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
REFERENCES
1. Norwood OT. Male pattern baldness: classification and incidence.
South Med J 1975; 68: 1359-65.
2. Rhodes T, Girman CJ, Savin RC, Kaufman KD, Guo S, Lilly FR,
et al. Prevalence of male pattern hair loss in 18-49 year old men.
Dermatol Surg 1998; 24: 1330-2.
3. Hamilton JB. Male hormone stimulation is prerequisite and
an incitant in common baldness. Am J Anat 1942; 71: 451-80.
4. Hamilton JB. Patterned loss of hair in man: types and incidence.
Ann N Y Acad Sci 1951; 53: 708-28.
5. Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE. Steroid
5*-reductase deficiency in man: an inherited form of male pseudohermaphroditism.
Science 1974; 186: 1213-5.
6. Kraemer HC. What is the right statistical measure of twin
concordance (or diagnostic reliability and validity?). Arch Gen Psychiatry
1997; 54: 1121-4.
7. Carr AB, Martin NG, Whitfield JB. Usefulness of the co-twin
control design in investigations as exemplified in a study of effects
of ascorbic acid on laboratory test results. Clin Chem 1981; 27:
1469-70.
8. Christian JC, Kang KW. Efficiency of human monozygotic twins
in studies of blood lipids. Metabolism 1972; 21: 691-9.
9. Zaslavskaia RM, Zolotaia RD, Lil'in ET. ''Partner control''
method of twin studies in evaluating the hemodynamic effects of nonachlazine.
Farmakol Toksikol 1981; 44: 357-60.
10. Carr AB, Einstein R, Lai LY, Martin NG, Starmer GA. Vitamin
C and the common cold: using identical twins as controls. Med J Aust
1981; 2: 411-2.
11. Gormley GJ. Finasteride: a clinical review. Biomed Pharmacother
1995; 49: 319-24.
12. Harris G, Azzolina B, Baginsky W, Cimis G, Rasmusson GH,
Tolman RL, et al. Identification and selective inhibition of an
isozyme of steroid 5a-reductase in human scalp. Proc Natl Acad Sci
USA 1992; 89: 10787-91.
13. Vermeulen A, Giagulli VA, De Schepper P, Buntinx A. Hormonal
effects of a 5 alpha-reductase inhibitor (finasteride) on hormonal levels
in normal men and in patients with benign prostatic hyperplasia. Eur
Urol 1991; 20 (suppl. 1): 82-6.
14. McConnell JD, Wilson JD, George FW, Geller J, Pappas F, Stoner
E. Finasteride, an inhibitor of 5*-reductase, suppresses prostatic dihydrotestosterone
in men with benign prostatic hyperplasia. J Clin Endocrinol Metab
1992; 74: 505-8.
15. Dallob AL, Sadick NS, Unger W, Lipert S, Geissler LA, Gregoire
SL, Nguyen HH, Moore EC, Tanaka WK. The effect of finasteride, a 5*-reductase
inhibitor, on scalp skin testosterone and dihydrotestosterone concentrations
in patients with male pattern baldness. J Clin Endocrinol Metab
1994; 79: 703-6.
16. Drake L, Hordinsky M, Fiedler V, Swinehart J, Unger WP, Cotterill
PC, Thiboutot DM, Lowe N, Jacobson C, Whiting D, Stieglitz S, Kraus SJ,
Griffin EI, Weiss D, Carrington P, Gencheff C, Cole GW, Pariser DM, Epstein
ES, Tanaka W, Dallob A, Vandormael K, Geissler L, Waldstreicher J. The
effects of finasteride on scalp skin and serum androgen levels in men
with androgenetic alopecia. J Am Acad Dermatol 1999; 41: 550-4.
17. Roberts JL, Fiedler V, Imperato-McGinley J, Whiting D, Olsen
E, Shupack J, Stough D, DeVillez R, Rietschel R, Savin R, Bergfeld W,
Swinehart J, Funicella T, Hordinsky M, Lowe N, Katz I, Lucky A, Drake
L, Price VH, Weiss D, Whitmore E, Millikan L, Muller S, Gencheff C, Carrington
P, Binkowitz B, Kotey P, He W, Bruno K, Jacobsen C, Terranella L, Gormley
GJ, Kaufman KD. Clinical dose ranging studies with finasteride, a type
2 5*-reductase inhibitor, in men with male pattern hair loss. J Am
Acad Dermatol 1999; 41: 555-63.
18. Kaufman KD, Olsen EA, Whiting D, Savin R, DeVillez R, Bergfeld
W, Price VH, Van-Neste D, Roberts JL, Hordinsky M, Shapiro J, Binkowitz
B, Gormley GJ. Finasteride in the treatment of men with androgenetic alopecia.
J Am Acad Dermatol 1998; 39: 578-89.
19. Leyden J, Dunlap F, Miller B, Winters P, Lebwohl M, Hecker
D, Kraus S, Baldwin H, Shalita A, Draelos Z, Markou M, Thiboutot D, Rapaport
M, Kang S, Kelly T, Pariser D, Webster G, Hordinsky M, Rietschel R, Katz
I, Terranella L, Best S, Round E, Waldstreicher J. Finasteride in the
treatment of men with frontal male pattern hair loss. J Am Acad Dermatol
1999; 40: 930-7.
20. McClellan KJ, Markham A. Finasteride: a review of its use
in male pattern hair loss. Drugs 1999; 57: 111-26.
21. Canfield D. Photographic documentation of hair growth in
androgenetic alopecia. Dermatol Clin 1996; 14: 713-21.
22. Barber BL, Kaufman KD, Kozloff RC, Girman CJ, Guess HA. A
hair growth questionnaire for use in the evaluation of therapeutic effects
in men. J Dermatol Treat 1998; 9: 181-6.
23. Van Neste D, Fuh V, Sanchez-Pedreno P, Lopez-Bran E, Wolff
H, Whiting D, Roberts J, Kopera D, Stene JJ, Calvieri S, Tosti A, Prens
E, Guarrera M, Kanojia P, He W, Kaufman KD. Finasteride increases anagen
hair in men with androgenetic alopecia. Brit J Dermatol 2000; 143:
804-10.
24. Kaufman K, Binkowitz B, Savin R, Canfield D. Reproducibility
of global photographic assessments of patients with male pattern baldness
in a clinical trial with finasteride. J Invest Dermatol 1995; 104:
659.
25. Kaufman KD for the Finasteride Male Pattern Hair Loss Study
Group. Long-Term (5 Years) Multinational Experience with Finasteride in
the Treatment of Men with Androgenetic Alopecia (Male Pattern Hair Loss).
Third Meeting of the Intercontinental Hair Research Societies,
2001 (abstr. 003).
26. US product circular for PROPECIA® (finasteride
1 mg tablets). In : Physicians' Desk Reference. 55th ed. Montvale,
NJ: Medical Economics Company, Inc., 2001: 2009-12.
27. Budd D, Himmelberger D, Rhodes T, Cash TE, Girman CJ. The
effects of hair loss in European men: a survey in four countries. Eur
J Dermatol 2000; 10: 122-7.
28. Cash TF. The psychosocial consequences of androgenetic alopecia:
a review of the research literature. Br J Dermatol 1999; 141: 398-405.
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