ARTICLE
Androgenetic
alopecia, also known as male pattern hair loss (MPHL), is characterized
by progressive miniaturization of hair follicles and loss of cosmetically
important terminal hair in the vertex, mid, and frontal regions of the scalp
[1]. Hair thinning and loss may begin any time after puberty, usually initially
with bitemporal recession. The hair loss may progress to varying degrees
in the frontal, mid scalp, and vertex areas with time, producing recognizable
patterns of loss [2, 3]. The expression of MPHL is genetically determined,
with a variable expression dependent on the inherited sensitivity to the
effects of androgens on the scalp [3, 4].
Scalp hair is affected by the conversion of testosterone to the potent
metabolite dihydrotestosterone (DHT) by the enzyme Type II 5alpha-reductase
[5-7]. Finasteride is an inhibitor of the human Type II 5alpha-reductase
enzyme, with no androgenic, antiandrogenic, estrogenic, antiestrogenic,
or progestational effects [8-10]. Inhibition of the Type II 5alpha-reductase
enzyme by finasteride inhibits the peripheral conversion of testosterone
to DHT, resulting in a significant decrease in DHT levels in serum and
tissue, including the scalp. The efficacy of treatment with finasteride
1 mg in men aged 18 to 41 years with mild-to-moderate MPHL
has been demonstrated in randomized, placebo-controlled trials that formed
the basis of approval of finasteride 1 mg (PROPECIA™) for
the treatment of men with MPHL [11, 12]. These studies demonstrated that
finasteride 1 mg resulted in an increase in scalp hair counts and
improvements in scalp hair growth compared with placebo, as assessed by
self-administered patient questionnaires, investigator clinical assessments,
and a panel of dermatologists rating standardized global photographs.
Extension of two of these studies for an additional 4 years confirmed
the superiority of finasteride 1 mg compared with placebo in improving
hair growth and slowing further hair loss [13]. Finasteride 1 mg
was generally well tolerated in these studies, with side effects limited
to transient sexual dysfunction in a small number of men. To better understand
the potential effect of older age on the response of men with MPHL to
finasteride 1 mg, the current study examined men aged 41 to
60 years with similar Norwood/Hamilton patterns of MPHL as were previously
studied in younger men.
Methods
Patient population
This study enrolled men between the ages of 41 to 60 years with
mild-to-moderate vertex hair loss according
to a modified Norwood/Hamilton classification scale (Grade II vertex,
III vertex, IV, or V) [3, 11, 14]. To participate, men were instructed
to maintain the same hair style and refrain from using any hair dyes or
hair enhancement products or surgical procedures for the duration of the
study. Patients were generally healthy, as determined by history, physical
examination, and screening laboratory tests. Patients were excluded from
the study if they had alopecia due to causes other than MPHL, had previously
had surgical correction of scalp hair loss, or had used topical minoxidil
within the previous year, were currently using drugs with androgenic or
antiandrogenic properties, or had ever used finasteride or other 5alpha-reductase
inhibitors.
Study design
This was a double-blind, randomized, placebo-controlled, parallel-group
study. The study protocol was approved by the Institutional Review Board
at each of 32 sites in the United States, and all patients provided
written informed consent. The study was conducted from July 1999 through
January 2002. Patients who met all eligibility criteria underwent a 2-week,
single-blind, placebo run-in period, during which compliance was evaluated.
Patients with at least 80% compliance, verified by tablet counts, were
randomized according to a computer-generated randomization schedule to
finasteride 1 mg or placebo in a 2:1 ratio, stratified according
to age decade (41-50 years, 51-60 years), for 24 months.
Efficacy assessments
Three predefined efficacy endpoints were used to provide a comprehensive
assessment of changes from baseline in scalp hair for men treated with
finasteride 1 mg compared with men treated with placebo. The primary
endpoint measurement of hair growth/loss was an independent assessment
of standardized global photographs of the vertex scalp by an expert panel
of dermatologists blinded to treatment. Secondary efficacy endpoints were
a patient self-assessment of scalp hair and an investigator clinical assessment
of changes in scalp hair growth/loss since baseline.
Global photographic assessment
Standardized global photographs of the vertex scalp area were taken at
baseline and at Months 6, 12, 18, and 24 as described previously
[11, 12, 15, 16]. All film was processed at Qualex Laboratories (Fairlawn,
NJ) and sent to a central site (Canfield Scientific, Inc., Fairfield,
NJ) for quality assurance. Paired (baseline and post-treatment) global
photographs of the vertex scalp (primary endpoint) were evaluated by a
panel of three dermatologists who were blinded to study center, patient,
and treatment and who were experienced in photographic assessment of hair
growth. Each dermatologist compared photographs taken at baseline and
at each subsequent time point and rated the paired photographs separately
based on a 7-point scale: - 3 = Greatly decreased, - 2 = Moderately
decreased, - 1 = Slightly decreased, 0 = No change,
1 = Slightly increased, 2 = Moderately increased,
3 = Greatly increased. The score "Don't know" was used when
technical issues with the photographs did not allow evaluation.
Patient self-assessment
A validated self-administered Hair Growth Questionnaire [17] was given
to patients to measure their perception of scalp hair growth. This questionnaire
consisted of four questions of treatment effectiveness compared to baseline
(bald spot getting smaller, appearance of hair, growth of hair, slowing
down hair loss) and three questions on patient satisfaction with the appearance
of their hair (satisfaction with frontal hairline, satisfaction with hair
on top, satisfaction with hair overall).
Investigator clinical assessment
Investigators assessed a patient's change in vertex hair growth/loss from
baseline at Months 6, 12, 18, and 24 using the same 7-point scale
as was used for the global photographic assessment. Investigators had
a baseline photograph of each patient to aid in making comparisons.
Safety
Safety assessments included clinical and laboratory evaluations and reports
of adverse experiences, including sexual adverse experiences, which were
collected by spontaneous patient reporting.
Laboratory evaluations
Laboratory measurements, including hematology, urinalysis, serum chemistry,
DHT, and testosterone (T), were performed at baseline and every 6 months
by a central reference laboratory (Medical Research Laboratories, Highland
Heights, KY). Investigators received baseline laboratory results for DHT
and T but remained blinded to levels of these hormones once patients were
randomized. The current guideline for interpreting levels of PSA during
treatment with finasteride 1 mg recommends that PSA values be doubled
for comparison to normal ranges in untreated men. [18, 19] PSA level was
measured at Months 12 and 24 and adjusted by doubling (+ 0.1 ng/mL
if the patient's PSA level before doubling was odd-numbered, in order
to protect the blind) in the finasteride-treated group. Patients with
an actual (placebo) or algorithm-adjusted (finasteride) PSA level > 4 ng/mL
at Month 12 were discontinued from the study. Patients were notified
of elevated actual or algorithm-adjusted PSA levels at both Months 12 and
24, and appropriate follow-up evaluation was recommended.
Statistical analyses
All efficacy analyses were based on a modified intention-to-treat population,
defined as all randomized patients who received at least one dose of double-blind
study medication and had at least one valid post-baseline measurement.
A data analysis plan prespecified all primary and secondary endpoint analyses.
For all efficacy analyses, missing data on treatment were estimated by
carrying data forward from the previous post-baseline visit. This approach
considers patients in the analysis according to the group to which they
were randomized. Tests for interaction were done for the primary and secondary
endpoints at the primary time point, Month 24. An interaction term with
p-value < 0.10 was considered statistically significant.
Primary and secondary efficacy endpoints were also summarized descriptively
by age decade (41-50 years, 51-60 years). All statistical tests
were two-sided and were declared statistically significant at the 0.05 level.
A supportive analysis of the global photographic assessment data was conducted
using a Per-Protocol approach. This analysis excluded observations associated
with violations to the protocol that could affect efficacy measurements.
Missing data were not imputed for the Per-Protocol analysis.
An analysis of variance (ANOVA) model that included terms for site, treatment,
and age decade was used to analyze the global photographic assessment
and the investigator clinical assessment comparing the mean rating scores
for each treatment group at each time point, based on the 7-point rating
scale (minimum value = - 3.0; maximum value = 3.0).
Secondary analyses of global photographic assessment and investigator
clinical assessment were performed using the Cochran-Mantel-Haenszel test
stratifying by age decade (41-50 years, 51-60 years). The response
was dichotomized into categories of positive response ([moderately or
greatly increased] and [slightly, moderately, or greatly increased]) versus
all other categories. Patient self-assessment was analyzed by a global
test across all seven questions using O'Brien's rank-sum test and by an
ANOVA model of each individual question that included the same terms as
for the primary endpoint. The sample size of 424 randomized patients
provided > 90% power to detect a 0.35 difference between
treatment groups for the global photographic assessment at Month 24 (two-sided
test at the 5% level of significance). All computations were done using
SAS version 6.12 software.
Safety analyses
Safety and tolerability were assessed by statistical and clinical review
of adverse experiences and laboratory values. All patients who were randomized
to double-blind therapy and received at least one dose of study therapy
were included in the safety analyses. Laboratory endpoints of percent
change from baseline in serum PSA and testosterone were analyzed using
ANOVA. The model for ANOVA included terms for site, treatment, and age
decade.
Results
Patient accounting
Patient accounting and disposition are summarized in Fig. 1.
Of the patients randomized, 71% of patients completed the 24-month
trial. The proportion of patients completing the study was similar between
treatment groups (72% in the finasteride group and 68% in the placebo
group).
Patient baseline characteristics
Baseline patient demographics, including age and racial origin, were similar
between treatment groups (Table
I), except for a slightly higher proportion of patients with Norwood/Hamilton
classification Grade V at study entry in the finasteride group (43%) compared
with the placebo group (36%). Patient age ranged from 41 to 60 years,
with a mean age of 50 years. The majority of patients were white
(87%). Treatment groups were similar with regard to age of onset of hair
thinning/loss (median age of 35 years) and family history of baldness
(80% for first degree relatives and 54% for second degree relatives).
Looking within each patient age decade, a slightly higher incidence of
men with Norwood/Hamilton Grade V MPHL in the age decade 51 to 60 years
(46%) was observed when compared with that in the decade 41 to 50 years
(36%), consistent with older men being more likely to have more advanced
stages of MPHL. Treatment compliance was 99% in both treatment groups,
based on patient accounting of missed doses recorded after questioning
the patient at each visit.
Global photographic assessment
Analysis of the global photograph assessments showed a statistically significant
improvement in hair growth in patients in the finasteride group compared
with those in the placebo group beginning at Month 6 and continuing
through Month 24 (p < 0.001 for all time points; Fig. 2).
Further, the magnitude of the difference between the finasteride and placebo
groups increased with time.
The distribution of response at Month 24 is shown in Fig. 3.
Thirty-nine percent of patients treated with finasteride were rated
as improved by global photographic assessment compared with 4% of placebo-treated
patients. Twenty-three percent of patients in the placebo group showed
worsening of hair loss after 24 months compared with 6% of patients
treated with finasteride. Results were similar using a Per-Protocol analysis.
Global photographs of representative subjects from the placebo and finasteride
groups who were rated by the expert panel as having decreased or increased
hair growth from baseline are shown in Fig. 4.
Improvement among finasteride-treated men aged 41 to 50 years
was numerically greater than the improvement observed in men aged 51 to
60 years (Fig. 5).
Patient self-assessment
The seven questions from the Hair Growth Questionnaire were used to evaluate
patient self-assessment of treatment effect. Plots of the proportion of
patients with a positive self-assessment for each of the seven questions
at each time point are displayed in Fig. 6.
There was significant improvement in patient-perceived scalp hair growth
and satisfaction with appearance of scalp hair for the finasteride group
compared with the placebo group as early as Month 6, the first time point
evaluated (p = 0.037), with superiority of the effect of finasteride
compared with placebo increasing through Month 24 (p < 0.001 at
Month 12, 18, and 24). Results of patient self-assessment within each
age decade favored finasteride, similar to those seen in the analysis
for all patients.
Investigator clinical assessment
There was a significant improvement in scalp hair growth based on investigator
clinical assessment of changes in hair growth/loss from baseline in the
finasteride group compared with the placebo group at all time points (Fig. 7).
The difference between the groups increased with time. At Month 24,
the between-group difference was statistically significant in favor of
finasteride (p < 0.001). Similar results were seen within
each age decade; however, among those patients treated with finasteride,
patients aged 41 to 50 years showed a numerically greater improvement
from baseline compared with patients aged 51 to 60 years (Fig.
8), consistent with the results of the global photographic assessment.
Dihydrotestosterone and testosterone
The finasteride group showed a significant mean percent decrease from
baseline in serum DHT levels of 63.8% at Month 24 (p = 0.010)
compared to a nonsignificant mean percent increase (5.7%) in serum DHT
levels at Month 24 in the placebo group (mean difference: - 69.5%,
p < 0.001). Patients treated with finasteride showed a significant
mean percent increase from baseline in serum T levels of 19% at Month
24 (p = 0.010), compared with a nonsignificant mean percent
increase from baseline of 4.5% at Month 24 in the placebo group (mean
difference: 14.5%, p = 0.011). Increases in serum T levels remained
within the normal physiologic range.
Safety
The clinical adverse experiences considered by the investigator to be
possibly, probably, or definitely drug-related that occurred during the
24-month treatment period summary is presented in Table
II. A slightly higher proportion of finasteride-treated patients (8.7%)
compared with placebo-treated patients (5.1%) experienced a drug-related
sexual adverse experience. Decreased libido was the most frequently reported
drug-related sexual adverse experience (4.9% of finasteride patients and
4.4% of placebo patients). Other reported drug-related sexual adverse
experiences were ejaculation disorder (2.8% of finasteride patients and
0.7% of placebo patients) and erectile dys function (3.8% of finasteride
patients and 0.7% of placebo patients). There was a small variance in
the percentage of patients reporting decreased libido between the decades
41 to 50 years and 51 to 60 years, but little variance
in the percent reporting ejaculation disorder or erectile dysfunction
(Table III). A similar
percentage of patients in each treatment group discontinued study drug
because of a drug-related sexual adverse experience (finasteride 2.1%
vs. placebo 2.2%).
Mean baseline serum PSA level was 0.9 ng/dL in both the finasteride
and placebo groups. Based on expected age-related increases in prostate
volume, mean baseline PSA level was higher in the older age decade (1.1 ng/mL
finasteride; 1.0 ng/mL placebo) than in the younger age decade (0.8 ng/mL
finasteride and placebo). As anticipated, treatment with finasteride significantly
decreased serum PSA levels from baseline compared to placebo (mean difference
in percent change: - 44.6% (95% CI: [ - 59.,0, - 30.3],
p < 0.001), with a slightly greater difference in men ages
51 to 60 years (mean difference in percent change: - 49.8
(95% CI: [ - 72.5, - 27.2], p < 0.001)
compared to men ages 41 to 50 years (mean difference in percent
change: - 41.5 (95% CI: [ - 61.3, - 21.7],
p < 0.001).
The protocol specified discontinuation and referral for urologic evaluation
of patients with a PSA value (actual or algorithm-adjusted > 4.0 ng/mL,
the upper limit of the normal range. Five patients at Month 12 and
six patients at Month 24 in the finasteride group discontinued the
study and were referred for urologic evaluation based on algorithm-adjusted
PSA levels > 4.0 ng/mL. No patient in the placebo group
had an actual elevated PSA level > 4.0 ng/mL during
the study. One of the finasteride-treated patients with algorithm-adjusted
PSA > 4 ng/mL had a prostate nodule detected on digital
rectal examination, and subsequent biopsy of the nodule revealed adenocarcinoma.
Discussion
The safety and efficacy of finasteride 1 mg for the treatment of
MPHL in men aged 18 to 41 years has been documented in placebo-controlled
clinical trials lasting up to 5 years [11-13]. Photographic evidence
of hair regrowth and slowing of hair loss after finasteride treatment
has been demonstrated in this population.
The current 2-year study demonstrated that treatment with finasteride
1 mg compared with placebo produced significant improvements in scalp
hair in men aged 41 to 60 years with MPHL, as measured by global
photographic assessment, patient self-assessment, and investigator clinical
assessment. Global photographic assessment of standardized clinical photographs
of the vertex scalp by an expert panel of dermatologists provides a highly
objective overall assessment of treatment efficacy based primarily on
scalp coverage. At Month 24, the mean scores for global photographic assessment
demonstrated signifi
cantly greater efficacy for the finasteride group (39% improved) compared
with the placebo group (4% improved). There were similar results favoring
treatment with finasteride compared with placebo in each age decade; however,
men aged 41 to 50 years showed numerically greater improvement
in hair growth based on global photographic assessment compared with men
aged 51 to 60 years.
The validated patient self-assessment questionnaire provides a reproducible
tool for the patient to judge his treatment benefit by asking specific
questions about the patient's hair growth or loss and his satisfaction
with the appearance of his hair. [17] Data from this self-assessment questionnaire
given every 6 months during treatment consistently demonstrated that
men treated with finasteride had a more positive self-assessment of their
hair growth and satisfaction with their appearance than men treated with
placebo. A small, predictable positive effect for each question was observed
in the placebo group. This phenomenon is typical of patient questionnaire
data, likely related to patient expectation of, and desire for, improvement.
Nevertheless, patients in the finasteride group perceived a significantly
greater effect of treatment on the improvement in growth and appearance
of their scalp hair than patients in the placebo group.
The investigator's assessment of the patient in the clinic provides a
clinically relevant assessment of the patient's hair growth or loss since
the start of study drug treatment. The mean scores for the investigator
clinical assessment demonstrated significantly greater efficacy for the
finasteride group compared with the placebo group. At Month 24, 60% of
finasteride-treated patients were rated by the investigator as improved
compared with 36% of placebo-treated patients. As with the patient self-assessment,
this endpoint had a greater placebo effect than the more objective endpoint
of global photographic assessment. Such an effect is not unusual in double-blind,
placebo-controlled trials and is often due to a general expectation bias
on the part of the patient's treating physician. Despite this apparent
placebo effect, investigator clinical assessment determined that improvement
in hair growth was greater for men in the finasteride group than for those
in the placebo group.
Treatment with finasteride 1 mg was generally well-tolerated in this
study. As demonstrated in other clinical trials with finasteride, sexual
adverse experiences were reported by slightly more men treated with finasteride
than with placebo. The incidences of these adverse experiences were slightly
greater in each treatment group in this study compared to incidences observed
in younger men (ages 18-41), with male pattern hair loss in prior studies
[11]. This increase in incidence may reflect age-related physiological
changes in sexual function [20, 21]. However, the percentage of men who
discontinued study drug due to a drug-related sexual adverse experience
in this study was similar between the finasteride and placebo groups.
CONCLUSION
In summary, treatment with finasteride 1 mg improves vertex scalp
hair in men aged 41 to 60 years with predominantly vertex male
pattern hair loss. Improvement was evident by 6 months of treatment
and continued through 24 months. Finasteride was shown to be generally
well tolerated in this age group. These findings, together with previously
published data from studies with men aged 18 to 41 years, demonstrate
the efficacy and safety of finasteride in the treatment of men aged 18 to
60 with mild-to-moderate, predominantly vertex male pattern hair
loss.
Investigators in the Male Pattern Hair Loss Study Group: Russell B. Caldwell,
Zoe D. Draelos, Lynn A. Drake, Frank E. Dunlap, Maria K. Hordinsky, H.
Irving Katz, Steven E. Kempers, Judith A. Koperski, Stephen J. Kraus,
Mark Lebwohl, Howard J. Luber, Anne W. Lucky, Amy J. McMichael, Bruce
H. Miller, Jeffrey J. Miller, Marc F. Naylor, Thomas P. Nigra, Elise A.
Olsen, Jerold L. Powers, Vera H. Price, Elyse S. Rafal, Marvin J. Rapaport,
Janet L. Roberts, Neil S. Sadick, Ronald C. Savin, Linda F. Stein, Daniel
M. Stewart, Steven H. Sutter, James M. Swinehart, Eduardo H. Tschen, Kenneth
Washenik, and David A. Whiting.
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