McGinley J, Gautier T, Cai L, Yee B, Epstein J, Pochi P. The androgen control of sebum production. Study of subjects with dihydrotestosterone deficiency and complete androgen insensitivity. J Clin Endocrinol Metab 1993;76:524 – 8.
Vol. 72, No. 1, July 1999
Comparison of finasteride and flutamide in the treatment of idiopathic hirsutism Leopoldo Falsetti, M.D., and Alessandro Gambera, M.D. Department of Gynecological Endocrinology, University of Brescia, Brescia, Italy
Objective: To compare the effectiveness of finasteride and flutamide in the treatment of idiopathic hirsutism. Design: Randomized study. Setting: Department of Gynecological Endocrinology, University of Brescia, Italy. Patient(s): Forty-six women with idiopathic hirsutism were selected. Intervention(s): Patients were assigned randomly to receive 5 mg of finasteride once daily or 250 mg of flutamide twice daily for 12 consecutive months. Main Outcome Measure(s): Hirsutism was evaluated at 6 and 12 months of therapy by measuring the Ferriman-Gallwey score and the terminal-hair diameters (mm) taken from different body areas. Blood samples were taken and side effects were monitored during the treatment. Result(s): Both finasteride and flutamide induced a statistically significant decrease in hirsutism scores and hair diameters at the end of 12 months. Finasteride reduced the Ferriman-Gallwey score by 20.5% at 6 months and by 34.2% at 12 months, and hair diameter by 18.9%–23.6% at 6 months and by 29.6%–37.9% at 12 months. Flutamide reduced the Ferriman-Gallwey score by 26.6% at 6 months and by 50.9% at 12 months, and hair diameter by 22.3%–28.2% at 6 months and by 47.7%–56.5% at 12 months. Flutamide did not induce hormonal variations, whereas finasteride increased T levels by 60% and decreased 3a-androstanediol glucuronide by 69.5% at 12 months. Conclusion(s): Both drugs were effective in the treatment of idiopathic hirsutism, but flutamide was more effective than finasteride. (Fertil Sterilt 1999;72:41– 6. ©1999 by American Society for Reproductive Medicine.) Key Words: Finasteride, flutamide, idiopathic hirsutism
Hirsutism in a woman with regular ovulatory menstrual cycles and normal serum androgen levels is usually defined as idiopathic hirsutism. Idiopathic hirsutism affects 10%–15% of hirsute women (1, 2). Patients with idiopathic hirsutism have increased sensitivity of the pilosebaceous unit to androgens. Increased 5a-reductase enzyme activity, converting T to dihydrotestosterone in the hair follicle, is considered the major mechanism underlying abnormal skin sensitivity to androgens (3). Received November 16, 1998; revised and accepted February 11, 1999. Reprint requests: Leopoldo Falsetti, M.D., Via Tirandi, 13-Scala F, 25128 Brescia, Italy. 0015-0282/99/$20.00 PII S0015-0282(99)00183-1
Numerous studies have documented an increase in 5a-reductase activity in the pubic skin of hirsute patients, even in idiopathic hirsutism (3, 4). The activity of 5a-reductase, and consequently the formation of dihydrotestosterone and 5a-reductase metabolites such as 3a-androstanediol glucuronide (5, 6), can be regulated by an increase in the circulating androgenic precursors, the insulin/insulin-like
growth factor-1 system, and genetic factors (7, 8). Therefore, 5a-reductase is a key step in hirsutism. Two genes encoding for 5a-reductase enzymes have been cloned recently. They are called 5a-reductase type 1 and type 2. Studies using specific inhibitors of 5a-reductase type 1 and type 2 (finasteride) showed that 5a-reductase type 2 enzymatic activity is predominant in urogenital sinus (including prostate and genital skin), whereas 5a-reductase type 1 is predominant in the pubic skin of normal women and hirsute patients (9). The distribution and role of type 1 are less clear. It has been cloned independently from scalp skin (10) and is present in nonsex skin such as the forearm and chest (11). Finasteride, a member of the 4-azasteroid family of compounds, is a strong inhibitor of 5a-reductase type 2 activity and is used for the 41
treatment of benign prostatic hyperplasia. The dihydrotestosterone concentration falls by 60%– 80% in men treated with a dose of 5–400 mg (12). The decrease in serum dihydrotestosterone is accompanied by a reduction in 3a-androstanediol glucuronide and a rise in plasma T concentration. However, finasteride has greater affinity for 5a-reductase type 2 at the dose used clinically (5 mg/d) than type 1, but the specificity of the two isoenzymes is incomplete (13).
from each body area at their cutaneous base. Each hair was then fixed on a slide with a transparent resin that solidifies with air and was covered with another slide. Hair was measured with a micrometer, applied to an optical microscope (310 magnification), at the constant distance of 0.8 mm from the base. Measurement of the hair diameter from each body area, expressed in micrometers (mm), represented the means 6 SD of the measurements of three hairs.
Flutamide (aaa-trifluoro-2-methyl-41-nitro-m-propionotoluidide) is a nonsteroidal selective antiandrogen with no progestogenic, glucocorticoid, androgenic, estrogenic, or antigonadotropic action used in the treatment of prostatic carcinoma and evaluated recently in hirsute women. After oral administration, flutamide is broken down rapidly into numerous plasma metabolites, among which is 2-hydroxyflutamide, the main one responsible for the drug’s antiandrogenic activity (14). Hydroxyflutamide acts as a competitive inhibitor of the cytoplasmic and nuclear binding of androgens to the receptor. Serious liver toxicity from flutamide is uncommon with a standard regimen of 750 –1,500 mg/d, with an estimated incidence ranging from 0.36% to 5% (15). The drug does not cause menstrual irregularity.
Other Evaluations
Because of the potential teratogenicity of both drugs (ambiguous genitalia in the male fetus), adequate contraception is mandatory and pregnancy must not be attempted until $3 months after cessation of therapy. The aim of this randomized study was to compare the effectiveness of finasteride and flutamide in idiopathic hirsutism.
MATERIALS AND METHODS Patients Forty-six women with idiopathic hirsutism, between 18 and 29 years of age, were included in our randomized study. All patients gave written informed consent to participate in the study. No patient had used any medication in the previous 6 months. All subjects were selected according to the following criteria: hirsutism, regular ovulatory menstrual cycles, normal serum androgen levels, LH:FSH ratio ,1, and normal serum sex hormone-binding globulin (SHBG) and 17a-hydroxyprogesterone (17-OHP) both in basal conditions and after the ACTH stimulation test performed during the follicular phase of the cycle. Ovulatory cycles were documented by midluteal-phase plasma P levels (.4 ng/mL).
Evaluation of Hirsutism Hirsutism was always evaluated by a single examiner with the Ferriman-Gallwey score (16) and with measurement of the hair diameter. Women with a Ferriman-Gallwey score $8 were included in this study. Terminal hairs were taken from four different parts of the body: face (chin), abdomen (immediately below the umbilicus), anterior mid-thigh, and forearm. Three hairs were cut 42
Falsetti and Gambera
Finasteride and flutamide
At 6 and 12 months of treatment, all patients underwent hirsutism evaluation with the Ferriman-Gallwey score and measurement of the hair diameter, hematochemical examinations (hemochrome, glycemia, azotemia, creatinemia, electrophoretic protidogram, total and fractionated bilirubinemia, transaminases, and alkaline phosphatase), and hormonal assays including SHBG, LH, FSH, 17-OHP, androstenedione (A), total T and free T, DHEAS, 3a-androstanediol glucuronide, and fasting insulin. Hormonal assays were assessed for 2 consecutive days at 8:00 AM in the early follicular phase of the menstrual cycle. During therapy, all hirsute women had an interview every 3 months to establish the course of the menstrual cycles and side effects. Patients were advised to avoid pregnancy during treatment because of possible feminization of a male fetus. Sexually active women were advised to use contraception barrier methods (condoms) during the study. Patients were randomly assigned in a 1:1 ratio to receive either 5 mg of finasteride (Prostide; Sigma Tau, Milan, Italy) once daily or 250 mg of flutamide (Eulexin; ScheringPlough, Milan, Italy) twice daily for 12 months. The control group to measure the vellus hair diameter consisted of 20 women with a mean (6SD) age of 24.2 6 3.2 years and a mean body mass index of 22.3 6 2.8 kg/m2. These women had regular cycles, normal serum androgen levels, and no androgenic symptoms. Control women also underwent hormone assays in the early follicular phase of the menstrual cycle. The study protocol was approved by the clinical research ethics committee of the University of Brescia.
Hormone Assays Serum LH, FSH, and SHBG levels were determined by an immunoradiometric assay method (Radim; Pomezia, Rome, Italy). The remaining hormones were tested using commercial RIA kits: for 17-OHP, A, T, and free T, Diagnostic Products Corporation (Los Angeles, CA); for DHEAS, Immunotech (Marseille, France); for insulin, Medgenix (Brussels, Belgium); and for 3a-androstanediol glucuronide, Diagnostic Systems Laboratories (Webster, TX).
Statistical Analysis
All values were expressed as means 6 SD. Student’s paired t-tests were used to compare mean hormone levels before and after treatment. The percentages of change in Vol. 72, No. 1, July 1999
TABLE 1 Basal serum hormone levels in patients with idiopathic hirsutism and in the control group. Hormone level LH (mIU/mL) FSH (mIU/mL) 17-OHP (ng/mL) A (ng/mL) T (ng/mL) Free T (pg/mL) DHEAS (mg/mL) 3a-diolG (ng/mL) Insulin (mU/mL) SHBG (nmol/L)
Idiopathic hirsutism (n 5 46)
Controls (n 5 20)
3.8 6 1.4 5.5 6 1.6 0.7 6 0.2 2.0 6 0.4 0.5 6 0.1 1.9 6 0.6 2.1 6 0.8 6.0 6 1.1* 5.0 6 2.1 46.0 6 6.5
3.6 6 0.9 5.8 6 1.3 0.6 6 0.4 1.9 6 0.4 0.4 6 0.1 1.8 6 0.6 1.8 6 0.5 1.5 6 0.5 5.1 6 1.1 47.0 6 9.6
Note: Values are means 6 SD. 3a-diolG 5 3a-androstanediol glucuronide. * P,.001, idiopathic hirsutism versus controls.
hirsutism scores between treatments were tested with oneway analysis of variance. Statistical analysis of hair diameters was performed with use of the Wilcoxon signed-rank test.
RESULTS The mean (6SD) patient age was 22.1 6 6.1 and 22.5 6 5.4 years, and the mean (6SD) body mass index was 22.7 6 3.1 and 22.2 6 3.3 kg/m2 for the finasteride and flutamide treatment groups, respectively. Table 1 shows the basal endocrine profiles of patients with idiopathic hirsutism. No statistically significant differences were seen compared with the control group, except for serum levels of 3a-androstanediol glucuronide, which were significantly higher in idiopathic hirsutism (6.0 6 1.1 versus 1.5 6 0.5 ng/mL). In women with idiopathic hirsutism, the mean basal overall Ferriman-Gallwey score was 16.7 6 3.2, and hair diameters were 51.2 6 5.0 mm in the face, 74.0 6 5.6 mm in the abdomen, 73.1 6 4.9 mm in the thigh, and 49.0 6 4.7 mm in the forearm (Table 2). Statistical analysis indicated that in patients with idiopathic hirsutism, the hair diameters in each area of the body were significantly higher than those of the control group. Table 3 shows the basal hormone levels before and after 6 and 12 months of treatment with finasteride and flutamide. Finasteride produced a statistically significant increase in T at 6 months (0.7 6 0.1 ng/mL) and at 12 months (0.8 6 0.2 ng/mL) and an equally significant reduction in 3a-androstanediol glucuronide at 6 months (2.4 6 0.8 ng/mL) and at 12 months (1.8 6 0.4 ng/mL). Flutamide did not change the hormone profile. The Ferriman-Gallwey scores for hirsutism after 6 and 12 months of treatment with finasteride and flutamide are shown in Table 4. The Ferriman-Gallwey score decreased FERTILITY & STERILITYt
significantly in both treatment groups. Finasteride decreased the Ferriman-Gallwey score by 20.5% at 6 months (from 16.1 6 3.8 to 12.8 6 3.4) and by 34.2% at 12 months (from 16.1 6 3.8 to 10.6 6 3.1). Flutamide decreased the score by 26.6% at 6 months (from 17.3 6 3.1 to 12.7 6 2.8) and by 50.9% at 12 months (from 17.3 6 3.1 to 8.5 6 3.3). The percentage change in the Ferriman-Gallwey score with flutamide was significantly higher than that with finasteride at the end of 12 months of treatment. Table 5 shows the hair diameters in the basal condition and after treatment with finasteride and flutamide. Both drugs significantly decreased hair diameters at 6 and 12 months. Finasteride reduced hair diameters by 18.9%–23.6% at 6 months and by 29.6%–37.9% at 12 months; flutamide by 22.3%–28.2% at 6 months and by 47.7%–56.5% at 12 months. Hairs in the abdomen were the most sensitive to both drugs, decreasing by 23.6% at 6 months and by 37.9% at 12 months with finasteride and by 28.2% at 6 months and by 56.5% at 12 months with flutamide. Hairs in the forearm were the least sensitive to treatment (18.9% at 6 months and 29.6% at 12 months with finasteride; 22.3% at 6 months and 47.7% at 12 months with flutamide). The decrease in facial hair at 6 and 12 months (21.8% and 36.3%, respectively, with finasteride; 27.5% and 54.0% with flutamide) was always greater than that of the thigh (19.7% and 33.7% with finasteride; 23.4% and 51.3% with flutamide). Flutamide was significantly more active than finasteride in decreasing hair diameters at 12 months. During therapy with both antiandrogens, changes in the menstrual cycle were not observed. All patients in the finasteride group completed the study, and side effects were moderate: headache in 3 patients (13%), dry skin in 5 (21.7%), and reduction in libido in 2 (8.7%). This drug did not modify hematochemical variables. Two women (8.7%) in the flutamide group dropped out of the study at 7 months: one (4.3%) because of nausea and vomiting and another (4.3%) because of high transaminase levels. In the remaining 21 patients, flutamide caused a
TABLE 2 Basal hair diameters (mm) in patients with idiopathic hirsutism and in controls. Site Face Abdomen Thigh Forearm
Idiopathic hirsutism (n 5 46)
Controls (n 5 20)
51.2 6 5.0* 74.0 6 5.6* 73.1 6 4.9* 49.0 6 4.7*
27.6 6 1.6 35.2 6 5.1 33.0 6 5.3 26.6 6 3.5
Note: Values are means 6 SD. * P,.001, idiopathic hirsutism versus controls.
43
TABLE 3 Serum hormone levels with finasteride and flutamide treatment. Finasteride Hormone level LH (mIU/mL) FSH (mIU/mL) 17-OHP (ng/mL) A (ng/mL) T (ng/mL) Free T (pg/mL) DHEAS (mg/mL) 3a-diolG (ng/mL) Insulin (mU/mL) SHBG (nmol/L)
Flutamide
Baseline
6 mo
12 mo
Baseline
6 mo
12 mo*
3.5 6 1.5 5.1 6 1.6 0.7 6 0.2 2.0 6 0.3 0.5 6 0.1 1.9 6 0.5 2.1 6 0.6 5.9 6 1.2 5.0 6 2.1 45.3 6 6.1
3.6 6 0.9 5.3 6 0.8 0.8 6 0.3 2.2 6 0.6 0.7 6 0.1† 2.1 6 0.5 2.0 6 0.6 2.4 6 0.8† 5.2 6 1.8 43.3 6 5.3
3.7 6 1.2 5.2 6 1.1 0.8 6 0.2 2.3 6 0.5 0.8 6 0.2† 2.2 6 0.4 1.9 6 0.7 1.8 6 0.4† 5.1 6 1.6 43.1 6 5.9
4.1 6 1.2 5.9 6 2.1 0.6 6 0.3 1.9 6 0.4 0.5 6 0.2 1.8 6 0.5 2.2 6 0.7 6.1 6 1.1 5.2 6 2.2 46.5 6 7.0
4.3 6 1.3 6.0 6 2.2 0.7 6 0.2 1.8 6 0.4 0.4 6 0.2 2.0 6 0.4 2.0 6 0.8 5.8 6 1.4 5.3 6 1.2 47.0 6 7.8
4.2 6 1.7 5.8 6 2.0 0.7 6 0.2 1.7 6 0.5 0.4 6 0.1 1.7 6 0.5 2.0 6 0.9 5.7 6 1.4 5.2 6 1.6 46.0 6 8.2
Note: Values are means 6 SD. 3a-diolG 5 3a-androstanediol glucuronide. * Twelve-month values refer to 21 patients in the flutamide group. † P,.001, 6 and 12 months versus baseline.
reduction in libido in 3 patients (14.3%), gastrointestinal disorders in 3 (14.3%), and dry skin in 13 (62%). Dry skin appeared after 2 months of therapy.
DISCUSSION This randomized study has shown that both finasteride and flutamide are effective in women with idiopathic hirsutism. Flutamide was more effective than finasteride for hirsutism and seborrhea. In fact, flutamide reduced the Ferriman-Gallwey score by 50.9%, the hair diameter by 47.7%– 56.5%, and sebum production in 62% of women; results with finasteride were 34.2%, 29.6%–37.9%, and 21.7%, respectively. Our hormone results demonstrated that finasteride, a 5areductase type 2 selective inhibitor, increased serum levels of T by 40% at 6 months and by 60% at 12 months, and reduced 3a-androstanediol glucuronide by 59.3% at 6 months and by 69.5% at 12 months. Flutamide did not change the basal hormone profile. Decreasing 3a-androstanediol glucuronide, a dihydrotestosterone metabolite, with finasteride confirms its peripheral origin as well as the hyperfunction of 5a-reductase in idiopathic hirsutism and the importance of dihydrotestosterone for hair growth. We noted no important side effects or changes in hematochemical variables in the finasteride group, and all patients completed the study. Flutamide, on the other hand, induced high transaminase levels in 1 patient (4.3%) and nausea and vomiting in 1 (4.3%), and so 21 patients completed the study. Therefore, flutamide presents a higher risk-benefit ratio than finasteride, and its chronic administration requires repeated monitoring of liver function. Our study also showed concordance in the hirsutism evaluation between the Ferriman-Gallwey score (subjective 44
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Finasteride and flutamide
evaluation) and the hair-diameter measurement (objective evaluation). In the literature, the results of these antiandrogens on idiopathic hirsutism are controversial. Nearly all investigators calculated the Ferriman-Gallwey score, a semiquantitative estimation of hirsutism that does not represent an objective measurement of hair growth and is operator dependent. Ciotta et al. (17) administered 7.5 mg/d of finasteride in 9 women with idiopathic hirsutism and noticed a reduction in the Ferriman-Gallwey score by 26% after 6 months and by 47% after 9 months of therapy. Tolino et al. (18) reported that finasteride at 5 mg/d caused a 60% decrease in the Ferriman-Gallwey score in 10 patients with idiopathic hirsutism at 6 months. Moghetti et al. (19) reported a 47.2% reduction in the Ferriman-Gallwey score of 12 patients with idiopathic hirsutism at 6 months. Castello et al. (20) showed that the mean Ferriman-Gallwey score was lowered by 63% after 12 months of finasteride therapy in 14 patients with mild idiopathic hirsutism. Wong et al. (21) and Erenus et al.
TABLE 4 Ferriman-Gallwey scores and changes with finasteride and flutamide treatment. Treatment
Baseline
6 mo
Change (%)
12 mo*
Change (%)
Finasteride Flutamide
16.1 6 3.8 17.3 6 3.1
12.8 6 3.4† 12.7 6 2.8†
20.5 26.6
10.6 6 3.1† 8.5 6 3.3†‡
34.2 50.9
Note: Values are means 6 SD, except as noted. * Twelve-month values refer to 21 patients in the flutamide group. † P,.001, finasteride and flutamide at 6 and 12 months versus baseline. ‡ P,.01, flutamide versus finasteride at 12 months.
Vol. 72, No. 1, July 1999
TABLE 5 Hair diameters (mm) and changes with finasteride and flutamide treatment. Finasteride Site Face Change Abdomen Change Thigh Change Forearm Change
(%) (%) (%) (%)
Flutamide
Baseline
6 mo
12 mo
Baseline
6 mo
12 mo*
51.0 6 5.0 — 74.1 6 5.6 — 73.0 6 4.9 — 48.7 6 4.8 —
39.9 6 4.2† 21.8 56.6 6 5.3† 23.6 58.6 6 4.1† 19.7 39.5 6 3.8† 18.9
32.5 6 4.3† 36.3 45.4 6 4.2† 37.9 48.4 6 4.0† 33.7 34.3 6 3.5† 29.6
51.6 6 5.2 — 73.8 6 6.0 — 73.5 6 4.7 — 49.2 6 5.1 —
37.4 6 4.4† 27.5 53.0 6 5.1† 28.2 56.3 6 4.0† 23.4 38.2 6 4.3† 22.3
23.7 6 3.9†‡ 54.0 32.1 6 4.7†‡ 56.5 35.8 6 3.1†‡ 51.3 25.7 6 4.9†‡ 47.7
Note: Values are means 6 SD, except as noted. * Twelve-month values refer to 21 patients in the flutamide group. † P,.001, finasteride and flutamide at 6 and 12 months versus baseline. ‡ P,.01, flutamide versus finasteride at 12 months.
(22) compared finasteride (5 mg/d) with spironolactone in 2 and 7 women with idiopathic hirsutism, respectively. They reported a decrease in the Ferriman-Gallwey score with finasteride by 11% at 6 months (21) and by 15.1% at 9 months (22). Most investigators reported an increase in T by 40%–70% and a decrease in 3a-androstanediol glucuronide by 56%– 81% with finasteride.
Flutamide, on the other hand, is more effective than finasteride on hirsutism and seborrhea/acne because it is able to block the peripheral receptors of both T and dihydrotestosterone by competition. Imperato-McGinley (27) showed that sebum production was depressed in subjects with complete insensitivity to androgens but not in those with congenital deficiency of 5a-reductase.
Other investigators studied the effects of flutamide on idiopathic hirsutism. Couzinet et al. (23) administered 500 mg/d of flutamide in 10 women with idiopathic hirsutism for 12 months and observed a reduction in the Ferriman-Gallwey score by 69.5%. Erenus et al. (24) studied the same number of patients and dosage of flutamide and found a decrease in the Ferriman-Gallwey score by 39.5% after 6 months and by 46.4% after 9 months of therapy. Moghetti et al. (25), using 375 mg/d of flutamide for 12 months, reported a decrease in the Ferriman-Gallwey score after 8 months of treatment by 55% and after 12 months by 71%. Grigoriou et al. (26) treated 11 women with idiopathic hirsutism with flutamide (500 mg/d) for 9 months, and the Ferriman-Gallwey score decreased by 30.1%. Unlike us, some investigators reported a statistically significant decrease in T and DHEAS after flutamide treatment (25).
On the basis of our results, it is evident that finasteride and flutamide must be given continuously and for a long time. However, chronic use of these antiandrogens can induce numerous problems related to contraception, the risk of pregnancy, and the need for repeated monitoring of liver function in patients receiving flutamide treatment. For these reasons, we believe that in sexually active women, it is necessary to administer these antiandrogens with an oral contraceptive.
The lesser effectiveness of finasteride in comparison with flutamide on hirsutism and seborrhea could be due to various factors: [1] The increase in T per se could have a direct effect on target tissues; [2] finasteride has a limited action on 5a-reductase type 1, which is theoretically more involved in hirsutism, although no studies have defined the isoform of 5a-reductase that increases in hirsutism (9); and [3] finasteride may be unable to decrease dihydrotestosterone production under a threshold value that is ineffective on the pilosebaceous apparatus. Our study in fact documents a decreased but persistent secretion of 3a-androstanediol glucuronide after 12 months of therapy with finasteride. FERTILITY & STERILITYt
Despite the high risk/benefit ratio, we believe that at present, flutamide is more effective for the treatment of idiopathic hirsutism. In the future, the use of specific 5areductase type 1 inhibitors could improve the treatment of idiopathic hirsutism. References 1. Barbieri RL. Hyperandrogenic disorders. Clin Obstet Gynecol 1990; 33:640 –54. 2. Knochenhauer ES, Azziz R. Advances in the diagnosis and treatment of the hirsute patient. Curr Opin Obstet Gynecol 1995;7:344 –50. 3. Serafini PC, Lobo RA. Increased 5a-reductase activity in idiopathic hirsutism. Fertil Steril 1985;43:74 – 8. 4. Serafini PC, Ablan F, Lobo RA. 5a-reductase activity in the genital skin of hirsute women. J Clin Endocrinol Metab 1985;60:349 –55. 5. Horton R. Dihydrotestosterone is a peripheral paracrine hormone. J Androl 1992;13:23–7. 6. Greep N, Hoopes M, Horton R. Androstanediol glucuronide plasma clearance and production rates in normal and hirsute women. J Clin Endocrinol Metab 1986;62:22–7. 7. Lobo RA. Hirsutism in polycystic ovary syndrome: current concepts. Clin Obstet Gynecol 1991;34:817–25. 8. George FW, Russel DW, Wilson JD. Feed-forward control of prostatic growth: dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5a-reductase. Proc Natl Acad Sci USA 1991;88: 8044 –7.
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9. Mestayer CH, Berthaut I, Portois MC, Wright F, Kuttenn F, Mowszowicz I, et al. Predominant expression of 5a-reductase type 1 in pubic skin from normal subjects and hirsute patients. J Clin Endocrinol Metab 1996;81:1989 –93. 10. Harris G, Azzolina B, Baginsky W. Identification and selective inhibition of an isozyme of steroid 5a-reductase in human scalp. Proc Natl Acad Sci USA 1992;89:10787–91. 11. Thigpen AE, Silver RI, Guileyardo JM, Casey ML, McConnell JD, Russell DW. Tissue distribution and ontogeny of steroid 5a-reductase isozyme expression. J Clin Invest 1993;92:903–10. 12. Royer S, Rittmaster RS. Finasteride. N Engl J Med 1994;330:120 –5. 13. Dallob AL, Sadick NS, Unger W, Lipert S, Geissler LA, Gregoire SL, et al. The effect of finasteride, a 5a-reductase inhibitor, on scalp skin testosterone and dihydrotestosterone concentrations in patients with male pattern baldness. J Clin Endocrinol Metab 1994;79: 703– 6. 14. Brogden RN, Clissold SP. Flutamide: a preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in advanced prostatic cancer. Drugs 1989;38:185–203. 15. Crownover RL, Holland J, Chen A, Krieg R, Young BK, Roack M III, et al. Flutamide induced liver toxicity including fatal hepatic necrosis. Int J Radiat Oncol Biol Phys 1996;34:911–5. 16. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 1961;21:1440 – 8. 17. Ciotta L, Cianci A, Calogero A, Palumbo MA, Marletta E, Sciuto A, et al. Clinical and endocrine effects of finasteride, a 5a-reductase inhibitor in women with idiopathic hirsutism. Fertil Steril 1995;64:299 –306. 18. Tolino A, Petrone A, Sarnacchiaro F, Cirillo D, Ronsini S, Lombardi G, et al. Finasteride in the treatment of hirsutism: new therapeutic perspectives. Fertil Steril 1996;66:61–5. 19. Moghetti P, Castello R, Magmani CM, Tosi F, Negri C, Armanini D, et al. Clinical and hormonal effects of the 5-alpha reductase inhibitor
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20.
21.
22. 23. 24. 25.
26.
27.
finasteride in idiopathic hirsutism. J Clin Endocrinol Metab 1994;79: 1115–21. Castello R, Tosi F, Perrone F, Negri C, Muggeo M, Moghetti P. Outcome of long-term treatment with the 5-alpha reductase inhibitor finasteride in idiopathic hirsutism. Clinical and hormonal effects during a 1 year course of therapy and 1 year follow up. Fertil Steril 1996;66: 734 – 40. Wong IL, Morris RS, Chang L, Spahn M, Stanczyk FZ, Lobo R. A prospective randomized trial comparing finasteride to spironolactone in the treatment of hirsute women. J Clin Endocrinol Metab 1995;80: 233– 8. Erenus M, Yu¨celten D, Durmusoglu F, Gu¨bu¨rz O. Comparison of finasteride versus spironolactone in the treatment of idiopathic hirsutism. Fertil Steril 1997;68:1000 –3. Couzinet B, Pholsena M, Young J, Schaison G. The impact of a pure anti-androgen (flutamide) on LH, FSH, androgens and clinical status in idiopathic hirsutism. Clin Endocrinol (Oxf) 1993;39:157– 62. Erenus M, Gu¨bu¨rz O, Durmusoglu F, Demircay Z, Pekin S. Comparison of the efficacy of spironolactone versus flutamide in the treatment of hirsutism. Fertil Steril 1994;61:613– 6. Moghetti P, Castello R, Negri C, Magmani CM, Fontanarosa MC, Armanini D, et al. Flutamide in the treatment of hirsutism: long-term clinical effects, endocrine changes and androgen receptor behavior. Fertil Steril 1995;64:511–7. Grigoriou O, Papadias C, Konidaris S, Antoniou G, Karakitsos P, Giannikos L. Comparison of flutamide and cyproterone acetate in the treatment of hirsutism: a randomized controlled trial. Gynecol Endocrinol 1996;10:119 –23. Imperato-McGinley J, Gautier T, Cai L, Yee B, Epstein J, Pochi P. The androgen control of sebum production. Study of subjects with dihydrotestosterone deficiency and complete androgen insensitivity. J Clin Endocrinol Metab 1993;76:524 – 8.
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