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Original Studies |
Reproductive Medicine Unit, Institute of Obstetrics and Gynecology, and the Department of Evolutionary-Experimental Biology (O.M.), University of Bologna, Bologna, Italy
Address all correspondence and requests for reprints to: Prof. Stefano Venturoli, Clinica Ostetrica e Ginecologica, Universitá di Bologna, Via Massarenti N.13, I-40138 Bologna, Italy.
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Abstract |
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Some differences existed among treatments with regard to effectiveness; EE-CPA and flutamide seem to be the most efficacious in improving hirsutism. For the hirsutism score, a greater decrease was seen with EE-CPA (-60 ± 18%) than with finasteride (-44 ± 13%; P < 0.01) and a greater decrease was seen with flutamide (-58 ± 18%) than with finasteride (-44 ± 13%; P < 0.05). Flutamide is the fastest in decreasing hair diameter; EE-CPA is the fastest in slowing down hair growth, even though at the end of the treatment there was a significant difference between flutamide and finasteride only (-41 ± 18% vs. -27 ± 14%; P < 0.05).
Flutamide, ketoconazole, and EE-CPA induced a significant decrease in
total and free testosterone, 5
-dihydrotestosterone,
dehydroepiandrosterone, dehydroepiandrosterone sulfate, and
androstenedione plasma levels. During the EE-CPA treatment,
gonadotropins were suppressed, and the sex hormone-binding globulin
level increased. Finasteride induced a decrease in
dehydroepiandrosterone sulfate and 5-dihydrotestosterone and an
increase in testosterone levels.
Very few side-effects were observed during treatment with low doses of flutamide, EE-CPA, and particularly finasteride. Flutamide induced a decrease whereas EE-CPA induced an increase in triglycerides and cholesterol, showing higher values within the normal range. Ketoconazole induced several side-effects and complications, and several people dropped out of the study.
Despite different modalities of action and significantly different effects on androgen levels, low doses of flutamide, finasteride, and EE-CPA constitute very satisfactory alternative therapeutic regimens in the treatment of hirsutism.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The aim of the present report was to compare, in a prospective, comparative, randomized study, as objectively as possible, the therapeutic efficacy as well as the endocrine and metabolic effects and reliability of low dose regimens of flutamide, finasteride, ketoconazole, and a combination of CPA and ethinyl estradiol (EE).
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Regular menses were reported by 29 of the 66 women; 32 had
oligomenorrhea, 3 had amenorrhea, and 2 had polymenorrhea. Thirty-eight
patients (58%) had ovulatory cycles (on the basis of typical
progesterone levels in the premenstrual phase), and 28 (42%) had
anovulatory cycles. Each patient underwent a complete medical and
gynecological examination. In accordance with our codified parameters
(21), all subjects had an etiological diagnosis of hirsutism. None of
the women gave evidence of a hormonally active adrenal gland, an
ovarian tumor, or Cushing’s, PRL, or thyroid disorder. Twenty-seven
patients (41%) had a diagnosis of polycystic ovary syndrome; 18 had
anovulatory or oligoovulatory cycles, elevated plasma LH concentrations
(LH/FSH ratio >2), high levels of testosterone and androstenedione,
and ecographic evidence of enlarged polycystic ovaries. Nine patients
had the concomitant presence of high dehydroepiandrosterone sulfate
levels. Fourteen hirsute patients (21%) suffered from a mild form of
nonclassic adrenal hyperplasia with high 17-hydroxyprogesterone
values, as diagnosed by ACTH test (21). Twenty-five patients (38%)
were classified as having idiopathic hirsutism because they did not
present any of the clinical features found in the other groups and had
ovulatory cycles. In the entire population studied the hirsutism score
ranged from 7–22.
Patients were randomized into four groups for treatment, independently of the diagnosis made. No significant differences were observed between groups regarding the prevalence of the diagnosis of hirsutism, clinical parameters, and menstrual rhythm or ovulatory/anovulatory cycles; thus, the patients were randomized into four comparable groups. Group 1 (n = 15; age, 22.6 ± 4 yr; BMI, 22.9 ± 2 kg/m2) received 250 mg/day flutamide, group 2 (n = 15; age, 23.2 ± 3 yr; BMI, 22.5 ± 3 kg/m2) received 5 mg/day finasteride, group 3 (n = 16; age, 23.2 ± 5 yr; BMI, 23.0 ± 3 kg/m2) received 300 mg/day ketoconazole, and group 4 (n = 20; age, 22.9 ± 4 yr; BMI, 22.6 ± 2 kg/m2) received a treatment regimen with low EE and CPA doses (the patients received 0.01 mg EE/day for the first week, 0.02 mg EE/day for the second week, and 0.01 mg EE/day for the third week, followed by a pause of 7 days, then 12.5 mg CPA/day administered in a reverse sequential regimen during the first 10 days of each treatment cycle). We planned a 12-month therapy period, and either the barrier method or intrauterine contraception was employed during the study in sexually active women to avoid any risk of conception.
Clinical and hormonal controls were performed in basal conditions and after 3, 6, 9, and 12 months. Each woman was studied during the early follicular phase of her menstrual cycle (3–6 days after the onset of a spontaneous menstrual flow) when present or at random in amenorrheic patients in basal conditions and after 180 and 360 days of treatment.
The study was approved by the ethical committee of the Institute of Obstetrics and Gynecology of the University of Bologna, and informed consent was obtained from each patient. All procedures followed in this study were in accordance with the Helsinki Declaration of 1975.
Hirsutism evaluation, clinical side-effects, endocrine and biochemical
parameters [blood glucose, cholesterol, high density lipoprotein
cholesterol, triglycerides, aspartate aminotransferase (AST), alanine
aminotransferase (ALT), 
-glutamyltransferase, alkaline phosphatase,
bilirubin, antithrombin III, and fibrinogen] were determined at each
control visit.
Hirsutism and hair growth evaluation
Hirsutism was evaluated with a 2-fold criteria of control so as to have a method of analysis as objective as possible. 1) Hirsutism grading was codified by calculating the hirsutism score according to the modified Ferriman and Gallwey method (22), and the normal range was considered to be no higher than 8. Two patients with a total score of 7 were included because a severe regional (upper lip and thigh) hair growth, and the entry criteria for all patients was a score of 7 or greater. 2) As previously reported (12), hair parameters were codified using an IBAS image analyzer (Kontron Bildanalyze GmbH, Munich, Germany), a special image analysis processor with a sensitivity of 0.001 mm. First, all patients were shaved in a prefixed area of the right thigh. After 90 days, at least 20 hairs (basal hair growth) were cut from the same thigh area using curved scissors; then the area was reshaved, and treatments were started. This same procedure was repeated after 90, 180, 270, and 360 days of therapy. The mean diameter, hair length, and daily growth rate (obtained by dividing the length of each hair by the number of the days elapsed between shaving and the subsequent cut) were estimated. Considering that anagen hair growth on the thigh has a mean duration of 22 days and that the complete hair cycle is 84 days (23), a 90-day period of basal observation seems to be correct for establishing the mean basal hair growth in each group.
Self-reported evaluation
Patients’ self-evaluation of the clinical outcome of the treatment was obtained. Each patient rated his appreciation as dissatisfied, satisfied, or highly satisfied.
Hormone assay
Blood samples were drawn at 0800 h; all samples from each
subject were run in the same RIA. The RIA techniques used for hormonal
measurements were: gonadotropins (FSH-LH) and PRL, rapid double
antibody (kits purchased from Biodata, Rome, Italy);
17-hydroxyprogesterone (17-P) and progesterone (P), chromatographic
separation on Sephadex LH-20 columns; dehydroepiandrosterone sulfate
(DHAS) performed directly on diluted plasma, testosterone (T),
5-dehydrotestosterone (DHT), androstenedione (A), and
17ß-estradiol (E2), TLC on silica gel 60 F254;
dehydroepiandrosterone (DHA), plasma extraction with ethyl ether, as
previously described (24), using an ACTH kit purchased from CIS
(Gif-Sur-Yvete, France) and a cortisol (F) kit purchased from
Diagnostic Systems Laboratories (Webster, TX); free testosterone (Tf),
the Coat-A-Count free testosterone procedure of Diagnostic Products (Los Angeles, CA); and sex hormone-binding globulin
(SHBG), noncompetitive liquid phase immunoradiometric assay (Farmos
Diagnostic, Oulunsalo, Finland).
Statistical analysis
Paired and unpaired Student’s t tests and ANOVA were used for statistical analysis, as needed. Values are expressed as the mean ± SD.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Figure 1
shows the results of the
different regimens of therapy during the entire treatment period. In
each subject who finished the study, not less than 100 hairs were
analyzed by IBAS, both under basal conditions and during the entire
cycle of treatment. Under basal conditions, 1848 hairs were analyzed,
and 6800 hairs were analyzed during the entire cycle of treatment.
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; 14.2 ± 4.5) progressively decreased and
dropped to 6.4 ± 3.5 (P < 0.001; -55 ±
13%) after 12 months of treatment. The mean diameter (Fig. 1) fell
from 0.169 ± 0.02 to 0.133 ± 0.02 mm (P <
0.001; -21 ± 14%), and the mean daily rate of hair growth (Fig. 1) fell progressively from 0.153 ± 0.03 to 0.084 ± 0.04
mm/day (P < 0.001; -41 ± 18%).
In group 2 (finasteride), hirsutism improved in all
subjects. The mean basal score (Fig. 1; 12.4 ± 4.8) slowly
dropped during therapy to 6.9 ± 3.5 (P < 0.02;
-44 ± 13%) after 12 months of treatment. The mean diameter
(Fig. 1) fell from 0.174 ± 0.02 to 0.147 ± 0.02 mm
(P < 0.001; -16 ± 12%), and the mean daily
rate (Fig. 1) of hair growth fell from 0.127 ± 0.05 to 0.095
± 0.04 mm/day (P < 0.005; -27 ± 14%).
In group 3 (ketoconazole), 8 of 16 subjects who started the therapy
stopped taking the drug within 180 days because of several side-effects
and complications; hirsutism had improved in the 8 subjects who
concluded the 12-month therapy period (mean basal score, 13.8 ±
4.4; 12-month therapy score, 6.5 ± 4.8; P <
0.005; -53 ± 18%; Fig. 1). The mean diameter (Fig. 1) fell
progressively from 0.177 ± 0.01 to 0.148 ± 0.02 mm
(P < 0.005; -14 ± 12%), and the mean daily
rate of hair growth (Fig. 1) fell from 0.129 ± 0.03 to 0.090
± 0.04 mm/day (P < 0.005; -30 ± 21%). Six of
8 hirsute subjects who interrupted the therapy had slower hair growth
during the therapy on the basis of their subjective evaluations.
In group 4 (EE-CPA), hirsutism improved in all subjects. The mean basal
score (Fig. 1; 13.3 ± 5.1) dropped to 6.1 ± 5.5
(P < 0.001; -60 ± 18%) after 12 months of
treatment. The mean diameter (Fig. 1) fell from 0.164 ± 0.05 to
0.138 ± 0.02 mm (P < 0.001; -20 ± 11%).
The mean daily rate (Fig. 1) of hair growth decreased during the first
90 days and fell from 0.127 ± 0.05 to 0.090 ± 0.03 mm/day
(P < 0.001) (-28 ± 21%) after 12 months.
Comparative data among groups
There were no significant differences among groups with respect to
their clinical basic data, endocrine parameters (Tables
1 and 2),
hirsutism score, or basal hair characteristics (Fig. 1).
For the hirsutism score (Fig. 1), no differences (by ANOVA,
P = NS) were observed among the groups during the
control period, confirming the efficacy of all four treatments.
However significantly higher differences were observed in the
percentage of decrease (Fig. 2) at the end of treatment in the cases of
flutamide vs. finasteride (-55 ± 18%
vs. -44 ± 13%; P < 0.05) and EE-CPA
vs. finasteride (-60 ± 18%
vs. -44 ± 13%; P < 0.01).
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), significant differences were observed at 90
days (F = 3.94; P < 0.01), 180 days (F =
3.6; P < 0.01), and 270 days (F = 6.7;
P < 0.001) among the groups. Flutamide induced the
quickest decrease in hair diameter during treatment (at 90 days of
treatment) even though the differences in the percent decrease
disappeared at the end of treatment (Fig. 2).
For the hair growth rate (Figs. 1 and 2),
significant differences among groups were observed at 90 days (F =
3.6; P < 0.02) and 180 days (F = 5.1;
P < 0.003). Finasteride was the slowest
in decreasing hair growth, whereas EE-CPA was the quickest. Flutamide
acted progressively, and there was a significant difference between
flutamide and finasteride (-41 ± 18%
vs. -27 ± 14%; P < 0.05) at the end
of treatment (Fig. 2).
Hormone concentrations
Tables 1 and 2 show the mean hormonal values under basal
conditions and during the different treatments. In group 1, flutamide
induced a significant decrease in 17-P, Tf, T, DHT, A, DHAS, DHA, and F
and an increase in E2 levels. In group 2,
finasteride induced a significant decrease in DHAS,
E2, and DHT mean values and an increase in T and
Tf mean values. In group 3, the mean plasma levels of T, Tf, DHT, DHA,
DHAS, and A decreased progressively during ketoconazole treatment,
whereas FSH, LH, E2, F, ACTH, and 17-P values
increased. In group 4 during treatment with EE/CPA, there was a
decrease in LH, E2, 17-P, T, Tf, A, DHA, and DHAS
and an increase in F and SHBG plasma levels.
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)In group 1, only a few, transient and slight side-effects occurred, and all subjects concluded the period of treatment. After 6 months of treatment, cholesterol (-11%) and triglycerides (-22%) values dropped significantly, with respect to the basal values. No changes were observed in the other parameters.
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In group 3, major side-effects and complications occurred during the first 90 days of treatment. A high number of patients dropped out within the first 180 days. Mean AST, ALT, and alkaline phosphatase levels increased progressively to the upper limit of the normal adult range. Two subjects had very high AST and ALT values. Triglycerides (-25%) and cholesterol (-17%) values decreased progressively. No changes were observed in the other parameters.
In group 4, some subjects experienced a mild weight gain (<2 kg) after 6–9 months of treatment and had mild transient side-effects. One subject suffered from irregular menstrual bleeding, and one dropped out because of persistent amenorrhea during the ninth month of therapy. Cholesterol mean values increased progressively (+21%) up to the upper limit of normal values (<250 mg/dL), and mean triglycerides values increased progressively (+38%), but they remained within the normal range (20–175 mg/dL).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Low as well as high doses of flutamide alone (4, 25) were effective. The hirsutism score decreased progressively (-55%), and the improvement of hirsutism was associated with a rapid decrease in hair diameter (-11% after 3 months) and a progressive decrease in the daily hair growth rate (-41% after 12 months). A net decrease in T, Tf, DHT, A, 17-P, DHA, and DHAS plasma levels during treatment was observed, in agreement with some reports (26, 27) and in disagreement with others (1, 2, 5, 28), suggesting that the efficacy of flutamide must be ascribed to a reduction of androgen synthesis and to its action on target tissues. At a dose of 250 mg/day flutamide, neither liver failure nor the side-effects generally seen with high doses (2, 4, 27, 29, 30) were observed. Moreover, a significant decrease in the cholesterol and triglycerides values was observed, in contrast to the data reported by Dodin et al. (4).
Finasteride, generally used at a dose of 5 mg/day (6, 7, 8, 9, 10), caused a significant decrease in the hirsutism score (-44%), hair diameter (-16%), and daily hair growth rate (-27%). In our experience, the results were less satisfactory than those reported by some (7, 8, 9, 10), but in accordance with others (31, 32). The administration of finasteride has been associated with a decrease in DHT plasma values (7, 8, 10) and an increase in T levels (7, 8, 9, 10, 31); moreover, our data showed a decrease in DHAS levels, suggesting a slight inhibitory effect on adrenal steroidogenesis. Clinical parameters did not change, and no side-effects were reported during the administration of finasteride, confirming its favorable clinical applicability.
Using a low dose ketoconazole treatment regimen, the hirsutism score improved markedly in the patients who completed 12 months of therapy (-53%), and both hair diameter (-14%) and daily hair growth rate (-30%) decreased significantly. However, eight patients dropped out of the study because of side-effects and complications. We believe that ketoconazole should be used with caution. Our findings confirm a decrease in T, Tf, A, DHT, and DHAS values and an increase in 17-P values, and give evidence of a strong inhibition of 17- hydroxylase, 17,20-desmolase, and 11-hydroxylase activity (12, 33, 34).
High EE-CPA doses are very effective (15, 16, 17, 18, 20); in the present study we used very low amounts of EE and CPA, and we confirm their high efficacy. Hirsutism progressively improved (as much as 60% less), and hair shaft diameter decreased significantly (-20%), even though the initial slowing of hair growth (-30% at 90 days) did not improve any further after the first 3 months of therapy. The beneficial effect of EE-CPA seems to be related to the well known peripheral effect and to the decrease in both ovarian and adrenal androgens as well as the increase in SHBG reached despite the low EE doses given. The effects of the EE-CPA on lipid metabolism are still being debated (35, 36, 37, 38). Despite the low EE doses employed, an increase in triglycerides, which remained within the normal range, and a slight increase in total cholesterol were observed. The few transient side-effects reported during CPA-EE treatment did not require discontinuing the therapy.
In correctly evaluating and comparing the results of different treatments of hirsutism, we added the evaluation of the hair growth rate to the hirsutism score (22) and hair shaft diameter (31). This is a parameter whose behavior is partially independent of the hirsutism score and hair diameter (39), and this may explain the differences in the time response to the different therapies.
Finasteride appears to be the drug with the slowest time of action; it induces the least decrease in hirsutism score of the four treatments. However, the drug is highly effective, as the hair diameter at the end of the treatment is similar to that found with the other therapies. It is the best tolerated, and this therapy is probably the most effective in treating normoandrogenic hirsutism.
The EE-CPA combination induces the quickest reduction of hair growth and gives the greatest hair score decrease after 12 months of treatment. It is the treatment of choice in ovarian and adrenal hirsutism in sexually active women, because of steroid suppression, contraceptive effects (40) due to gonadotropin suppression, and optimal control of the menstrual cycle.
Flutamide has a quick and progressive effect on all parameters up to 12 months, very similar to the effects of EE-CPA and ketoconazole. The strong suppression of both adrenal and ovarian androgens without interference with gonadotropin secretion, the improved glucose tolerance (41), the cholesterol and triglycerides reduction, as well as the absence of side-effects at low doses enable this drug to be used in a flexible way, especially for hyperandrogenism in nonsexually active adolescents, in obese subjects, and in patients at cardiovascular risk.
Ketoconazole improves all parameters of hirsutism, as do the other treatments; however, in view of its important and frequent side-effects and complications, its use should be discouraged.
Finally, we emphasize that the treatment of hirsutism is aimed at the cause, and that each drug acts in its own way on anagen or telogen, hair diameter, or hair growth. However, the drugs employed in the present report together with spironolactone (42), which competes at the androgen receptor level, currently constitute very satisfactory alternative therapeutic regimens in the treatment of hirsutism.
Received May 11, 1998.
Revised September 23, 1998.
Accepted December 18, 1998.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-reductase inhibitor
finasteride in idiopathic hirsutism. J Clin Endocrinol Metab. 79:1115–1121.[Abstract]
-reductase inhibitor, in women with idiopathic
hirsutism. Fertil Steril. 64:299–306.[Medline]
-reductase inhibitor finasteride in idiopathic hirsutism: clinical
and hormonal effects during a 1-year course of therapy and 1-year
follow-up. Fertil Steril. 66:734–740.[Medline]
-reductase inhibitor, on circulating
androgens and gonadotropin secretion in hirsute women. J Clin
Endocrinol Metab. 79:831–835.[Abstract]
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