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Am J Clin Dermatol 2007; 8 (5): 285-290
O
RIGINAL
R
ESEARCH
A
RTICLE
1175-0561/07/0005-0285/$44.95/0
© 2007 Adis Data Information BV. All rights reserved.
Efficacy of 5% Minoxidil versus Combined 5%
Minoxidil and 0.01% Tretinoin for Male Pattern
Hair Loss
A Randomized, Double-Blind, Comparative Clinical Trial
Hyo Seung Shin,
1
Chong Hyun Won,
2
Seung Ho Lee,
1
Oh Sang Kwon,
1
Kyu Han Kim
1
and Hee Chul Eun
1
1 Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea
2 Department of Dermatology, Seoul National University Boramae Hospital, Seoul, Korea
Background: 5% topical minoxidil solution has been widely used to stimulate new hair growth and help stop
Abstract
hair loss in men with androgenetic alopecia (AGA). However, it is not convenient for patients to continue
applying the solution twice daily on a regular basis. Tretinoin is known to increase the percutaneous absorption
of minoxidil and, therefore, to enhance the response of AGA to minoxidil. For this reason, it was assumed that
tretinoin would be helpful in alleviating the inconvenience associated with the recommended twice-daily
application of minoxidil.
Objective: To compare the efficacy and safety of therapy using a combined solution of 5% minoxidil and 0.01%
tretinoin once daily with those of the conventional 5% topical minoxidil therapy applied twice daily in the
treatment of AGA.
Methods: A total of 31 male patients (aged 28–45 years, mean 39.7 ± 4.5) with AGA (Hamilton-Norwood
classification type III–V) were randomly assigned into two groups, one in which 5% minoxidil was applied to the
scalp twice daily and the other in which the combined agent was applied once daily at night together with a
vehicle placebo in the morning. The efficacy parameters were: (i) changes in total hair count, non-vellus hair
count, anagen hair ratio, linear hair growth rate, and mean hair diameter assessed by macrophotographic image
analysis; and (ii) the patient’s and investigator’s subjective assessments.
Results: After therapy, increases in the macrophotographic variables of total hair count and non-vellus hair
count were shown in both treatment groups. There were no statistically significant differences between the two
treatment groups with respect to changes in macrophotographic variables or scores on subjective global
assessments by patients and the investigator. The incidence of adverse effects such as pruritus or local irritation
was similar in the 5% minoxidil group (4 of 14 subjects) and the combined agent group (5 of 15 subjects).
Conclusion: The efficacy and safety of combined 5% minoxidil and 0.01% tretinoin once-daily therapy appear
to be equivalent to those of conventional 5% minoxidil twice-daily therapy for the treatment of AGA.
Androgenetic alopecia (AGA), the most common form of alo- US FDA. Minoxidil lengthens the duration of the anagen phase
pecia in men, is a genetically determined, cosmetic disorder usual- and shortens the latent period of the hair cycle.
[4]
In addition,
ly beginning from about the late twenties and affecting approxi- topical application of minoxidil increases the size of the hair
mately half of all adult males aged >50 years.
[1,2]
Shortening of the follicles.
[5]
However, the exact mechanism of action of the drug
anagen phase and miniaturization of the follicles are prominent in has not been fully elucidated.
[6]
AGA.
[3]
The effect of minoxidil correlates with the concentration and
Minoxidil, originally developed for the treatment of hyperten- amount of the applied agent. Olsen et al.
[7,8]
showed that twice-
sion, is the most popular topical agent for AGA approved by the daily application of minoxidil was superior to once-daily applica-
286 Shin et al.
tion for the treatment of AGA. Therefore, its application twice prepared by AmorePacific R&D Center (Gyeonggi-do, Korea) and
daily for the treatment of AGA has been generally recommend- distributed by our clinical research center pharmacy. The two
ed.
[9]
Regular application of minoxidil is an important factor in products were indistinguishable in terms of appearance, smell, and
effective treatment.
[10]
However, from a practical point of view, it viscosity. The patients were instructed to spray 1mL of the agent
is not easy for patients to regularly apply minoxidil daily. and massage their scalp softly twice daily. The test group applied
the placebo (vehicle, 95% alcohol plus 5% propylene glycol)
In a previous study,
[11]
the percutaneous absorption of 2%
without minoxidil or tretinoin in the morning and the combined
minoxidil was increased nearly 3-fold by 0.05% tretinoin, which
preparation in the evening. Therefore, the test group was treated
increases the permeability of the stratum corneum. When minox-
once a day, in contrast to the control group that applied 5%
idil combined with tretinoin was applied only once daily, the
minoxidil twice daily.
urinary excretion of minoxidil was significantly higher than that of
minoxidil alone applied twice daily.
[11]
Moreover, 0.5% minoxidil
Study Protocol
plus 0.025% tretinoin (95% alcohol plus 5% propylene glycol
vehicle) applied twice daily to the affected scalp area was reported
The patients visited the hospital a total of five times. At the first
to prolong the anagen hair ratio and induce new hair growth.
[12]
visit, a baseline global photograph of their scalp was taken, after
These findings suggest that tretinoin can be helpful in alleviating
which the scalp hairs on the transitional zone between the bald
the inconvenience associated with the recommended twice-daily
region and normal hairy region were shaved to create a round area
application of minoxidil. In this study, we compared the efficacy
1.5cm in diameter. The reference point was tattooed at the center
and safety of the combined 5% minoxidil and 0.01% tretinoin
of the shaved round area. Three days later, phototrichogram
topical preparation applied once daily with those of 5% minoxidil
images were obtained by taking close contact photographs with a
applied conventionally twice daily in the treatment of AGA.
digital camera (Coolpix 8400
®
,
1
Nikon Corporation, Tokyo, Ja-
pan) at a magnification of ×30 in the previously shaved region.
Patients and Methods
The camera was mounted with a rigid magnifying lens to ensure
that the images were always taken at the same distance from the
Patient Selection
scalp surface. After application of a drop of water to minimize
light scattering, the lens was pressed on to the shaved area so that
Thirty-one male patients ranging from 28 to 45 years of age
the newly grown hairs were flattened on to the scalp surface. We
(mean 39.7 ± 4.5 years of age) with a clinical diagnosis of AGA
recorded the exact time when shaving and taking of the photo-
type III–V (Hamilton-Norwood classification) volunteered to par-
trichogram were undertaken in order to calculate the exact dura-
ticipate in this study. Patients with other medical problems were
tion of new hair growth. Patients were than randomly assigned to
excluded. No patients had used any products or taken any drugs
one of the two treatment groups.
that might have affected hair growth for ≥6 months prior to this
At the 9-week visit, a global photograph was taken again, and
study.
the patient’s and investigator’s subjective assessments were made.
Patients were randomly divided into two groups (the test [n =
At the 18-week visit, the final global photograph was taken and
16] and control [n = 15] groups) by four-block randomization
final assessments were made by the patient and investigator. The
using a table of random sampling numbers. The random numbers
previously tattooed reference area was then shaved again in prepa-
and the allotment table were not made available to investigators
ration for the second phototrichogram. Three days later, on the last
and patients until after all study evaluations had been completed.
visit, the second phototrichogram for evaluation of the efficacy of
Written informed consent was obtained from all patients prior
the treatment was taken.
to participation in the study. The Institutional Review Board of
Seoul National University Hospital approved the conduct of the
Measurements
study.
Five biologic parameters of hair growth (total hair count, non-
Products Tested
vellus hair count, anagen hair ratio, linear hair growth rate, and
The 5% minoxidil solution and the combined topical prepara- mean hair diameter) at baseline and post-treatment were measured
tion consisting of 5% minoxidil and 0.01% tretinoin were transpar- by macrophotographic image analysis. Total hair count, linear hair
ent liquids in 95% alcohol plus 5% propylene glycol vehicle length, and hair diameter in the digitized images were measured by
1 The use of trade names is for product identification purposes only and does not imply endorsement.
© 2007 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2007; 8 (5)
Combined 5% Minoxidil and 0.01% Tretinoin for Hair Loss 287
Table I. Characteristics of study volunteers (n = 29)
No. of subjects Hamilton-Norwood classification
III IIIa IIIv V Va
Combined minoxidil and tretinoin 1 0 9 0 5
once-daily group (n = 15)
Minoxidil twice-daily group (n = 14) 2 1 8 1 2
Total (n = 29) 3 1 17 1 7
image analysis software (Image J 1.34s, Wayne Rasband, Bethes- Results
da, MD, USA). Hairs thicker than 40µm in diameter were counted
as non-vellus hair.
[13]
In addition, hairs with growth rates >200
Enrolled Patients
µm/day were classified as anagen hair, allowing the anagen hair
Initially, 31 otherwise healthy patients with AGA were en-
ratio (anagen hair count/total hair count) to be calculated.
[14]
rolled, but one patient in the control group and another patient in
At 9 and 18 weeks, patients were asked to rate the improvement
the test group withdrew after missing a follow-up visit. Thus, 15
in their hair loss on a 10-point scale, where 0 meant no change or
patients in the test group and 14 patients in the control group
worse and 10 indicated complete recovery. They also graded their
completed the study. No significant difference in the age of the
satisfaction with the result on a 10-point scale, where 0 meant
patients was observed between the two groups (mean ± SD 39.3 ±
complete disappointment and 10 indicated full satisfaction.
4.2 years for the test group vs 40.2 ± 4.8 years for the control
group). The most common AGA subtype was grade IIIv in the
The investigator’s assessment of the efficacy of the treatment
Hamilton-Norwood classification (table I).
was conducted by one designated investigator (HSS) and per-
formed by comparing global photographs obtained at the first visit,
Biologic Parameters of Hair Growth Characteristics
9 weeks, and 18 weeks. The results of the evaluation were rated
before Treatment
into five grades as follows: 4 = excellent (improved >75%); 3 =
good (improved 51–75%); 2 = fair (improved 26–50%); 1 = poor
No significant difference in total hair count, non-vellus hair
(improved <25%); 0 = no change or worse.
count, anagen hair ratio, linear hair growth rate, and mean hair
diameter was observed between the two groups before treatment
(table II).
Statistical Methods
Treatment Efficacy Within Each Group
A statistical analysis was performed using SPSS 11 software
(SPSS, Chicago, IL, USA) with a p-value of <0.05 being consid-
The total hair count and non-vellus hair count increased signifi-
ered significant. The non-parametrical Mann-Whitney test and
cantly after 18 weeks of treatment in both groups (p < 0.05). Mean
Wilcoxon signed rank test were used to evaluate differences in
hair diameter was also markedly increased in the control group (p
biologic parameters of hair growth characteristics and the patients’
< 0.05). In the test group the increase in mean hair diameter was of
and investigator’s assessments between the two groups.
borderline significance (p = 0.064). Neither anagen hair ratio nor
Table II. Biologic parameters of hair growth in the two treatment groups at baseline
Parameter Combined minoxidil and tretinoin once-daily group
a
Minoxidil twice-daily group
a
p-Value
Total hair count (n/cm
2
) 124.2 ± 8.5 124.0 ± 7.5 NS
Non-vellus hair count (n/cm
2
) 42.7 ± 5.8 33.4 ± 4.3 NS
Anagen hair ratio 0.554 ± 0.020 0.571 ± 0.025 NS
Linear hair growth rate (µm/d) 336.6 ± 10.6 302.2 ± 13.1 NS
Mean hair diameter (µm) 36.2 ± 1.3 34.8 ± 2.1 NS
a Values are mean ± standard error.
NS = not significant.
© 2007 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2007; 8 (5)
288 Shin et al.
Table III. Biologic parameters of hair growth at baseline and after 18 weeks of treatment in the two treatment groups
Parameter Baseline
a
After treatment
a
p-Value
Combined minoxidil and tretinoin once-daily group
Total hair count (n/cm
2
) 124.2 ± 8.5 142.4 ± 7.3 <0.05
Non-vellus hair count (n/cm
2
) 42.7 ± 5.8 48.8 ± 5.6 <0.05
Anagen hair ratio 0.554 ± 0.020 0.521 ± 0.037 NS
Linear hair growth rate (µm/d) 336.6 ± 10.6 331.1 ± 9.3 NS
Mean hair diameter (µm) 36.2 ± 1.3 38.1 ± 1.4 NS
Minoxidil twice-daily
Total hair count (n/cm
2
) 124.0 ± 7.5 139.9 ± 9.1 <0.05
Non-vellus hair count (n/cm
2
) 33.4 ± 4.3 47.4 ± 5.3 <0.05
Anagen hair ratio 0.571 ± 0.025 0.557 ± 0.035 NS
Linear hair growth rate (µm/d) 302.2 ± 13.1 317.7 ± 13.8 NS
Mean hair diameter (µm) 34.8 ± 2.1 37.4 ± 1.8 <0.05
a Values are mean ± standard error.
NS = not significant.
linear hair growth rate showed any significant differences after Safety Evaluation
treatment (table III).
Five patients in the test group (n = 15) and four patients in the
Treatment Efficacy between Groups
control group (n = 14) complained of scalp itching or prickling.
Among them, two patients in the control group had folliculitis on
No significant differences in percentage changes in biologic
their scalps. However, symptoms were mild in all cases and the
parameters of hair growth (total hair count, non-vellus hair count,
patients were able to continue application of the drugs. All adverse
anagen hair ratio, linear hair growth rate, and mean hair diameter)
effects were self-limiting and were no longer present after a few
were observed between the two groups after 18 weeks of treat-
days.
ment. The p-values all exceeded 0.05 (table IV).
Discussion
Patients’ and Investigator’s Subjective Assessments
The patient’s subjective assessment score and satisfaction score Among the various drugs used for the treatment of AGA, the
did not show any significant differences between the test group most popular topical agent, which is also approved by the FDA, is
and the control group during the study (table V). Similarly, the minoxidil. After application, minoxidil is converted to minoxidil
investigator’s subjective assessment score did not show any signif- sulfate, an active metabolite of the parent drug, by sulfotransferase
icant difference between the test group and the control group enzymes. Minoxidil sulfate opens an adenosine triphosphate-sen-
during the study (table VI). sitive potassium channel, which functions to relax vascular
Table IV. Comparison of changes in biologic parameters of hair growth between the two treatment groups
Change (%)
a
Combined minoxidil and tretinoin Minoxidil twice-daily group
b
p-Value
once-daily group
b
Total hair count 17.3 ± 3.8 12.9 ± 2.5 NS
Non-vellus hair count 23.4 ± 7.7 55.4 ± 19.6 NS
Anagen hair ratio
–
7.0 ± 4.1
–
2.9 ± 3.7 NS
Linear hair growth rate
–
1.3 ± 1.8 5.6 ± 3.1 NS
Mean hair diameter 5.4 ± 2.5 8.7 ± 3.4 NS
a Change (%) = (parameter at week 18 – parameter at baseline) / (parameter at baseline) × 100.
b Values are mean ± standard error.
NS = not significant.
© 2007 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2007; 8 (5)
Combined 5% Minoxidil and 0.01% Tretinoin for Hair Loss 289
Table V. Comparison of patients’ subjective assessment scores between the two treatment groups
Subjective score
a
Combined minoxidil and tretinoin Minoxidil twice-daily group
b
p-Value
once-daily group
b
Improvement (at 9wk) 3.1 ± 0.6 2.6 ± 0.6 NS
Improvement (at 18wk) 4.2 ± 0.6 3.7 ± 0.8 NS
Satisfaction (at 9wk) 3.0 ± 0.6 3.1 ± 0.7 NS
Satisfaction (at 18wk) 4.2 ± 0.6 3.9 ± 0.8 NS
a Graded on a 10-point scale, where a score of 0 means no change or complete disappointment and a score of 10 means complete recovery or full
satisfaction.
b Values are mean ± standard error.
NS = not significant.
smooth muscle. Therefore, increasing cutaneous blood flow has ies.
[8,19]
However, in contrast to previous studies that reported an
increase in anagen hair ratio with minoxidil therapy,
[4,19]
neither
been regarded as the main mechanism of action of minoxidil.
[15,16]
the combined agent nor conventional 5% minoxidil were found to
Tretinoin has been shown to alter the stratum corneum barrier
improve anagen hair ratio or linear hair growth rate in the current
and increase the percutaneous absorption of minoxidil which, in
study. Since minoxidil is reported to shorten the latent telogen
turn, enhances the response of AGA to minoxidil.
[11]
Moreover,
phase,
[4]
the lack of change in these parameters with treatment in
retinoic acid promotes the growth of hair follicles and the forma-
our study was not expected. It is possible that these results re-
tion of vessels via a molecular signaling pathway.
[17]
In addition,
flected seasonal variations in hair growth, as our study was per-
we have recently demonstrated that hair growth was significantly
formed between summer and autumn.
[20]
Otherwise, some exogen
enhanced by the combination of minoxidil plus retinol (vitamin A)
hair might have interfered with anagen hair growth by blocking its
compared with minoxidil alone via dual mechanisms: (i) activa-
path. These factors might at least partially explain why anagen hair
tion of extracellular signal-regulated kinase (Erk) and Akt signal-
ratio and linear hair growth rate were not significantly affected by
ing; and (ii) prevention of apoptosis by increasing the B-cell
treatment in this study.
leukemia/lymphoma (Bcl)-2/Bcl-2-associated X (Bax) protein ra-
Both groups demonstrated similar improvements in subjective
tio.
[18]
Therefore, enhancement of transepidermal absorption of
global assessment of therapy by patients and the investigator.
minoxidil and a direct stimulatory influence on hair growth have
The occurrence of adverse effects such as pruritus or local
been proposed as the mechanisms of action of tretinoin on hair
irritation was similar in both groups. Based on these results, it was
growth. However, it has not yet been determined which is more
inferred that the combined preparation is as safe as conventional
predominant in terms of promoting hair growth.
minoxidil.
In this study, we found that the application of the combined 5%
minoxidil and 0.01% tretinoin solution just once daily showed an
Conclusion
equivalent treatment effect to that of 5% minoxidil applied twice
daily in terms of changes in hair growth characteristics such as
This study was a randomized, double-blind, comparative
total hair count, non-vellus hair count, anagen hair ratio, linear hair
clinical trial designed to compare the efficacy of a combined
growth rate, and mean hair diameter. The increases in total hair
solution of 5% minoxidil and 0.01% tretinoin with that of conven-
count, non-vellus hair count, and mean hair diameter observed in
tional 5% minoxidil in the treatment of AGA. Topical tretinoin has
our study correlate well with those reported in previous stud-
been shown to increase the percutaneous absorption of minoxidil.
Table VI. Comparison of investigator’s subjective assessment scores between the two treatment groups
Subjective score
a
Combined minoxidil and tretinoin Minoxidil twice-daily group
b
p-Value
once-daily group
b
At 9wk 1.2 ± 0.2 0.9 ± 0.2 NS
At 18wk 1.6 ± 0.3 1.8 ± 0.4 NS
a Graded on a 4-point scale, where a score of 0 means no change or worse and a score of 4 means >75% improvement.
b Values are mean ± standard error.
NS = not significant.
© 2007 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2007; 8 (5)
290 Shin et al.
7. Olsen EA, DeLong ER, Weiner MS. Long-term follow-up of men with male
Therefore, we presumed that a combined solution of 5% minoxidil
pattern baldness treated with topical minoxidil. J Am Acad Dermatol 1987 Mar;
and 0.01% tretinoin would be effective for the treatment of AGA,
16 (3 Pt 2): 688-95
even when it is applied only once daily. There were no significant
8. Olsen EA, Dunlap FE, Funicella T, et al. A randomized clinical trial of 5% topical
differences in percentage changes in biologic parameters of hair
minoxidil versus 2% topical minoxidil and placebo in the treatment of androge-
netic alopecia in men. J Am Acad Dermatol 2002 Sep; 47 (3): 377-85
growth characteristics between the two groups after 18 weeks of
9. Olsen EA, Messenger AG, Shapiro J, et al. Evaluation and treatment of male and
treatment. There were also no statistical differences between the
female pattern hair loss. J Am Acad Dermatol 2002 Sep; 47 (3): 377-85
two groups in the subjective global assessment of treatment by
10. Buhl AE, Waldron DJ, Kawabe TT, et al. Minoxidil stimulates mouse vibrissae
patients and the investigator. The adverse effects of the combined
follicles in organ culture. J Invest Dermatol 1989 Mar; 92 (3): 315-20
solution were all mild. In conclusion, although this study had
11. Ferry JJ, Forbes KK, VanderLugt JT, et al. Influence of tretinoin on the percutane-
limitations, such as the small number of patients analyzed, the lack
ous absorption of minoxidil from an aqueous topical solution. Clin Pharmacol
of a placebo group, and the fact that no treatment group received
Ther 1990 Apr; 47 (4): 439-46
5% minoxidil once daily, our results suggest that the efficacy and
12. Bazzano GS, Terezakis N, Galen W. Topical tretinoin for hair growth promotion.
J Am Acad Dermatol 1986 Oct; 15 (4 Pt 2): 880-3
safety of combined 5% minoxidil and 0.01% tretinoin adminis-
13. Rushton DH. Chemical and morphological properties of scalp hair in normal and
tered once daily are equivalent to those of conventional 5%
abnormal states. Aberystwyth: University of Wales, 1988
minoxidil administered twice daily for the treatment of AGA.
14. Hayashi S, Miyamoto I, Takeda K. Measurement of human hair growth by optical
Since there is usually an inverse relationship between administra-
microscopy and image analysis. Br J Dermatol 1991 Aug; 125 (2): 123-9
tion frequency and compliance,
[21,22]
use of combined 5% minox-
15. Meisheri KD, Cipkus LA, Taylor CJ. Mechanism of action of minoxidil sulfate-
idil and 0.01% tretinoin once daily could be a useful alternative,
induced vasodilation: a role for increased K+ permeability. J Pharmacol Exp
with a high rate of compliance, for the treatment of AGA.
Ther 1988 Jun; 245 (3): 751-60
16. Winquist RJ, Heaney LA, Wallace AA, et al. Glyburide blocks the relaxation
response to BRL 34915 (cromakalim), minoxidil sulfate and diazoxide in
Acknowledgments
vascular smooth muscle. J Pharmacol Exp Ther 1989 Jan; 248 (1): 149-56
17. Madani KA, Bazzano GS, Chou AC. Effects of vitamin A status on cellular retinoic
acid-binding protein in rat skin and testes. Eur J Clin Chem Clin Biochem 1991
This study was financially sponsored by AmorePacific R&D Center,
May; 29 (5): 317-20
Gyeonggi-do, Korea. The authors have no conflicts of interest that are directly
18. Yoo HG, Chang IY, Pyo HK, et al. The additive effects of minoxidil and retinol on
relevant to the content of this study.
human hair growth in vitro. Biol Pharm Bull 2007 Jan; 30 (1): 21-6
19. Abell E. Histologic response to topically applied minoxidil in male pattern alope-
cia. Clin Dermatol 1988 Oct-Dec; 6 (4): 191-4
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© 2007 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2007; 8 (5)
