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

Methods

Subjects

This investigation was conducted as a prospective cohort study and was approved by the institutional review board of the Department of Obstetrics and Gynecology of the University of Bologna. All of the procedures were in accordance with the Helsinki Declaration of 1975. Over the 15-year period from January 1991 to January 2006, 101 white women with a clinical diagnosis of FPHL of different intensity who presented to the Reproductive Medicine Unit of the University of Bologna were enrolled in the study. Their main clinical data are reported in Table 1. Participation in the study was offered to all consecutive patients presenting for treatment. These patients requested treatment for FPHL, which was their main symptom, and presented no other sign of hyperandrogenism, such as hirsutism and/or acne; at the most, a slight form of hypertrichosis was present, for which patients did not request treatment. The natural history of FPHL in this cohort of subjects was permanent and slightly worsening if untreated. None of these patients had taken part in our recent studies on hirsutism[23] and acne.[24] A total of 17 (16.8%) women reported menstrual irregularities with polycystic ovary stigmata, but none was amenorrheic. Each patient underwent complete clinical and laboratory examinations. Women with other hair loss disorders, such as alopecia areata, cicatricial alopecia, anagen effluvium by chemotherapeutic agents, and trichotillomania, were excluded from the study. Other general exclusion criteria were tumors of ovarian/adrenal origin, prolactinoma, thyroid disorders, iron deficiency, Cushing's syndrome, diabetes mellitus, obesity (body mass index ≥30), and hepatic and thromboembolic disease. Patients who had received hormonal or cosmetic treatment during the 6 months preceding the study were also excluded.

Study Design

After written informed consent was obtained, study subjects received flutamide with or without an oral contraceptive over 4 years. In particular, they received flutamide 250 mg/day (Eulexin, Schering-Plough, Milan, Italy) during the first year as a loading dose, 125 mg/day during the second year as a continuing dose, and 62.5 mg/day during the third and fourth years as a maintenance dose. Patients underwent a clinical examination every 6 months, except during the last year, in which it was done once. Thereafter, some patients continued treatment with flutamide 62.5 mg/day out of protocol, according to their personal satisfaction, up to 7 or 8 years and, although not included in this study, were checked yearly until treatment was discontinued. Patients were assigned to 1 of the following 2 treatment groups: the first group (n = 33) received only flutamide; the second group (n = 68) received flutamide in association with ethinyl estradiol (0.030 mg/day) plus gestodene (0.075 mg/day) monophasic oral contraceptive (Ginoden, Bayer-Schering, Milan, Italy) for 21 days/month. The groups were not randomized since selection was based on patients' requests. In the flutamide-only group, women who were not sexually active and were adequately instructed to avoid pregnancy if the situation changed or women who employed barrier methods or intrauterine contraception to avoid any risk of conception were included. In the flutamide plus oral contraceptive group, all of the women who needed hormonal contraception were included. No significant differences were observed in mean (SD) age, height, weight, and body mass index in the 2 groups.

Treatment with flutamide with or without oral contraception was initiated on the first day of the menstrual cycle. Before treatment, all patients were studied in the early follicular phase of the menstrual cycle (3–5 days of the cycle). During treatment, patients in the first group were studied in the early follicular phase, at baseline, whereas patients in the second group were studied in a random day of the artificial cycle. All patients were instructed not to use topical minoxidil and/or other cosmetic treatments for scalp hair during the study.

The safety, tolerability, biochemical, clinical, and endocrine evaluations were determined as follows. During the study, adverse effects assessment was done continuously by direct relationship with the patients; general biochemistry and hepatic function evaluations were done quarterly; clinical evaluation (degree of alopecia) was done semiannually except for the last year, in which it was done once; and endocrine evaluation (hormonal profile) was performed yearly.

Alopecia Evaluation

The clinical diagnosis of FPHL was made by clinical history, clinical examination of the distribution of hair loss, noninvasive methods such as pull and wash tests, and biochemical investigations. Alopecia was assessed according to the Ludwig scale,[25] which rates the severity of androgenetic alopecia in females. In particular, grade 1 is considered to be an overall thinning of density of the scalp, usually beginning at the top of the head. Grade 2 is considered to be a further diffuse thinning at the crown of the head, and grade 3 is considered to be a nearly full hair loss at the crown of the head, which may end in advanced baldness. Throughout the study, the same investigator examined the same patient, and only 3 investigators with more than 20 years of experience were authorized to grade the alopecia.

Moreover, patients' self-evaluations of scalp hair growth during treatment were obtained systematically at the end of each year during treatment. Each patient rated her appreciation as highly satisfied, satisfied, or dissatisfied.

Assays

Biochemical investigations of the hormonal profile were studied in the peripheral blood, which was collected by venipuncture between 0800 and 0900 hours. The blood was immediately centrifuged and serum was stored frozen at –20 °C until assayed. All serum hormones were measured in duplicate. The radioimmunoassay techniques used for steroid measurements were testosterone, 5α-dihydrotestosterone (DHT), and androstenedione, by thin-layer chromatography on silica gel 60 F254 as previously described;[26] dehydroepiandrosterone (DHA), by plasma extraction with ethyl ether, dried and redissolved in buffer solution; dehydroepiandrosterone sulphate (DHA-S) directly on diluted plasma, as previously described;[27] and free testosterone, by the Coat-A-Count procedure (Diagnostic Products Corp., Los Angeles, CA). The intra- and interassay variables, respectively, were 4.5% and 9.3% for testosterone; 8.3% and 13% for DHT; 7% and 10.5% for androstenedione; 6.9% and 8.9% for DHA; 3.6% and 5.6% for DHA-S; and 3.2% and 3.4% for free testosterone.

Statistical Analysis

The Shapiro-Wilk test was used to assess the normal distribution of the parameters. Laboratory and clinical data were analyzed with various general linear models to evaluate the effect of group and time on the variable of interest (alopecia). Friedman analysis and relative post hoc test and z-test for 2 proportions were also applied, when appropriate. A value of p < 0.05 was accepted as statistically significant. Results are expressed as mean (SD).

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