REPRODUCTIVE ENDOCRINOLOGY

FERTILITY AND STERILITY VOL. 79, NO. 1, JANUARY 2003 Copyright 2003 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. REPRODUCTIVE ENDOCRINOLOGY Treatment of hyperandrogenic alopecia in women Enrico Carmina, M.D., a and Rogerio A. Lobo, M.D. b University of Palermo, Palermo, Italy Objective: To determine the effectiveness of various antiandrogens for the treatment of premenopausal women with hyperandrogenic alopecia. Design: Randomized, unmasked trial of three treatments in 36 hyperandrogenic women with alopecia and observation, without treatment, in 12 other similar patients. Setting: Endocrinologic outpatient practice in Italy. Participant(s): A total of 48 hyperandrogenic women with alopecia and 30 age- and weight-matched controls for the assessment of androgen levels. Intervention(s): Randomization to cyproterone acetate (50 mg) with ethinyl estradiol (EE) in a reverse sequential regimen; flutamide (250 mg) or finasteride (5 mg) daily; all for 1 year. Twelve similar patients were observed without treatment for 1 year. Main Outcome Measure(s): Ludwig scores for hair thinning as well as patient and investigator assessments of treatment effectiveness. Result(s): Flutamide resulted in a reduction of 21% in Ludwig scores (2.3 0.2 to 1.8 0.1). The other treatment effects were not statistically significant. Patient and investigator assessments showed a similar trend. Conclusion(s): Flutamide at a dose of 250 mg daily induced a modest improvement in alopecia after 1 year, whereas cyproterone acetate and finasteride were not effective. Treatment for more than 1 year may be required for better results. (Fertil Steril 2003;79:91 5. 2003 by American Society for Reproductive Medicine.) Key Words: Alopecia, hyperandrogenism, antiandrogens Received December 19, 2001; revised and accepted July 5, 2002. Reprint requests: Rogerio A. Lobo, M.D., Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, 630 West 168 Street, New York, New York 10032 (FAX: 212-305-4326; E- mail: ral35@columbia.edu). a Department of Obstetrics and Gynecology. b Department of Obstetrics and Gynecology, Columbia University, College of Physicians and Surgeons, New York, New York. 0015-0282/03/$30.00 PII S0015-0282(02)04551-X Androgenic alopecia is a common form of alopecia in which androgens gradually transform normal-sized scalp hair follicles to miniaturized hair follicles. Progressively, there is a thinning of scalp hair and a pattern of hair loss that is greatest in the frontal/parietal regions (1, 2). Although it is generally believed that the pathogenesis of hyperandrogenic alopecia is related to an excessive activity of androgen on the scalp, in many affected women circulating androgen levels are normal (3, 4) and an increased scalp sensitivity to androgens has been suggested (2). Among those women with increased circulating levels of androgen, no particular pattern of increased androgen production has been linked with hyperandrogenic alopecia (3, 5), although some investigators have suggested the presence of adrenal hyperandrogenism (4). In the setting where circulating androgens are normal, it is likely that scalp sensitivity to androgens is the important component of the pathophysiology. Studies of peripheral androgen metabolism in alopecia have been inconclusive. Although it has been shown that type I 5 -reductase activity is increased in female hyperandrogenic alopecia, this may be the consequence of increased circulating androgens (6). On the other hand, we and other researchers have shown that women with hyperandrogenic alopecia have a characteristic pattern of increased 5 -reduced androgen metabolites, particularly 3 -androstanediol sulfate (5, 7). These androgen metabolites, however, are highly dependent on circulating androgens as substrate, and the sulfate derivatives correlate well with adrenal androgens (8). Treatment of androgenic alopecia has been disappointing (2, 9). In contrast to the reasonably good results obtained in women with hirsutism or acne, classic antiandrogen therapies have been generally unsuccessful. In the past several years antiandrogenic agents have become available and have been studied for the 91

treatment of hirsutism (10). In this study, we assessed the effects of two agents (flutamide and finasteride) in women with hyperandrogenic alopecia (11, 12). We compared the effects of these treatments to the effects of a well-studied antiandrogen cyproterone acetate (13). In this study we also had the opportunity to assess the effects of no treatment. TABLE 1 Baseline mean Ludwig scores and serum androgens in groups of women with hyperandrogenic alopecia who were randomized to treatment or were observed for 1 year. MATERIALS AND METHODS Alopecia scores T (ng/dl) Unbound T (pg/ml) DHEAS ( g/ml) Forty-eight hyperandrogenic women were studied (mean age 25 2 years, mean body mass index [BMI] 24.3 2) who presented consecutively with the chief complaint and diagnosis of androgenic alopecia over a period of 3 years. Only premenopausal women with increased serum androgens were included. Serum androgens that were higher than the mean 2 SD of levels in ovulatory controls were considered elevated. Frontal hair thinning was assessed as grade I, II, or III according to the Ludwig classification (14). A picture of the frontal parietal region was obtained in each patient and was used for comparisons at the end of the treatment. Mild hirsutism (evaluated by Ferriman-Gallwey- Lorenzo index) was present in 10 patients (21%) and menstrual irregularities (oligomenorrhea) were present in 20 women (42%) with androgenetic alopecia. Thirty normal ovulatory women, matched for age and body weight, served as controls. In all patients and controls, a blood sample was obtained during the follicular phase of the cycle (days 5 6), after an overnight fast for T, unbound T, and DHEAS. These values were used to confirm the presence of hyperandrogenism in all 48 subjects with androgenic alopecia. Thirty-six women were randomized to one of three treatments, each composed of 12 subjects: 1. cyproterone acetate (CPA) (50 mg/day 25 g of ethinyl estradiol [EE]) in a reverse sequential regimen (CPA from day 5 to day 15 of the cycle EE from day 5 to day 25 of the cycle) (15); 2. flutamide (250 mg/day); and 3. finasteride (5 mg/day). A dose of 250 mg was chosen for flutamide to minimize the potential for hepatic toxicity (16). Twelve women who were recruited for the study refused any treatment and were observed for 1 year without any therapy. These women had similar characteristics and the same degree of alopecia as women in the treatment groups. At the end of treatment (or observation) the following evaluation procedures were carried out: 1. Ludwig grade of frontal hair thinning. 2. Patient self-assessment (using a questionnaire [17], consisting of four questions: appearance of the hair, growth of hair, slowing down of hair loss, and general satisfaction with the therapy). 3. Investigator assessment. The hair density in the frontal parietal region was compared to that observed before treatment using a 7-point rating scale: greatly decreased ( 3), moderately decreased ( 2), slightly decreased ( 1), no CPA (n 12) 2.1 0.2 84 7 3.7 0.3 2.7 0.2 Flutamide (n 12) 2.3 0.2 89 11 3.7 0.2 2.9 0.3 Finasteride (n 12) 2.2 0.1 88 10 3.3 0.2 2.7 0.5 Observation (n 12) 2.1 0.3 81 11 3.3 0.2 3.1 0.5 No significant differences between groups were found. change (0), slightly increased ( 1), moderately increased ( 2), and greatly increased ( 3). All assessments were carried out by one of the authors (EC). Possible side effects and liver function tests were assessed at 3-month intervals. Institutional review board approval was obtained and all patients gave written informed consent. All subjects in this study were not dieting or receiving any medication for at least 3 months before starting the study. Serum hormone levels were measured by RIAs, which have been previously validated in our laboratory. Intra- and interassay coefficients of variation were less than 6% and 12%, respectively (18, 19). Statistical Analysis Mann-Whitney U was the test used to compare patients and controls; the response to therapy was assessed by analysis of variance. P.05 was considered statistically significant. Results are expressed as mean SE. RESULTS Women with alopecia in this study had significantly (P.01) increased levels of T, unbound T, and DHEAS in comparison with normal controls. Mean scores for alopecia and serum androgens were similar in each of the treatment groups (Table 1). After 1 year of treatment, only flutamide induced a significant, although small, decrease in Ludwig scores (from 2.3 0.2 to 1.8 0.1, P.05). The changes with the other agents were smaller and not significant. Flutamide resulted in a 21% decrease in scores (Fig. 1). The self-assessment evaluation also showed that flutamide gave the best results. Eight flutamide-treated patients reported the slowing down of hair loss and 5 of them declared general satisfaction with this treatment. However, improvement of general hair appearance and regrowth of hair were observed in only 3 patients (Table 2). With the 92 Carmina and Lobo Treatment of alopecia Vol. 79, No. 1, January 2003

FIGURE 1 Percent decrease of Ludwig scores in four groups of women with hyperandrogenic alopecia. Open bar, cyproterone acetate (CPA); solid bar, flutamide; striped bar, finasteride; dotted bar, observation group. Only flutamide ( 21%) showed a significant decrease as indicated by asterisk (P.05). FIGURE 2 Investigator assessment of scalp hair changes in four groups of women with hyperandrogenic alopecia. Open bar, cyproterone acetate (CPA); solid bar, flutamide; striped bar, finasteride; dotted bar, observation group. The improvement in assessment scores for flutamide was significantly (P.05) better than that for finasteride and the observation group as indicated by the asterisks. other agents, less favorable results were reported (Table 2). In patients treated with CPA, 3 observed slowing down of hair loss and general satisfaction with this treatment. Only one patient on finasteride and one in the observational group reported a slowing down of hair loss and were pleased with these results. The scores of investigator assessment also indicated that the best results were obtained with flutamide with a mean score of 0.9 0.2 (Fig. 2). However, this was not significant when compared to CPA (mean 0.5 0.2), but was greater compared to finasteride and the observation group (for both mean 0.1 0.2; P.05). In two patients, after 6 months of treatment with flutamide, a mild elevation of liver enzymes was observed (transaminases were very mildly elevated; 20% above the TABLE 2 The number of patients who reported improvement of alopecia using self-assessment with a standardized questionnaire (16). General hair appearance Hair regrowth Slowdown of hair loss General satisfaction with the therapy CPA (n 12) 1 2 3 3 Flutamide (n 12) 3 3 8 5 Finasteride (n 12) 0 1 1 1 Observation (n 12) 0 1 1 1 normal range). This was not thought to preclude treatment, which was continued with the full approval and knowledge of the patients. Liver function in these 2 patients was carefully evaluated every month. No further increase of liver enzymes was observed and 2 months after the end of the treatment the liver enzyme levels returned to normal. No other side effects were observed with flutamide. No side effects were reported during treatment with CPA or finasteride. DISCUSSION Although increased serum androgens have a major role in the pathogenesis of female hyperandrogenic alopecia, treatment has been found to be generally unsuccessful (2, 9). Several studies have compared the effects of different antiandrogens in the treatment of hirsutism (10), yet no such data exist for the treatment of hyperandrogenic alopecia (1). In this study we assessed and compared the effects of three different agents in the treatment of women with hyperandrogenic alopecia. Cyproterone acetate is a classic antiandrogen that is used widely in Europe and in Canada, but has not been marketed in the United States. We chose the classic regimen of a high dose (50 mg/day) in a reverse sequential regimen in combination with EE (15), although several other doses of CPA may be used. Previously, we had shown that high doses give better results than low doses in women with hirsutism (20). The second agent in this trial, flutamide, is a powerful competitive inhibitor of the androgen receptor and has been FERTILITY & STERILITY 93

shown to be effective in decreasing hirsutism (10, 11). It has been given in doses of 500 750 mg/day; lower doses (250 375 mg/day) have also been used (11, 16). Because flutamide has been associated with severe liver damage (21, 22), we chose to use 250 mg/day (16). The third agent, finasteride, is an inhibitor of 5 -reductase type II (23). It has been known for several years that 5 -reductase activity is increased in the androgenetic alopecia scalp, and this probably contributes to the pathogenesis of hair loss (24, 25). Finasteride, at a dose of 1 mg/day, has reduced male hair loss and has been approved for the treatment of male balding (23). Recently, a large trial (26) in women showed that finasteride (1 mg/day) was ineffective in female androgenetic alopecia. In this particular study, only postmenopausal women were evaluated. We considered that it is possible that the pathogenesis of postmenopausal androgenic alopecia and premenopausal hyperandrogenic alopecia are different. We decided to include finasteride in our trial and to use a larger dose, 5 mg/day, which has been shown to be beneficial for the treatment of hirsutism (12). Our study showed that all the agents had a small effect on the treatment of hyperandrogenic alopecia. However, there were some important differences. Although finasteride, at a dose of 5 mg/day, was ineffective and its effects were similar to that of the observation group, both flutamide and CPA exhibited some improvement of the alopecia. The best results were obtained with flutamide, which resulted in a 21% improvement of Ludwig scores, a reduction of hair loss (as reported by a self-assessment questionnaire in 8 of 12 patients, and a slight mean improvement of alopecia ( 1) by investigator assessment. These differences were statistically significant in comparison with the observation group who had no treatment. Although the total objective improvement was small and only a few patients (3 of 12) reported a subjective regrowth of hair, this may be due to the characteristics of cycles of hair growth on the scalp. The anagen phase of scalp hair growth has a duration of several years (from 2 to 8 years) and is much longer than that on the face (about 3 months). Therefore, it is possible that a protocol involving a very much longer observation period is needed to obtain significant findings of regrowth of scalp hair (27). It is unclear why, as opposed to treatment in men, finasteride is not effective in female androgenic alopecia. However, we propose that the scalp concentration of 5 -reductase isoenzymes in men and hyperandrogenic women may explain these differences. Finasteride is an inhibitor of type II 5 -reductase and in hyperandrogenic women with hirsutism or acne, there is mostly an increase of type I 5 reductase. It is conceivable, therefore, that in hyperandrogenic women with alopecia, scalp type I 5 -reductase predominates as it does in other hyperandrogenic women. Some evidence for this has been provided (28). Our study was limited by the fact that there were only 12 women in each group. Only a multicenter trial may be able to recruit more patients, and this may have resulted in more significant findings. We also did not treat women with placebo but have included an observational group whose characteristics of androgens and objective hair findings were similar. Although we have suggested that a longer treatment protocol may be necessary, a concern exists with the use of flutamide. Two of 12 women demonstrated mild elevations in liver enzymes, which were reversible, at the low dose of 250 mg used in this study. However, prolonged treatment may further increase this risk and although we are not proposing that only flutamide be used for alopecia, we present our findings using objective criteria. Perhaps newer agents in this class with less propensity for hepatocellular toxicity would be beneficial for prolonged treatment of hyperandrogenic alopecia. We also did not compare the use of spironolactone in this setting. Because it is difficult to recruit a large number of women with androgenic alopecia, we compared only flutamide, finasteride, and CPA. In conclusion, we have shown that a pure antiandrogenblocking agent, flutamide, improves hyperandrogenic female alopecia to a modest degree. Although this effect is relatively small and is mostly characterized by a reduction in hair loss, it is possible that longer treatment may result in better and more substantial regrowth of scalp hair. Our data also would suggest that finasteride is ineffective in this setting. References 1. Olsen EA. 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