Prospective Cohort Study on the Effects and Tolerability of Flutamide in Patients with Female Pattern Hair Loss

Roberto Paradisi, MD; Eleonora Porcu, MD; Raffaella Fabbri, BSc; Renato Seracchioli, MD; Cesare Battaglia, MD; Stefano Venturoli, MD

Disclosures

The Annals of Pharmacotherapy. 2011;45(4):469-475. 

In This Article

Discussion

FPHL is due to the progressive shortening of successive anagen cycles and increased telogen to anagen hair ratio, which causes, in genetically predisposed pigmented terminal hairs, a gradual miniaturization to vellus hairs in the presence of androgens.[8] Androgens act through androgen receptors in the dermal papilla, but the exact pathophysiologic mechanism in FPHL is still hard to define.[28] Nevertheless, androgens seem to play an important role in the pathogenesis of FPHL because most women with FPHL, although they may have normal circulating androgen levels[3,29,30] and no other clinical sign of hyperandrogenism,[31] may benefit from oral antiandrogen therapy.[11,28] For this reason, we have evaluated the efficacy, safety, and tolera- 472 n bility of the long-term use of flutamide in a large sample of patients with FPHL.

Our study indicates that flutamide administration, with or without an oral contraceptive, produces an evident clinical improvement in Ludwig scores and a lasting increase in objectively visible scalp density in the majority of patients, as confirmed by the high percentage (>70%) of satisfied or highly satisfied women in the patients' self evaluation of clinical outcome. Moreover, the study shows, for the first time, that amelioration in Ludwig scores may be maintained long term by using very low doses of the drug (62.5 mg/day). Additionally, our results confirmed marked reductions of serum androgens with flutamide treatment in both groups, a finding previously reported in hirsute[23] and acneic[24] patients. It is noteworthy that the addition of an oral contraceptive does not change the efficacy of flutamide in either clinical or biochemical data.

In the literature, only 2 studies[10,22] have reported on short-term efficacy of flutamide in the treatment of FPHL. Cusan et al.[22] observed that, in 6 of 7 women with androgenic alopecia, flutamide therapy resulted in an increase in cosmetically acceptable hair density during a period of 9 months. Carmina and Lobo[10] found that, in 8 of 12 women with hyperandrogenic alopecia, flutamide demonstrated a slowdown of hair loss and, in 5 of them, a general satisfaction with the therapy in a year of treatment. These authors argued that flutamide improves androgenetic alopecia to a modest degree but that a longer treatment and observation period is needed to obtain a more substantial regrowth of scalp hair. In confirmation of this, Stout and Stumpf[32] observed that a 12- month trial with finasteride is needed to assess stabilization of hair loss, but hair regrowth may take 2 years or longer. Scalp hair growth cycle has a duration of from 2 to 6 or 8 years and is much longer than the face hair growth cycle, which is approximately 3- 4 months.[1,8] Therefore, any treatment that aims at obtaining evident outcomes in FPHL must be more prolonged than similar treatments of hirsutism or acne. This is why there is common belief in the scientific community that classic antiandrogen therapies are generally unsuccessful or less effective in the treatment of FPHL, compared with better outcomes obtained in women treated for hirsutism or acne.[2,10] For this reason our study was designed as a 4-year treatment protocol. Our data assert that the improvement in the alopecia score during flutamide treatment is less marked in amount and percentage and more delayed in time than that obtained in the hirsutism score,[23] the difference being even more striking with acne and seborrhea scores.[24]

It is peculiar that the employment of a potent antiandrogen, such as flutamide, in FPHL has been so underutilized. Recently, Scheinfeld[28] observed that flutamide is not in common use by dermatologists and it is hard to know whether it will find a place in FPHL treatment. This limited use of flutamide in FPHL is certainly due to the well-known high risk of severe liver toxicity.[33,34] However, flutamide hepatotoxicity appears to be dose-dependent rather than idiosyncratic;[35–37] therefore, when it is administered at very low doses, this risk may completely disappear,[37] whereas its potent antiandrogen activity remains complete and unaltered at low doses.[36] This statement is further confirmed by our data. In fact, among the 62 patients who withdrew from the study, only 4 interrupted treatment because of transaminase increases, whereas most patients (n = 32) were lost to follow-up during the last year of treatment, after satisfactory outcomes had been obtained. Therefore, they had less reason to continue therapy, and many others (n = 26) were lost for reasons not related to therapy (wish to get pregnant, no more contraceptive need, change of address, modification of psychological self-evaluation and appearance).

Stout and Stumpf[32] reported that finasteride and other antiandrogens, such as flutamide, remain potential second-line agents for FPHL and may be an option for women who do not respond to or tolerate topical minoxidil, considered to be a first-line agent. Carmina and Lobo[10] showed that flutamide is more effective than finasteride in FPHL. Moreover, Sintov et al.[38] demonstrated that flutamide gel also has a significantly higher effect than finasteride gel in stimulating hair growth in human bald scalp grafted onto mice. Our data show that flutamide, at very low doses (62.5 mg/day, ~1 mg/kg/day), has complete hepatic tolerability and causes significant longterm efficacy in FPHL; thus, flutamide could be rightfully considered a first-line therapeutic option at least equal, if not superior, to minoxidil in FPHL treatment.

Our work has some limitations because changes in FPHL during treatment have been evaluated by subjective scorings, commonly used in clinical practice, as a semiquantitative measure of degree of FPHL. We performed, in particular, an expert investigator clinical assessment of scalp hair growth, using the Ludwig scale; noninvasive methods such as pull and wash tests and an objective patients' self-assessment of scalp hair growth, (whereas we did not perform a scalp biopsy) as well as a direct hair count per specific unit area and global standardized photographic assessment of the head by an expert panel. That may render difficult the differential diagnosis with chronic telogen effluvium. However, the fairly large number of subjects examined and the strength of the statistical significance give credibility to the notion that our outcomes would be confirmed by more objective assessments. Another limitation of the study is the absence of a control group, although this deficiency is not too relevant because both groups received treatment. We advocate a larger series of patients with a placebo-controlled study to confirm flutamide efficacy in the treatment of FPHL, since very low doses of flutamide appear to carry no risk of liver toxicity.

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