Prospective randomized study comparing the long-acting ...

FERTILITY AND STERILITYt VOL. 71, NO. 1, JANUARY 1999 Copyright © 1998 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.

Prospective randomized study comparing the long-acting gonadotropin-releasing hormone agonist triptorelin, flutamide, and cyproterone acetate, used in combination with an oral contraceptive, in the treatment of hirsutism Fernando Pazos, M.D., Ph.D.,* Hećtor F. Escobar-Morreale, M.D., Ph.D., Jose´ Balsa, M.D., Ph.D., Jose´ M. Sancho, M.D., Ph.D., and Ce´sar Varela, M.D., Ph.D. Department of Endocrinology, Hospital Ramoń y Cajal, Madrid, Spain

Received June 11, 1998; revised and accepted August 13, 1998. Presented in part at the 77th Annual Meeting of the Endocrine Society, Washington, D.C., June 12–15, 1995. Reprint requests: Ce´sar Varela, M.D., Ph.D., Department of Endocrinology, Hospital Ramoń y Cajal, Carretera de Colmenar km 9,100, 28034 Madrid, Spain (FAX: 34-91-336-9016). * Present address: Department of Endocrinology, Hospital Universitario Marque´s de Valdecilla, Santander, Spain. 0015-0282/98/$19.00 PII S0015-0282(98)00414-2

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Objective: To compare triptorelin, cyproterone acetate (CPA), and flutamide, in combination with an oral contraceptive, in the treatment of hirsutism. Design: Prospective randomized study. Setting(s): Tertiary care hospital. Patient(s): Thirty-nine hirsute women with idiopathic or functional ovarian hyperandrogenism. Intervention(s): Patients were randomly assigned to receive triptorelin (3.75 mg IM every 28 days), CPA (100 mg/d orally on days 1–10 of the menstrual cycle), or flutamide (250 mg orally twice daily). All the patients also received a triphasic oral contraceptive. Main Outcome Measure(s): Before and after 3 and 9 months of treatment, the Ferriman-Gallwey score, hepatic function, and gonadal and adrenal steroid profiles were evaluated. Results: Thirty-three patients completed the 9-month study period. The Ferriman-Gallwey score decreased in all the groups. In the patients treated with CPA or flutamide, a decrease in the hirsutism score was noted as soon as after 3 months of treatment. This decrease was more pronounced after 9 months of treatment, especially in the patients who received flutamide, who had lower hirsutism scores compared with the other treatment groups. None of the patients had abnormal liver function test results. There was a mild increase in serum lipid concentrations, mostly in the group treated with triptorelin. Conclusion(s): Triptorelin, CPA, and flutamide are effective drugs for the treatment of hirsutism. Flutamide results in a greater reduction in the hirsutism score, but CPA also offers satisfactory results at a much lower cost. Triptorelin has no advantages over flutamide and CPA, and is the most expensive of the three drugs tested. (Fertil Sterilt 1999;71:122– 8. ©1998 by American Society for Reproductive Medicine.) Key Words: Triptorelin, flutamide, cyproterone acetate, hirsutism, functional ovarian hyperandrogenism, treatment

The available therapies for hirsutism include, among other drugs, GnRH agonists (GnRH-a), cyproterone acetate (CPA), flutamide, and oral contraceptives (1). In several studies (2–5), the prolonged administration of long-acting GnRH-a to hirsute women resulted in reduced ovarian androgen secretion and clinical improvement of hirsutism. Cyproterone acetate appears to act by both binding to the androgen receptor and reducing androgen biosynthesis (6, 7). In addition, CPA has a strong

progestogen effect, which inhibits the increase in gonadotropin secretion that is induced by the decrease in serum testosterone concentrations (8). The nonsteroidal drug flutamide blocks the binding of androgens to their receptor (9) and also has been shown to reduce androgen synthesis (10) and to increase the metabolism of androgens to inactive molecules (11). Oral contraceptives have several beneficial effects in the treatment of hirsutism. Treatment

with oral contraceptives results in decreased serum concentrations of androgens and gonadotropins (12). Moreover, the administration of oral contraceptives increases sex hormonebinding globulin (SHBG) synthesis and secretion (12), reducing the availability of serum androgens to their target tissues. The combined administration of GnRH-a or antiandrogens and oral contraceptives has several advantages over the administration of these drugs separately. The administration of a GnRH-a plus an oral contraceptive results in profound suppression of gonadal androgens while avoiding the adverse effects of hypoestrogenism (menopausal flushing, vaginal mucous atrophy, decrease in bone mineral mass). The use of an oral contraceptive, by inhibiting ovarian androgen secretion and reducing serum androgen concentrations (12), facilitates the effect of the antiandrogen on the pilosebaceous unit. Finally, antiandrogen drugs should be used in combination with an effective contraceptive method in sexually active and fertile women because the administration of the antiandrogen alone could result in the feminization of a male fetus. In the present prospective and randomized study, we compared the clinical efficacy, serum steroid profiles, and safety of the depot long-acting GnRH-a triptorelin, CPA, and flutamide, in the treatment of hirsutism. For the reasons outlined earlier, all these drugs were administered in combination with a triphasic oral contraceptive.

MATERIALS AND METHODS Forty-five consecutively seen women who were referred to the Department of Endocrinology of the Hospital Ramoń y Cajal for the evaluation of hirsutism were included in the study. Hirsutism was defined by the presence of excessive body hair distributed in an androgen-dependent pattern, with a Ferriman-Gallwey score of .7 (range, 8 –36) (13). Menstrual cycle intervals were evaluated on recall for every patient. Oligomenorrhea was defined by the presence of three or more cycles of .35 days in the previous 6 months and amenorrhea by the lack of vaginal bleeding for 3 months. None of the patients was hypertensive, had evidence of Cushing’s disease or drug-induced hirsutism, or had any previous illness contraindicating the use of any of the drugs tested. Hyperprolactinemia, thyroid disease, and acromegaly were ruled out by appropriate testing. Idiopathic hirsutism or functional ovarian hyperandrogenism was diagnosed according to combined ACTH plus triptorelin testing (14). In brief, patients who presented with normal serum testosterone levels before and during triptorelin-induced gonadal suppression were considered to have idiopathic hirsutism, whereas patients who presented with increased testosterone levels that normalized during ovarian suppression were considered to have functional ovarian hyperandrogenism. FERTILITY & STERILITYt

Six patients were considered to have adrenal hyperandrogenism because their serum testosterone concentrations remained elevated during gonadal suppression, and they were excluded from the study. One of the patients with adrenal hyperandrogenism presented with an adrenal androgen-secreting adenoma, which was surgically excised, two patients had serum 17a-hydroxyprogesterone (17-OHP) responses to ACTH compatible with homozygous nonclassic 21-hydroxylase deficiency, and three patients had no obvious enzyme deficiency and were considered to have functional adrenal hyperandrogenism (14). Patients with adrenal hyperandrogenism, with the exception of the patient with the adrenal adenoma, received lowdose dexamethasone treatment. Therefore, only patients with idiopathic hirsutism or functional ovarian hyperandrogenism were recruited for treatment with triptorelin, CPA, or flutamide, in combination with an oral contraceptive. The study was approved by the local ethics committee, and informed consent was obtained from all patients.

Experimental Design At baseline, patients were randomly assigned to three groups of 13 patients each, after stratification for the presence of functional ovarian hyperandrogenism. In group 1, patients received triptorelin (3.75 mg IM every 28 days, D-Trp6-GnRH, Decapeptyl; LASA-Ipsen, Barcelona, Spain). Patients assigned to group 2 received CPA (100 mg/d on days 1–10 of the menstrual cycle, Androcur; Schering, Madrid, Spain), whereas in group 3, patients were treated with flutamide (250 mg twice daily, Grisetin; LASA-Ipsen). All the patients received a triphasic oral contraceptive containing ethinyl estradiol and levonorgestrel (0.03 1 0.05 mg/d on days 1– 6, 0.04 1 0.075 mg/d on days 7–11, and 0.03 1 0.125 mg/d on days 11–21, Triagynon; Schering). Treatment was started 2 days after a spontaneous or medroxyprogesterone acetate–induced menstruation. A complete physical examination, including determination of a Ferriman-Gallwey score, was performed at baseline and after 3 and 9 months of treatment. Two experienced investigators were responsible for determination of the Ferriman-Gallwey score in all the patients. Each investigator evaluated a similar number of patients from each treatment group. These investigators were blinded to the treatment received by the patient, but they knew the point during the study at which the Ferriman-Gallwey score was being determined. No crossexamination was performed. Blood samples were obtained at baseline, month 3, and month 9 for measurement of LH, FSH, E2, testosterone, SHBG, 11-deoxycortisol (S), 17-OHP, DHEA and DHEAS, and D4-androstenedione (D4-A). Samples were obtained between days 2 and 5 of the menstrual cycle, at 8:30 –9:00 AM, after an overnight fast. In addition, in patients treated with triptorelin, an acute 1-24 ACTH (250 mg IV, Synacthen; Ciba-Geigy, Basel, Switzerland) test also was performed. 123

TABLE 1 Clinical characteristics of the groups of hirsute women. Treatment group Triptorelin 1 TOC (n 5 11) Cyproterone acetate 1 TOC (n 5 10) Flutamide 1 TOC (n 5 12)

Age (y)

Body mass index (kg/m2)

Menstrual cycle length (d)

No. with FOH

21.9 6 1.6 20.4 6 1.3 22.3 6 1.2

24.5 6 1.5 25.1 6 0.9 23.2 6 1.2

34.0 6 2.1 30.0 6 1.6 39.0 6 2.6

6 5 7

Note: Values are means 6 SEM, with the exception of the number of patients with functional ovarian hyperandrogenism (FOH) in the different treatment groups, which is expressed in absolute values. TOC 5 triphasic oral contraceptive.

Assays

Fasting plasma levels of total bilirubin, g-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, total cholesterol, high-density lipoprotein cholesterol, and triglycerides were measured by Hitachi Autoanalyzers (models 747 and 704; Hitachi Corporation, Tokyo, Japan) with reactives provided by Boehringer Mannheim GmbH (Mannheim, Germany). Testosterone, cortisol (F), S, 17-OHP, DHEAS, D4-A, and E2 were determined with the use of commercially available RIA kits (testosterone, E2, and F: Sorin Biomedica S.p.A., Saluggia, Italy; S: ICN Biomedicals, Inc., Costa Mesa, CA; 17-OHP: Immunochem Corporation, Carson, CA; DHEAS: Diagnostic Products Corporation, Los Angeles, CA; D4-A: Incstar, Stillwater, MN). The mean intra-assay and interassay coefficients of variation (CVs), as reported by the manufacturers, were as follows: testosterone, 7.9% and 10.4%; F, 4.6% and 6.9%; S, 4.1% and 12.6%; 17-OHP, 9.6% and 11.8%; DHEAS, 4.5% and 5.6%; D4-A, 6.9% and 10.7%; and E2, 5.0% and 11.9%, respectively. Dehydroepiandrosterone was measured by RIA after extraction with dichloromethane (Diagnostic Products Corporation) and had intra-assay and interassay CVs of 7.5% and 8.4%, respectively. Sex hormone-binding globulin was measured with the use of an immunoradiometric assay (Orion Diagnostica, Espoo, Finland) with intra-assay and interassay CVs of 4.9% and 5.3%, respectively. Luteinizing hormone and FSH were measured with the use of immunoradiometric assays (CIS Bio International, Gif-sur-Yvette, France) with intra-assay and interassay CVs of 1.7% and 5.1%, and 3.5% and 5.3%, respectively. The S and 17-OHP responses to ACTH stimulation were calculated as the area under the curve of the response by the trapezoid rule, avoiding the influence of basal steroid concentrations on the absolute values reached after ACTH stimulation.

Statistical Analysis

The data are expressed as means 6 SEM in the text, tables, and figures. The data were analyzed by repeatedmeasures analysis of variance, introducing the treatment group as the between-subjects effect and the month of treatment as the within-subjects effect. When this analysis resulted in statistically significant differences, these differ-

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Three treatments for hirsutism

ences were identified further with the Newman-Keuls test (between-subjects effect) and with repeated paired t-tests (within-subjects effect). P ,.05 was considered statistically significant.

RESULTS The 9-month study was completed by 33 of the 39 patients; 2 patients in the triptorelin group, 3 patients in the CPA group, and 1 patient in the flutamide group were lost to follow-up, did not comply with treatment, or had adverse effects (see later). At baseline, there were no differences in age, body mass index, prevalence of menstrual disturbances, Ferriman-Gallwey score, or steroid profiles among the three groups of patients (Tables 1 and 2, Fig. 1). The prevalence of functional ovarian hyperandrogenism was similar in all the groups (Table 1). All the groups experienced a decrease in the FerrimanGallwey score with respect to baseline values (Table 2). This decrease was noticeable after 3 and 9 months of treatment with CPA and flutamide, but only after 9 months of treatment with triptorelin (Table 2). To compare the three drug regimens, avoiding the influence of the baseline value, the Ferriman-Gallwey score by month 9 was expressed as a percentage of the initial value. Patients treated with flutamide showed a lower percentage value than patients treated with CPA or triptorelin (Table 2), suggesting a higher efficacy of flutamide in reducing the Ferriman-Gallwey score. Serum gonadotropin and E2 concentrations decreased during treatment in all the groups (Fig. 1). Treatment with triptorelin resulted in lower LH concentrations by month 9 compared with treatment with CPA or flutamide (Fig. 1). Although E2 levels decreased markedly during treatment compared with baseline (Fig. 1), the patients did not complain of hot flushes or other estrogen withdrawal symptoms. Serum testosterone concentrations decreased by months 3 and 9 with respect to baseline in all the treatment groups (Fig. 1), although in the group treated with flutamide, the difference with respect to baseline did not reach statistical significance by month 9 (Fig. 1). Serum SHBG concentrations increased with respect to baseline by months 3 and 9 in Vol. 71, No. 1, January 1999

TABLE 2 Evolution of the Ferriman-Gallwey scores before and during treatment of hirsute women with triptorelin, cyproterone acetate, or flutamide, in combination with a triphasic oral contraceptive. Baseline

Month 3

Month 9

Treatment group

F-G score

F-G score

Percentage of baseline

F-G score

Percentage of baseline

Triptorelin 1 TOC Cyproterone acetate 1 TOC Flutamide 1 TOC

15.6 6 1.8 12.9 6 1.4 15.8 6 1.0

12.6 6 1.1 9.8 6 1.1* 10.5 6 0.9*

(83 6 3) (75 6 4) (66 6 5)‡

10.9 6 1.0* 8.4 6 0.8† 8.5 6 1.0†

(72 6 4) (67 6 4) (53 6 4)§

Note: Values are means 6 SEM. Values in parentheses represent the Ferriman-Gallwey (F-G) scores expressed as a percentage of the baseline value. TOC 5 triphasic oral contraceptive. * P ,.01 vs. baseline. † P ,.001 vs. baseline. ‡ P ,.05 vs. the triptorelin 1 TOC group. § P ,.01 vs. the triptorelin 1 TOC and cyproterone acetate 1 TOC groups.

all the groups (Fig. 1), and reached higher values by month 9 in patients treated with flutamide compared with patients treated with triptorelin (Fig. 1). Serum levels of D4-A and DHEA decreased only in patients treated with triptorelin (Fig. 1), whereas serum levels of DHEAS showed a marked reduction by months 3 and 9 with respect to baseline only in patients treated with flutamide (Fig. 1). In the patients treated with triptorelin, the S and 17-OHP responses to ACTH were evaluated after 9 months of treatment. Serum basal 17-OHP levels and the 17-OHP response to ACTH were decreased by month 9 compared with baseline (Fig. 2), whereas basal serum S levels and the S response to ACTH showed no statistically significant change (Fig. 2). As stated earlier, six patients did not complete the 9-month study. Two patients in the CPA group were not compliant with the medication regimen and were excluded from the study, and another patient in this group refused further treatment after intermenstrual spotting. One patient in the triptorelin group moved to another city, and a second patient in this group refused any further treatment of hirsutism of personal reasons. The only serious adverse effect, requiring discontinuation of treatment, occurred in a patient treated with flutamide and consisted of deep venous thrombosis of the lower limbs associated with pulmonary embolism. Several other patients reported mild side effects such as nausea, intermenstrual spotting, and breast tenderness, which disappeared with continuation of treatment. Three of the patients in group 3 received a reduced dose of flutamide (250 mg/d) within 1 week of the beginning of treatment because of persistent nausea. These side effects were not distinctly associated with any of the drugs tested. No changes in the parameters of hepatic function were found during treatment with any of the drugs (data not shown). In contrast, a mild increase in serum total cholesterol and triglycerides was found in group 1 by months 3 and 9, whereas patients in group 3 had a mild increase in serum triglycerides by month 3 (Table 3). FERTILITY & STERILITYt

DISCUSSION Long-acting GnRH-a (3, 4), CPA (6, 15), and flutamide (15–18) have been shown to be effective in the treatment of hirsutism. However, randomized studies comparing the efficacy of the three drugs, in association with an oral contraceptive, have not been reported to date. Our data, in addition to confirming the efficacy of the three treatment regimens used, also suggest that flutamide might produce better results in the treatment of hirsutism. A significant reduction in the hirsutism score was noted as soon as 3 months after the initiation of therapy in the groups treated with flutamide and CPA, but not in the group treated with triptorelin, in which a reduction in the hirsutism score was noted only after 9 months of treatment. Early reduction in the hirsutism score (after only 3 months of treatment) has been reported with flutamide, alone or in combination with an oral contraceptive (17, 18), and with CPA (19) in combination with an oral contraceptive, even when administered at doses much lower than the doses used in our study (17–19). In our series, the early clinical response to flutamide and CPA was maintained over time, after 9 months of treatment, the reduction in the Ferriman-Gallwey score was greater in patients treated with flutamide than in patients treated with triptorelin or CPA. Grigoriou et al. (15) recently found a nonsignificant trend toward a greater reduction in the hirsutism score in patients treated with flutamide compared with CPA. Finally, our results also confirm a previous report (20) suggesting that triptorelin has no advantage, in terms of efficacy, over CPA in the treatment of hirsutism. All the regimens used in this study were effective in reducing serum testosterone concentrations. Serum testosterone concentrations were markedly reduced in the patients treated with triptorelin and CPA, but this decrease was less important in the group treated with flutamide, and testosterone levels were higher in this group compared with the other 125

FIGURE 1

FIGURE 2

Serum concentrations of testosterone (T), D4-androstenedione (D4-A), DHEA and DHEAS, sex hormone-binding globulin (SHBG), LH, FSH, and E2 at baseline and after 3 and 9 months of treatment with triptorelin (TR), cyproterone acetate (CPA), or flutamide (FL), in combination with a triphasic oral contraceptive. Values are means 6 SEM. *P ,.05 vs. baseline; †P ,.01 vs. baseline; ‡P ,.05 vs. the group treated with triptorelin; §P ,.01 vs. the group treated with triptorelin; \P ,.05 vs. the group treated with CPA.

Basal and ACTH-stimulated serum 17a-hydroxyprogesterone (17-OHP) and 11-deoxycortisol (S) levels in patients treated with triptorelin in combination with a triphasic oral contraceptive, at baseline and after 9 months of treatment. The responses to ACTH are represented as the area under the curve (AUC) of the response to avoid the influence of basal steroid concentrations. Values are means 6 SEM. *P ,.05 vs. baseline.

Treatment with flutamide also resulted in a decrease in serum DHEAS concentrations, whereas the concentrations of this steroid remained unchanged in the other treatment groups. The decrease in serum levels of DHEAS, a steroid that is secreted almost exclusively by the adrenal gland (21), has been documented previously in hirsute patients treated with flutamide (15, 22–24), suggesting a direct inhibitory effect of flutamide on adrenal androgen secretion. Other studies (25, 26) have not found a reduction in serum DHEAS levels during flutamide administration to hirsute patients.

two groups. This finding may be related to the increase in serum SHBG levels seen during treatment, which was higher in the patients treated with flutamide. The higher serum SHBG concentrations might explain the increased serum testosterone concentrations, because total rather than free concentrations of this hormone were measured. The higher SHBG levels in patients treated with flutamide compared with patients treated with triptorelin might be related to a stronger blockade of androgen action at the liver by flutamide. 126

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In addition to its possible interaction with adrenal androgen secretion, a recent study also suggests that flutamide, when used alone in young hyperandrogenic women, reduces ovarian androgen synthesis through restoration of ovulation (27), which might result from a direct blockade of the steroidogenic enzymes of androgen biosynthesis in ovarian thecal cells. According to our present results, flutamide has the advantage over CPA and triptorelin of not only reducing ovarian androgen production but also decreasing adrenal androgen hypersecretion, a frequent finding in patients with idiopathic hirsutism or functional ovarian hyperandrogenism (28, 29). Vol. 71, No. 1, January 1999

TABLE 3 Lipid profiles of hirsute women treated with triptorelin, cyproterone acetate, or flutamide, in combination with a triphasic oral contraceptive, before and after 3 and 9 months of treatment. Mean 6 SEM of indicated lipid level (mg/dL) Lipid profile Total cholesterol Triptorelin 1 TOC Cyproterone acetate 1 TOC Flutamide 1 TOC HDL cholesterol Triptorelin 1 TOC Cyproterone acetate 1 TOC Flutamide 1 TOC Triglycerides Triptorelin 1 TOC Cyproterone acetate 1 TOC Flutamide 1 TOC

Baseline

Month 3

Month 9

178 6 8 178 6 4 155 6 12

193 6 8 182 6 16 178 6 8

197 6 8* 182 6 8 162 6 8

54 6 4 58 6 4 58 6 4

58 6 4 46 6 8 62 6 4

54 6 8 54 6 4 62 6 4

71 6 9 80 6 12 71 6 14

103 6 14* 80 6 9 96 6 12

97 6 16* 96 6 9 98 6 12*

Note: Values are means 6 SEM. HDL 5 high-density lipoprotein; TOC 5 triphasic oral contraceptive. * P ,.05 vs. baseline.

As expected by its mechanism of action, namely downregulation of GnRH receptors in the pituitary, triptorelin administration resulted in a profound suppression of serum LH levels, which were markedly reduced in patients treated with this drug compared with patients treated with flutamide, and also were mildly reduced compared with patients treated with CPA. The lower LH levels in the group treated with triptorelin resulted in a decrease in serum D4-A and DHEA levels, which was not observed in the other treatment groups. Despite this reduction in circulating androgen levels, triptorelin appeared to be less effective than flutamide or CPA in terms of clinical responses, because the decrease in the hirsutism score with triptorelin was significant only after 9 months of treatment and was less pronounced than in the other treatment groups. These findings probably are related to the lack of antiandrogenic effects at the receptor level of the triptorelin regimen. Serum FSH, as opposed to LH levels, decreased to a similar extent in the three groups of patients. In the patients treated with triptorelin, the increase in serum 17-OHP and S levels in response to ACTH stimulation served to evaluate the influence of ovarian function on adrenal steroidogenesis in hirsute patients. Whereas the serum S response by month 9 showed no change with respect to baseline, the increase in 17-OHP in response to ACTH decreased by month 9, suggesting an improvement in adrenal 21-hydroxylase function during prolonged gonadal suppression. This finding is in agreement with a previous study in women with nonclassic 21-hydroxylase deficiency (30), in which the clinical and biochemical expression of this deficiency appeared to be reduced during ovarian suppression. FERTILITY & STERILITYt

Treatment usually was well tolerated in all the patients and the only serious event, which occurred in a patient treated with flutamide, appeared to be related to the oral contraceptive component, because the patient presented with thromboembolic disease. There has been concern about liver toxicity associated with the use of flutamide. Severe hepatic lesions, including massive hepatic necrosis resulting in death, have been described in patients treated with flutamide for prostate cancer (31), at doses higher than the dose used here for hirsutism. However, flutamide-induced hepatotoxicity also has been described in the treatment of hirsutism (32). Because the toxic effects of flutamide on the liver appear to be dose-dependent, treatment of hirsutism with low doses of flutamide (250 mg/d) has been investigated. Treatment of hirsutism with low doses of flutamide appears to be as effective as treatment with higher doses and does not induce elevation of hepatic enzymes (17, 18, 26). Although we used a standard flutamide dose of 500 mg/d, we did not observe any change in the serum indices of hepatic function, even in patients who reported nausea as an adverse effect. Cyproterone acetate, although related to the development of liver tumors in cellular and animal experiments (33), has not been reported to be associated with any significant adverse effect in the treatment of hirsutism, and we did not observe any significant side effect in our series. In contrast, a mild increase in serum triglycerides and total cholesterol concentrations was observed in the group treated with triptorelin. This result might suggest some degree of hypoestrogenism in these patients, although elevations in the serum lipid profiles have not been described during combined GnRH-a and oral contraceptive treatment of hirsutism by other investigators (2). Finally, not only the efficacy and toxicity but also the cost of treatment must be considered before recommending any of the treatment regimens studied. Although in our series, treatment with flutamide provided better results than the other regimens, treatment with CPA also resulted in early and sustained reductions in the hirsutism score, at half the cost of flutamide treatment. In contrast, treatment with triptorelin cannot be recommended according to our present results, because the reduction in the hirsutism score took longer to occur, was not superior to that associated with flutamide or CPA and had an undesirable impact on serum lipid profiles, and because triptorelin is the most expensive of the three drugs tested. In conclusion, flutamide, CPA, and triptorelin, when used in combination with an oral contraceptive, are effective in the treatment of hirsutism. Flutamide appears to be more effective in reducing the hirsutism score than the other drugs used in this study. However, this advantage may be counterbalanced by its risk of hepatotoxicity. In contrast, CPA, which is much less expensive than flutamide, appears to be safe and effective in the treatment of hirsutism. 127

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Vol. 71, No. 1, January 1999