Finasteride improves male pattern hair loss in a randomized study in identical twins

ARTICLE

Male pattern hair loss (MPHL) affects 50% of men by the age of 50 [1, 2]. This condition is thought to be under genetic control, occurring in males with an inherited sensitivity of scalp hair follicles to the deleterious effects of androgens [3, 4]. Subjects with a defect in the enzyme 5*-reductase (5*R) type 2, which converts testosterone into dihydrotestosterone (DHT), do not develop MPHL, suggesting that this condition can be prevented by inhibiting 5*R type 2 [5].

Studies in monozygotic twins are commonly conducted to examine the influence of genetic and environmental factors on phenotypic traits [6]. Similarly, monozygotic twins are ideally suited to determine the extent of drug efficacy in the treatment of a condition, such as MPHL, whose expression is determined by genetics [7]. As identical twins share the same genetic make-up, comparison between the responses of each subject in a twin pair, when one receives drug and the other receives placebo, allows for rigorous examination of the effects due to drug treatment in a limited number of subjects. This approach has been used for over 20 years [7-10].

Finasteride is a potent, selective, orally-active inhibitor of the enzyme 5*R type 2 in humans, lowering serum and scalp DHT levels without having intrinsic androgenic, anti-androgenic, estrogenic, anti-estrogenic or progestational effects [11-16]. Finasteride 1 mg/day has been shown to significantly increase hair count and hair weight, improve the ratio of anagen to telogen hairs, improve scalp coverage based on assessment of standardized clinical (global) photographs, and improve patients' satisfaction with the appearance of their hair [17-21]. Since its launch in 1998, finasteride 1 mg has been used by over one million men worldwide.

In this unique study, the efficacy of finasteride 1 mg/day was compared with placebo in genotypically identical twins with male pattern hair loss. The primary efficacy objective was to determine whether finasteride reduced hair loss as determined by assessments of standardized clinical photographs in comparison to placebo. Secondary efficacy objectives were to determine the effects of finasteride on hair count and on patient self-assessment of changes in scalp hair since study start. This study thus assessed the effects of finasteride treatment by monitoring the changes in phenotype in genotypically identical twins.

Patients and methods

Patients

Nine pairs of male, Caucasian, identical twins between 20 and 45 years old, with grade II vertex, III vertex, IV or V male pattern hair loss according to a modified Norwood/Hamilton classification scale [1, 18], recruited from Arkansas, Colorado, Georgia and Texas, were enrolled. As would be expected in a study of identical twins, demographics and baseline characteristics were comparable between the two treatment groups (Table I). Both twins in each pair had the same Norwood/Hamilton classification and were in good physical and mental condition. Major exclusion criteria included: a history of any significant illness or condition that might confound the results of the study or pose an additional risk in administering finasteride to the patient; surgical correction of scalp hair loss; and the use of minoxidil or any 5*R inhibitor within 12 months prior to study initiation.

Institutional Review Board approval of the protocol was obtained prior to study initiation and all patients gave written informed consent prior to entry in the study.

Study design

This was a randomized, placebo-controlled, double-blind study conducted in a single-center in the United States. After screening, each patient in each pair of twins was randomized to receive either finasteride 1 mg/day or placebo for one year.

Patients were instructed not to alter their hair style or dye their hair during the study period. The primary efficacy assessment was by comparison of pre- and post-treatment standardized clinical (global) photographs of the vertex scalp [18, 21], using the Canfield photography system [21] at baseline and Month 12. This technique has been previously validated to generate reproducible results [24]. Each patient had pictures taken of the vertex and superior-frontal scalp, as well as of the anterior and temporal hairlines, at baseline and Months 6 and 12. A dermatologist (Elise A. Olsen, M.D.), experienced in the assessment of standardized clinical photographs and blinded to patient treatment, assessed changes from baseline using a 7-point rating scale, ranging from "greatly decreased hair growth" to "greatly increased hair growth", centered at no change [18]. Global photographs of the superior-frontal scalp, and of the anterior and temporal hairlines, were also obtained, assessed and analyzed as secondary endpoints.

Macrophotography for hair counts was done at baseline and Month 12 with the Canfield photography system [21]. A small dot tattoo was placed on the scalp at baseline to identify the center of a 1 cm² circular target area at the anterior leading edge of the vertex balding region to be used for hair counts [23]. Hair counts were obtained from macrophotographs at Canfield Scientific, Inc. (Fairfield, NJ, USA), using a technique that has been previously described [18, 21].

Patients self-assessed the changes in their scalp hair since study start using a validated, self-administered hair growth questionnaire [18, 22] consisting of four questions on treatment efficacy and three questions on satisfaction with appearance of scalp hair (Table II). These questionnaires were completed at Months 6 and 12.

Analysis of serum DHT levels at baseline and Month 12 provided evidence of the biochemical activity of finasteride. Serum DHT, as well as serum testosterone, levels were assayed in a central laboratory (Quest Diagnostics, Irving, Texas).

Any reports of adverse events (AEs) were collected at each clinic visit during the treatment period, and the intensity and the relationship to treatment of any reported AEs were evaluated.

Statistical methodology

A data analysis plan pre-specified all primary and secondary endpoints.

The sample size of 18 patients provided 80% power to detect the 0.7 unit difference in global photographic assessment score that was observed between the finasteride and placebo groups at one year in the Phase III studies with finasteride 1 mg in men with vertex hair loss [18].

All demographic and analytical between-group differences were assessed using paired t-tests for continuous data and the Mantel-Haenzel test for categorical data. The t-tests were used to analyze within group changes from baseline. Paired t-tests were used for comparing the two treatment groups with respect to changes from baseline.

Non-parametric methods were used to corroborate the primary results (not presented). Data are presented as mean ± 1 standard error (SE).

If any data from a twin pair were missing at a specific time point, the twin pair was excluded from the analysis of paired data at that time point.

Results

Baseline demographics

As expected in a study of identical twins, baseline characteristics of the two treatment groups were generally similar (Table I). The mean age (± SE) for the 18 patients (nine who received finasteride and nine who received placebo) was 38.6 ± 2.5 years. For the finasteride and placebo groups, the self-reported age at which hair loss was first noticed by the patient differed slightly (29 ± 2.2 and 25 ± 1.5, respectively; p = 0.12). The mean hair counts at baseline were nearly identical between the two treatment groups (163 ± 23 and 160 ± 20 hairs, finasteride and placebo, respectively).

Global photographic assessment

At Month 12, the assessments of global photographs demonstrated significant improvement from baseline for the finasteride group compared to the placebo group, based on both the vertex and superior-frontal views (p < 0.01 and < 0.05, respectively; Fig. 1). Based on these assessments, visible increases in vertex scalp hair were observed in 44% of finasteride patients (4/9), compared to 11% of placebo patients (1/9). Visible worsening in vertex scalp hair was observed in 56% of placebo patients (5/9) compared to none of the finasteride patients (0/9). Visible increases in superior-frontal scalp hair growth were observed in 67% of finasteride patients (6/9) compared to 22% of placebo patients (2/9), while none of the finasteride patients (0/9) showed visible worsening compared to 11% of placebo patients (1/9). No significant differences between treatment groups were observed in the photographic assessments of the temporal or anterior hairline views (data not shown). Representative examples of baseline and Month 12 vertex global photographs from twin patient pairs who received finasteride 1 mg or placebo during the study are illustrated in Figure 2 and a candid photograph of the same twin pair taken at Month 12 is illustrated in Figure 3.

Hair count

At Month 12, hair count data was available for 8/9 patients who received finasteride and for all (9/9) patients who received placebo. The change in hair count in the 1 cm² target area for the finasteride group (16 ± 4 hairs, p < 0.01) was significantly superior to the change in the placebo group (- 4 ± 5 hairs; p < 0.05, finasteride versus placebo) (Fig. 4). All patients in the finasteride group with data at Month 12 (8/8; 100%) demonstrated an increase in hair count, while 4/9 patients (44%) who received placebo lost hair by hair count (Fig. 5).

Patient self-assessment

At Month 12, more patients receiving finasteride self-reported improvement than patients receiving placebo for each of the seven hair growth questions (Table II; Fig. 6). Statistical significance (p < 0.05) in favor of the finasteride group was observed for two questions (change in appearance of hair; change in growth of hair), and results approached statistical significance (p < 0.1) for three other questions (change in the size of the bald spot; efficacy of treatment in slowing down hair loss; patient satisfaction with the appearance of hair on top of the head.

Serum DHT and testosterone

As anticipated, serum DHT levels were significantly decreased from baseline in the finasteride group at Month 12 (- 50.0 median percent change, p < 0.05), with no significant change observed in the placebo group. No significant changes from baseline serum testosterone levels were observed in either treatment group.

Adverse events

No serious clinical or laboratory adverse experiences occurred during the study and no treatment-related clinical or laboratory adverse experiences were reported.

Discussion

The normal course of androgenetic alopecia is progressive over time [25]. In this unique study in male identical twins with androgenetic alopecia (male pattern hair loss), treatment with finasteride slowed the progression of hair loss and enhanced hair growth compared to treatment with placebo. This study supports previously published data [18-20, 23] showing that finasteride 1 mg significantly improves scalp hair growth based on assessments of standardized clinical photographs, hair count, and patients' assessments of their scalp hair. Based on the two predefined endpoints utilizing photographic methods, none of the finasteride patients showed a deterioration in hair growth at 12 months, as evidenced by the absence of both visible worsening in assessments of standardized clinical photographs and reduction in hair count. In contrast, the majority of placebo patients demonstrated visible worsening in scalp hair coverage based on global photographic assessment of the vertex scalp at Month 12, and 44% sustained hair loss based on hair count.

The validated patient self-assessment hair growth questionnaire demonstrated that treatment with finasteride, in comparison to placebo, led to improvement in patients' scalp hair growth and increased satisfaction with the appearance of hair.

The finasteride group showed a significant decrease in serum DHT levels after 12 months of treatment, while baseline levels were maintained in the placebo group. This difference was expected, as finasteride is a specific inhibitor of 5*R type II, which converts testosterone into DHT.

Finasteride was safe and well tolerated. No side effects related to treatment were reported during the 12-month study period. Prior clinical studies and marketed experience with finasteride have shown that the drug has an excellent safety profile [20, 26]. In large multicenter studies in men with male pattern hair loss, approximately 4% of subjects receiving finasteride 1 mg, compared with approximately 2% receiving placebo, reported transient side effects related to sexual function. However, in the present study, no subjects reported side effects related to sexual function.

This study, the first investigating the efficacy of finasteride in identical twins, allows one to evaluate the ''before'' and after effect of finasteride treatment in men with male pattern hair loss uniquely by observing phenotypic changes in genotypically identical twins. Because male pattern hair loss is under genetic control and identical twins share the same genetic code, the comparison of paired data between twins is a highly efficient way of rigorously evaluating the efficacy of a treatment in a limited number of patients, as each twin serves as the control for his brother. Thus, despite the necessarily limited sample size of this study, efficacy in favor of finasteride was demonstrated for the predefined endpoints in this study. This separation between treatment groups was achieved even though the phenotypic expression of male pattern hair loss, while similar in each twin pair, was not necessarily identical. This was evident by careful examination of baseline global photographs for each twin pair as well as by differences in patient self-report of the age of onset of hair loss. These findings suggest that while genetic influences predominate in the expression of male pattern hair loss in men, environmental influences may play a small role as well. A larger and longer study in male identical twins would likely yield additional insights into the phenotypic expression of male pattern hair loss in men and the response to treatment with finasteride.

Available data reveal that hair loss has a significant impact on individuals' own body image and quality of life [27, 28]. While only a minority of affected men suffer severe psychological side effects, many experience moderate stress and a decrease in self-esteem due to their hair loss [28]. Medical treatment to restore hair loss can help resolve this psychological distress. Therefore, it is important to ensure that patients with male pattern hair loss receive adequate treatment. This study provides further support for finasteride being an efficacious and acceptably safe treatment for male pattern hair loss.

CONCLUSION

Acknowledgements

The study was supported by an unrestricted grant from Merck & Co. Inc., Whitehouse Station, New Jersey, USA.

Article accepted on 13/11/01

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