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Comparison of Finasteride Versus Flutamide in the Treatment of Hirsutism

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Comparison of Finasteride Versus Flutamide in the Treatment of Hirsutism European Journal of Endocrinology (1999) 141 361–367 ISSN 0804-4643 CLINICAL STUDY Comparison of finasteride versus flutamide in the treatment of hirsutism Leopoldo Falsetti, Alessandro Gambera, Laura Legrenzi, Carmelo Iacobello1 and Giovanna Bugari1 Department of Gynaecological Endocrinology, University of Brescia, Italy and 13rd Laboratory of Hormonology, Spedali Civili di Brescia, Italy (Correspondence should be addressed to A Gambera, Via XXV Aprile, No. 10, 24058 Romano di Lombardia, Italy) Abstract Objective: To compare the effectiveness of finasteride and flutamide in the treatment of hirsutism in patients with polycystic ovary syndrome (PCOS) and with idiopathic hirsutism. Design: Randomized study. Patients: One hundred and ten hirsute patients were selected: 64 women with PCOS and 46 with idiopathic hirsutism. Methods: Patients were assigned randomly to receive 5 mg finasteride once daily or 250 mg of flutamide twice daily, for 12 consecutive months. Hirsutism was evaluated at 12 months of therapy, with the Ferriman–Gallwey score and with measurement of the terminal hair diameters (mm) taken from four different body areas. Blood samples were taken for assessment of endocrine and hematochemical parameters. Side effects were monitored during the treatment. Results: Both finasteride and flutamide induced a significant decrease in the hirsutism scores and hair diameters at the end of 12 months. Finasteride reduced the Ferriman–Gallwey score by 31.4% in the PCOS cases and by 34.2% in the idiopathic hirsutism cases, and hair diameter by 27.0–34.1% in PCOS and by 29.6–37.9% in idiopathic hirsutism. Flutamide reduced the Ferriman–Gallwey score by 56.7% in PCOS and by 50.9% in idiopathic hirsutism, and hair diameter by 50.3–60.0% in PCOS and by 47.7–56.5% in idiopathic hirsutism. Flutamide did not induce hormone variations, while finasteride increased testosterone levels by 40% in PCOS and by 60% in idiopathic hirsutism and decreased 3a-androstanediol glucuronide (3a-diolG) by 66.7% in PCOS and by 69.5% in idiopathic hirsutism. No important side effects or changes in the hematochemical parameters were observed with finasteride, while two patients (3.6%) in the flutamide group expressed abnormal transaminase levels after 6 months of treatment. Dry skin also appeared significantly more with flutamide (67.3%) than with finasteride (23.6%). Conclusions: Both drugs are effective in the treatment of hirsutism but flutamide is more effective than finasteride. European Journal of Endocrinology 141 361–367 resistance. Hirsutism is present in 60–83% of women Introduction with PCOS (6, 7). Hirsutism affects 5–8% of the whole female population of Idiopathic hirsutism is caused by increased sensitivity fertile age (1). Seventy to 80% of the hirsute women have of the pilosebaceous unit to normal circulating andro- hyperandrogenism, while 6–17% have normal androgen gen levels presumably caused by increased peripheral levels and regular ovulatory menstrual cycles (2, 3). 5a-reductase (5a-R) enzyme activity (8). Androgen-dependent hirsutism may be caused by Numerous studies have documented that in all abnormalities in the ovaries or in the adrenal glands, hirsute women, with or without hyperandrogenism, by exogenous androgen administration or by a combi- the 5a-R activity in the skin was steadily elevated (9). nation of these factors. Sixty-five to 85% of all women 5a-Reductase is therefore a key step in hirsutism. The with androgen excess have polycystic ovary syndrome activity of 5a-R and consequently the formation of (PCOS) or hyperthecosis (4, 5). PCOS is a clinical dihydrotestosterone (DHT) and 5a-reductase metabo- condition characterized by altered gonadotropin secre- lites such as 3a-androstanediol glucuronide (3a-diolG) tion, chronic anovulation, hyperandrogenism and a (10), can be regulated by an increase in the circulating variety of metabolic effects such as obesity and insulin androgenic precursors, as well as genetic factors (11, q 1999 Society of the European Journal of Endocrinology Online version via http://www.eje.org Downloaded from Bioscientifica.com at 10/02/2021 06:51:43PM via free access 362 L Falsetti and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (1999) 141 12) and the insulin–insulin-like growth factor-I (IGF-I) (SHBG) levels (Table 1). High dehydroepiandrosterone system (13). sulfate (DHEAS) levels (mean was 3.5 6 0.8 mg/ml) Two genes encoding for 5a-R enzymes have been were present in 22 patients. recently cloned. They are called 5a-R type 1 and 2 Forty-six patients were diagnosed as having idio- (5a-R1 and 5a-R2). Studies using specific inhibitors of pathic hirsutism because they had regular ovulatory 5a-R1 and 5a-R2 (finasteride) showed that 5a-R2 menstrual cycles, normal serum androgen levels, enzymatic activity is predominant in the urogenital normal SHBG and 17a-hydroxyprogesterone (17- sinus and in genital skin, whereas 5a-R1 is predomi- OHP), both in basal conditions and after the adreno- nant in the central nervous system (only type 1), in corticotropin (ACTH) stimulation test, performed pubic skin, in the adult scalp and in the nonsex skin of during the follicular phase of the cycle. Ovulatory the normal male, normal women and hirsute patients cycles were determined by the midluteal phase plasma (14–17). However, the distribution and role of 5a-R1 is progesterone levels (> 4 ng/ml). Hirsutism was always less clear. evaluated by the same physician with the Ferriman– Finasteride, a member of the 4-azasteroid family of Gallwey score (21) and with measurement of the hair compounds, is more effective against isoenzyme 5a-R diameter. A score greater than 7 is indicative of type 2 than type 1, but the specificity for the two hirsutism, but only women with a Ferriman–Gallwey isoenzymes is incomplete (18). Finasteride blocks the score that ranged from 11 to 23 were included in this conversion of testosterone to the more potent DHT. study. Concentrations of DHT fall by 60–80% in men treated Hairs were taken from four different parts of the body: with a dose of 5–400 mg (15). The fall in serum DHT is face (chin), abdomen (immediately below the umbilicus), accompanied by a reduction in metabolites of DHT such anterior midthigh and forearm. as 3a-diolG and by a rise in plasma testosterone Three terminal hairs were cut from each body area at concentrations. No side effects were reported in the their cutaneous base. Each hair was then fixed on a slide women using finasteride. with a transparent resin which solidifies with air, and Flutamide, a non-steroidal drug, is a pure peripheral was covered with another slide. Hair measurement was androgen antagonist. It is metabolized to 2-hydroxy- carried out with a micrometer, applied to an optical flutamide, an active metabolite which acts as a microscope (10 × magnification), at a constant distance competitive inhibitor of the cytoplasmic and nuclear of 0.8 mm from the base. Measurement of the hair binding of androgens to the receptor (19). The drug does diameter from each body area, expressed in micrometers not have a progestogenic or anti-gonadotropic action (mm), represented the mean 6 S.D. of the measurement of and thus does not cause menstrual irregularity. The use three hairs. of flutamide can be associated with liver toxicity with All patients underwent hematochemical examina- abnormal transaminase levels and cholestatic jaundice tions (hemochrome, glycemia, azotemia, creatinemia, (20). electrophoretic protidogram, total and fractioned bili- The aim of the present report is to compare the rubinemia, transminases and alkaline phosphatase), therapeutic efficacy of finasteride and flutamide on SHBG and hormonal assays, including LH, follicle- hirsutism in women with PCOS and idiopathic hirsutism. stimulating hormone (FSH), 17-OHP, androstenedione (A), total (T) and free (FT) testosterone, DHEAS, 3a- diolG and fasting insulin (I). Hormonal assays were Materials and methods assessed in the early follicular phase (5th to 7th day) of One hundred and ten hirsute women, between 18 and a spontanous menstrual cycle or progestin-induced 29 years of age, of which 64 with PCOS and 46 with menstrual bleeding (medrossiprogesterone acetato at a idiopathic hirsutism that were referred to the Depart- dose of 10 mg/day for 5 days). ment of Gynaecological Endocrinology of the University During therapy all hirsute women had an interview of Brescia, were included in the study, after written every 3 months, in order to establish the course of informed consent was given. No patients had Cushing’s the menstrual cycles and side effects. Hematochemical syndrome, evidence of enzymatic adrenal deficiency, examinations were repeated every 3 months in women history of drug-induced hyperandrogenism or an treated with flutamide and every 6 months in women endocrine profile compatible with androgen-producing with finasteride. Hormone samples were carried out neoplasm or prolactin (PRL) and thyroid disorder. at the start and at the end of the treatment (12th Diagnosis of PCOS was based on clinical and month). endocrine findings. Oligoamenorrhea was present in Patients were advised to avoid pregnancy during 45 (70.7%) patients, while secondary amenorrhea was treatment because of possible male fetus feminization. present in 19 (29.3%). All the 64 patients had Sexually active women were advised to use contra- anovulatory cycles and hirsutism. The hormonal profile ception barrier methods (condom) during the study. showed high luteinizing hormone (LH) levels (LH : FSH Patients of both groups were randomly assigned in ratio > 2), high levels of total and free testosterone and a 1 : 1 ratio to receive either 5 mg/day of finasteride androstenedione and low sex hormone-binding globulin (Prostide, Sigma Tau, Milan, Italy) or 250 mg of flutamide Downloaded from Bioscientifica.com at 10/02/2021 06:51:43PM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (1999) 141 Finasteride vs flutamide in treatment of hirsutism 363 Table 1 Basal plasma hormone levels (mean 6 S.D.) in patients with PCOS, idiopathic hirsutism and in control group.
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