Review

Topically Applied Minoxidil in Baldness
ERVIN NOVAK,
M.D., THOMASJ. FRANZ, M.D., JOHN T. HEADINGTON,
M.D.,
RONALD C. WESTER,
PH.D.

AND

idil and its metabolites can be removed by hemodialysis.
Fluid retention and hypertrichosis are the mostcommonly occurring side effects of minoxidil. Hairregrowth in a patient with male pattern baldness was
described in a case report of a hypertensive patient
treated twice daily with 20 mg oral minoxidil.6 The
extensive hair regrowth continued after 10 monthsof therapy. New and increased hair growth as a side
effect was also detected in an early clinical study
involving five of eight patients on oral minoxidil
therapy for 2 month^.^ Zappacosta' reported reversalof baldness in a patient on minoxidil for the treatmentof hypertension.
After the third week of therapy with oral minoxidil,
hypertrichosis usually appears between the eyebrowsand the hair line, in the malar and temporal areas,on the backs of the arms, on the shoulders, and on
the legs. Hair growth has been noted at all doselevels, although it appears later and is less marked
after the smaller doses of 10 mg or less per day. New
hair growth ceases abruptly when minoxidil therapy
i s discontinued, but the patient's appearance does
not return to normal for several months. Normal
hormonal assays were recorded in 50 patients who
and we doreceived minoxidil for 1 year or longer,'~~not believe that excessive hair growth is a result ofan endocrine abnormality.

From the Upjohn Company, Kalamazoo, Michigan, Schoolof Medicine, University of Washington, Seattle,
Washington, Medical School, University of Michigan, Ann
Arbor, Michigan, and School of Medicine and School of
Pharmacy, University of California, San Francisco, California

Minoxidil, an orally administered, peripheral vasodilator used to treat hypertension, causes hypertrichosis in more than 80% of users. The drug reduces
elevated blood pressure by decreasing peripheral
vascular resistance. Chemically, minoxidil i s 2,4-diamino-6-piperidinopyrimidine-3-oxide;it is soluble inwater to the extent of approximately 2 mg/ml, i smore readily soluble in propylene glycol or ethanol,and i s nearly insoluble in acetone, chloroform, or
ethyl acetate. Following oral administration of minoxidil and in association with the reduction in peripheral
vascular resistance, cardiac output is augmented, salt
and water are retained, and plasma renin activity
rises.',2When taken orally, minoxidil is at least 90% absorbed from the human gastrointestinal tract. Afterone 5-mg tablet of minoxidil, blood levels of theparent drug reach a maximum of 156.6 ng/ml within
the first hour and decline rapidly thereafter to 1.5
ng/ml within 24 hours (Table 1). The average plasma
half-life in humans is 4.2 hours for the combinationof parent drug and its metabolites. About 90% of
administered drug i s metabolized, predominantly by
conjugation with glucuronic
and parent drug
and metabolites are principally excreted in the urine.
Minoxidil does not bind to plasma proteins, and its
renal clearance corresponds to the glomerular filtration
rate. In the absence of functional renal tissue, minox-

Overview of Efficacy and Safety

Address for correspondence: E. Novak, M.D., The Upjohn
Company, 7254-24-2. 301 Henrietta Street, Kalamazoo, M I 49001.

82

Dermal acute toxicity studies in rats have shownthat minoxidil is not toxic when applied 10 mg/rat/
day and i s slightly toxic at 30 mg/rat/day and 60
mg/rat/day. While no gross or microscopic lesions
were found in the rat skin, the pharmacologic effects
included dose-related decreases in hemoglobin, decreased erythrocyte counts, decreases in serum sodium and chloride levels, and increases in serum
cholesterol and heart and liver weight.

No. 2

MlNOXlDlL IN BALDNESSTABLE1.

Mean Minoxidil Blood Levels from 20 Patients After Ingestion of One 5-rng Tablet

Hours
Mean concentration of minoxidil (ng/rnl)

0.0
6.65

1.o
156.5

We are conducting the clinical research program
for topical minoxidil slowly and with caution becauseof the potent action of the systemic formulation ofminoxidil on the cardiovascular system in hypertensive
patients. Initially, three 14-week studies involved
daily bilateral applications of 1%, 3%, or 5% minoxidil
to circular areas 2 cm in diameter on the scalps ofpatients with male pattern baldness. As expected, nosystemic side effects were observed. There was someevidence of hair growth stimulation, appreciably delayed and variable in occurrence among patients.
Long-term clinical studies of 6-12 months werestarted in 1980 and 1981. Since then, several clinicalstudies have been completed and new ones started.
For example, in one open-label study, we evaluatedthe effectiveness of twice-daily unoccluded applications of 5% minoxidil in men and women withalopecia areata and alopecia androgenetica. Therapy
was scheduled for 6 months in alopecia areata andfor 1 year in pattern baldness. Stimulation of hair
growth ranged from minimal early evidence to appreciable restoration toward typical terminal scalp hair.
It took 3-8 months to obtain the more definitive
evidence of stimulated hair growth. Other investigators who used a topically applied solution of 1%
minoxidil in three patients with alopecia areata unresponsive to conventional treatments found local
hair regrowth in the area of application within 4-6
weeks in two of the patients.”
Fenton and Wilkinson” induced hair growth in 22
of 30 (80.8%) patients with alopecia areata after 6
months of twice-daily topical applications of 1Yo
minoxidil lotion or ointment. Sixteen of these patients
grew acceptable terminal hair.
In a double-blind study, Headington and Novak’*
TABLE2.

0
3
4
5
9
13
25’
* p = 0.0625

2.5
71.0

4.0
54.4

7.0
23.3

11.0
7.8

16.0
5.7

24.0
1.5

treated 21 healthy men with pattern baldness withtwice-daily topical applications of 1Yo or Soh minoxidil
or the vehicle for minoxidil (water-propylene glycolalcohol). The shortest and longest hairs measured
were recorded for each treatment site through study
week 25 (Table 2). Medications were applied only
for 15.7 weeks (110 successive days), and no medication was applied during weeks 16-25. Results wereexpressed as the difference between an individual’s
minimum and maximum lengths of hair at baseline
and at each evaluation period. A minimal increase inmean hair length was seen in all treatment groups,
including the placebo group, between weeks 3-9
and at week 25. There were no statistically significant
differences among the groups in the hair growthduring the 12-week medication period.
After 15.7 weeks of treatment in this study, clinicaland statistical evaluations of the blood chemistries,
CBC, urinalysis, and EKC were similar for subjects
receiving the 1% or 5% solutions of minoxidil andthose receiving the placebo vehicle, nor was there adifference between mean pre- and postmedication
values in blood pressure, pulse rate, and body weights
in these subjects. Mild stinging, burning, itching, anderythema were noted only after the evaluation at
week 2 in 11 of 21 subjects (2 receiving 1% minoxidil,
4 receiving 5% minoxidil, and 5 receiving the vehicle).
These effects were thought to be due to the vehicle.

Absorption and Excretion After Topical Minoxidil
In animal and human topical absorption studies,
we have used I%,
3%, and 5% minoxidil in a
propylene glycol-ethanol-water vehicle. When vehicles containing propylene glycol-alcohol-water

Mean Hair Length (mm) in Topically Treated Area of Scalp in 21 Men with Pattern Baldness
1% Minoxidil

Week

83

Novak eta/.

5% Minoxidil

Placebo

N

Min

Max

N

Min

Max

N

Min

Max

7

1.o
1.o
1.4
1 .o
1.4
2.4
20.0

1.1
2.4
2.0
1.1
2.8
2.4
49.7

7
7
7
7
6
7
6

1.o
1.4
1.1
1.o
2.2
2.7
43.3

1.1
2.6
1.9
1.1
3.3
2.7
48.3

7
7
7
7
6
5
4

1.1
1.3
1.7
1.o
1.3
1.4
22.5

1.9
2.6
2.4
1.9
2.0
2.0
26.3

7
7

7
5

5
3

84

INTERNATIONAL JOURNAL OF DERMATOLOGY_

Percutaneous Absorption of Topical "C-Minoxidil in the Rat and Monkev

TABLE3.

_Vol. 24

March 1985

~

~

~

~

Drug
AnimalN

Concentration

Regimen% of Applied
Dose Absorbed'

Rat

5

1%

Rat

5

4%

MonkeyMonkev

34

1%
4%Single application
Single application after 9 daily applications
Single application
Single application after 9 daily applications
Single application
Single application

18.1%
35.6%
17.9%
26.0%
17.2%
5.6%

~

~

~~~~

* Derived from the percentage of applied dose of labeled drug excreted in urine and stool

were used, the in vitro transport data over 72 hours
showed a cumulative penetration of 3.0 mg, 3.7 mg,
and 4.0 mg of drug from the 1%, 3%, and 5%
minoxidil solutions, respectively. The extent of percutaneous absorption in the rat and monkey, based
upon the percentage of the applied dose of 14Cminoxidil excreted in the urine and stool, is shownin Table 3. In the rat and monkey, the skin of theapplication sites retained 30-78% of the applied
dose of ''C-minoxidil.
In ongoing clinical trials with topical minoxidil inpatients with alopecia areata and alopecia androgenetica or both, we are using applications of 1%, 3%,
and 5% minoxidil solutions once daily with or without
overnight occlusion. After therapy ranging from a few
months to 1 year in 150 patients, single-point andvariable time values of serum minoxidil in six patients
TABLE4.
Treatment Group

1% minoxidil

5% minoxidilaPlaceboMinoxidil Serum Levels' (ng/ml) in 2 I Men with Pattern Baldness

Patient No.

2
6
9
10
15
16
21
3
4
11
14
18
20
1

5
7
12
13
17
19

so tested at 2, 4, and 8 weeks tended to range fromnondetectable levels (radioimmunoassay sensitivityof 1.4 ng/ml) to a maximum of 6.2 ng/ml. In adouble-blind study of 21 men with pattern baldness,'*a radioimmunoassay with a sensitivity of 1.4 ng/ml
showed no consistency or trend in minoxidil serum
levels (Table 4). The highest levels of minoxidil (6.2
ng/ml) occurred in the 5% minoxidil group at week
2. One subject in the 1% minoxidil group had aserum level of 2.3 ng/ml minoxidil at week 2.
In a percutaneous absorption/excretion study, 1 O/O
or 5% solutions of ''C-minoxidil were applied topically to the scalps of 12 healthy men. At either dose,minoxidil was poorly absorbed through the skin. The
mean recovery of the applied doses in the urine wasless than 4% (Table 5). A fecal analysis was done in
six of these volunteers and no radioactivity was

Week 0Week 2

Week 4

Week 8

t1.4
t1.4
<1.4
4.4
tl.4
t1.4
t1.4
tl.4
<1.4
41.4
4.4
<1.4
t1.4
t1.4
~1.4
4.4
4.4
~ 1 . 4
t1.4
4.4
<1.4

t1.4
4.4
<1.4
c1.4
2.3
11.4
41.4
t1.4
c4.1
t1.4
2.9
t1.4
3.0
6.2
4.4
4.4
<1.4
t1.4
4.4
4.4
<1.4

c1.4
4.4
41.4
11.4
41.4
41.4
4.4
41.4
3.4
2.2
2.2
41.4
4.4
2.1
41.4
tl.4
4.4
4.4
41.4
cl.4
t1.4

t1.4
t1.4
<1.4
<1.4
t1.4
t1.4
1.4
1.9
<1.4
1.4
t1.4
41.4
t1.4
41.4
<1.4
41.4
t1.4
41.4
<1.4
<1.4
t1.4

Week 25

41.4
-

cl.4
t1.4
<1.4
t1.4
c1.4
41.4
11.4
41.4
t1.4
c1.4
41.4
11.4
t1.4

41.4

41.4
41.4

Radioimmunoassay (sensitivity of 1.4 ng/rnl) of serum drawn in morning before breakfast, about 10-1 2 hours after topical applicationof treatment solution.

MlNOXlDlL IN BALDNESS

No. 2

TABLE5.

85

Novak et a/.

Urinary Excretion of 'T-Minoxidil (% of Dose) After Topical Application to Normal Subjects
1% Minoxidil

5% Minoxidil

Application 1(Day 1 )Application 2(Day 9)Subiect

Application 1(Dav 1 )

7
9
12

3.91
4.26
2.82
9.33
0.91
2.00

2.60
3.63
1.05
2.38
1.25
3.1 1

2
3
6
8
10
11

3.06
2.76
0.89
1.65
1.01
1.62

4.47
1.05
0.27
0.71

Group mean f SD

3.87 2 2.94

2.34 t 1.02

1.83 2 0.90

1.57 k 1.55

Subiect

Application 2(Dav 9)~1
45detected. A mean of 4 3 4 5 % of the 1% and 5%
applications of radioactive minoxidil was recoveredfrom the surface of the skin (Table 6). The total
recovery of ''C-minoxidil in this study ranged from
42.9% to 47.2% for either dose at any of the test
periods. We presume that the remaining material
was lost from the surface of the skin to the environment. We evaluated the possibility that a portion of
applied minoxidil is bound within the skin and slowly
released to the systemic circulation, where it might
be below the limits of detection used in this study.
Biopsied tissue of the scalp from five patients 24hours after the second treatment showed radioactivity
Of o.ooolo/o to .oo15°/o.

Effect of Topical Minoxidil on Blood
Flow of the Scalp
Burton and c o - w ~ r k e r s ' ~ postulated,'~
increased
cutaneous perfusion with potent peripheral vasodilators. It has been suspected for a long time that
localized hypertrichosis is associated with increased
cutaneous blood flow in some cutaneous inflammatory conditions as well as with arteriovenous aneury~m.'~-'~TABLE6 .

~~

0.80
2.10

0'0, 1%,
In another double-blind study, we tested 03%, and 5% randomly assigned solutions of minoxidil
on the balding scalps of 16 human volunteers. On 2
consecutive days, an 0.25 ml volume of the formulations was uniformly spread over 100 cmz of thebald scalp. After 15 minutes, cutaneous blood flow
was recorded continuously for 40-60 minutes, thenintermittently for 4 hours. A single microcirculatory
flow parameter was measured by laser Doppler velocimetry ( L D V ) , ~ ~ - ~ O and changes in microcirculatory
blood volume were measured by photopulse plethysmography (PPC).z'*zz
The 5% minoxidil solution increased blood flow
when compared with the other treatments. As shownby LDV, on day 1 (Fig. 1) there was a statisticallysignificant increase (p = 0.0001) in mean blood flow
within 15 minutes of application; that flow was maintained at least through 1 hour. O n day 2 (Fig. 2),
blood flow stimulation increased (p = 0.0001) threefold within 15 minutes of application and remainedthat way for about 1 hour. With the photopulse
plethysmography technique, the mean blood perfusion response was statistically significant (p = 0.01)
only for application of the 5% minoxidil solution on
day 2.

Recovery of '"C-Minoxidil (% of Dose) From Surface of the Skin in Normal Subjects

1% Minoxidil

5% Minoxidil

Subject

Application 1(Day 1 )Application 2(Day 9)Subject

Application 1(Day 11

Application 2(Day 9)

1
4
5
7
9
12

37.1
37.7
27.2
69.9
27.9
60.2

45.9
45.9
46.1
44.8
24.2
58.4

2
3
6
8
10
11

57.3
23.5
37.7
40.3
56.9
54.1

63.4
2.4'
28.9
53.9
44.2
54.9

Group mean k SD

43.4 2 17.7

44.2 rt 1 1 . 1

45.0 ? 13.5

41.3 2 22.4

Subject used hair drier several hours after treatment was applied

86

INTERNATIONAL JOURNAL OF DERMATOLOGY

Histopathologic Findings in the Scalp After TopicalApplications of Minoxidil
I n a double-blind study by Headington and Novak,12 a 1% or 5% minoxidil solution or placebo wasapplied twice daily to three groups of seven healthy
men with pattern bladness. In all 21 patients, a4-mm Baker disposable punch was used t o obtain abiopsy from the vertex or from the parietal areas ofthe scalp pretreatment and at weeks 12 and 24.
Details of the histologic techniques used were published by H e a d i n g t ~ nQualitative.~~evaluation showedthat biopsies obtained from individuals receiving either topical minoxidil or placebo did not differ fromtheir pretreatment biopsies with respect t o semiquantitative determination of inflammation. There
was no suggestion of a direct toxic or irritant effector of allergic contact dermatitis, nor was epidermal
hyperplasia or dysplasia seen. The sebaceous epithelium and papillary reticular dermis appeared unaltered. Morphologic changes were not found in bloodvessels, including vessels of the follicular dermal
papillae. The seven subjects who received the 5%dose of minoxidil had a mean hair shaft diameter of
0.029 mm before treatment, which increased to
0.043 mm at 12 weeks and measured 0.042 m m at
24 weeks, although therapy was discontinued after
15.7 weeks. In this study, minoxidil and/or its vehicle
affected hair growth by induction or hypertrophy ofthe existing follicles.
Quantitative data from this study show that we
can determine from transverse sections of a scalp
biopsy a patient’s morphologic capability for response.
The identification of potential morphologic nonresponders is, of course, essential to the study of
topical stimulation of hair growth.
Comment
We are continuing an extensive program t o evaluate
the safety and efficacy of topical minoxidil in certain
alopecias. In our studies to date, 1% and 5% solutionsof topically applied minoxidil induced hair growth insome patients with alopecia areata (totalis, universalis)and alopecia androgenetica. The onset of stimulationof hair growth may be delayed 2-7 months, thestimulated hairs are pigmented, and the increase
ranges from minimal to 3 c m or more. The positive
hair growth stimulation seen t o date in our studies isquite variable among patients. Some patients who
applied topically the higher (5%) concentrations ofminoxidil to the scalp showed hypertrichosis on theface and extremities, suggesting a systemic side effect.
The mechanism by which minoxidil stimulates hair
growth is still unknown. At present, this stimulation

Vol. 24

1

600
500

loo

March 1985.-.

Minoxidil
M

0%

.-.

1%

0..
. . .o

3%

*
195

t l5

75

Drug
application

255

135

Time (minutes)

FIG. 1. Mean blood flow-time curve as shown by laser Doppler
velocimetry (LDV) following day 1 application of O%, YO, 3%,
and 5% topical minoxidil to bald scalps of four healthy men ateach dose.

i s attributed to a direct vasodilatory effect of minoxidil
on the skin vasculature, but other mechanisms are
possible. More basic and clinical research data areneeded to assess-the potential of topical minoxidil as
an agent to stimulate hair growth in patients withalopecia areata and alopecia androgenetica; we are
accumulating these data in our ongoing or proposedin vitro (tissue culture), animal, bioavailability, andhuman studies. Meanwhile, prescription and use ofcompounded topical minoxidil for alopecias in premature, potentially hazardous,24 and not recommended.

6oo

r

500t

Minoxidil
I

t

M

0%

0...

.-..-.
. .o

3%

A---A

5%

1%

loot

t

~~

l5

Drug
application

75

135

195

255

Time (minutes)

FIG. 2. Mean blood flow-tlme curve as shown by laser Doppler
velocimetry (LDV) following day 2 application of O%, I%, 3%,
and 5% topical minoxidil to bald scalps of four healthy men ateach dose.

No. 2

MlNOXlDlL IN BALDNESS

Acknowledgment
Dorothy J. Marshall provided editorial assistance.

Drug Nameminoxidil: Loniten

References
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Cardiovasc Dis. 1974;27:99-113.
2. Lowenthal DT, Affrime MB. Pharmacology and pharmacokinetics of minoxidil. J Cardiovasc Pharmacol. 1980;
2(suppl):93-106.
3. Cottlieb TB, Thomas RC, Chidsey CA. Pharmacokinetic studiesof minoxidil. Clin Pharmacol Ther. 1972;13:436-441.
4. Thomas RC, Hsi RSP, Harpootlian H, et al. Metabolism ofminoxidil, a new hypotensive agent. I. Absorption, distribution, and excretion following administration to rats, dogs,
and monkeys. J Pharm Sci. 1975;64:1360-1366.
5. Thomas RC, Harpootlian H. Metabolism of minoxidil, a new
hypotensive agent. 11. Biotransformation following oral administration to rats, dogs, and monkeys. J Pharm Sci.
1975;64:1366-1371.
6. Seidman M, Westfried M, Maxey R, et al. Reversal of male
Dattern baldness bv minoxidil: a case reDort. Cutis.
1981;28:551-553.
7. Earhart RN, Ball J, Nuss DD, et al. Minoxidil induced hypertrichosis: treatment with calcium thioglycolate depilatory.
South Med 1. 1977;70442-445.
8. Zappacosta AR. Reversal of baldness in patient receiving
minoxidil for hypertension. N Engl J Med. 1980;303:14801481.
9. Ryan JR, Jain AK, McMahon FC. Minoxidil treatment of severe
hypertension. Curr Ther Res. 1975;17:55-56.

Novak et a/.

87

10. Weiss VC, West DP, Mueller CE. Topical minoxidil in alopecia
areata. J Am Acad Dermatol. 1981;5:224-226.
11. Fenton DA, Wilkinson ID. Topical minoxidil in the treatmentof alopecia areata. Br Med J. 1983;2871015-1017.
12. Headington IT, Novak E. Clinical and histologic studies ofmale pattern baldness treated with topical minoxidil. Curr
Ther Res. 1984;36:1098-1106.
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14. Burton JL, Marshall A. Hypertrichosis due to minoxidil. Br J
Dermatol. 1979;101:593-595.
15. Ressmann AC, Butterworth T. Localized acquired hypertrichosis.
AMA Arch Dermatol Syphilol. 1952;65:458-463.
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Scientific Publications, 1972:1580.
17. Humphrey SJ, Wilson E, Zins GR. Whole body tissue bloodflow in conscious dogs treated with minoxidil (abstract.)
Fed Proc. 1974;33:583.
18. Holloway CA Jr, Watkins DW. Laser doppler measurement of
cutaneous blood flow. J Invest Dermatol. 1977;69306309.
19. Watkins D, Holloway GA Jr. An instrument to measure cutaneous blood flow using the Doppler shift of laser light.
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cutaneous blood flow in human balding scalps: pharmacodynamics measured by laser Doppler velocimetry andphotopulse plethysmography. J Invest Dermatol. (in press)
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Dermatol Allergy. 1983;6:42.

Hay Fever Can Be Dangerous

During the two-week period of July 22 to August 8, 1982, five people experienced
anaphylactic reactions after sustaining skin-abrasion injuries while riding on an Alpine Slide in
Vermont. The slide is an amusement ride that consists of a free-running sled that glides down
a mountainside on an asbestos-cement track. A case-control study was initiated and included
companions of the index cases, noncompanions with abrasion injuries, and six employees who
had also had recent abrasion injuries from the slide. Risk factors that were significantly
associated with the development of anaphylaxis included abrasions, a personal or family historyof allergic complaints, and a history of symptoms of allergic rhinoconjunctivitis at the time of
the abrasion injury. A large number of grass-pollen grains and mold spores were identified at
the site of the slide, and all four index cases who had skin tests with grass pollens had positive
reactions. A review of past records on the index slide and 27 similar amusement slides in the
United States revealed 24 additional cases of anaphylactic reactions, 22 of which followed skinabrasions occurring predominantly in late June to early August-the grass-pollination season in
the mountains. The evidence, although not conclusive, is consistent with the hypothesis that
this syndrome represents systemic anaphylaxis caused by pollen grains introduced into persons
who are allergic to grass through skin abrasions sustained while riding the amusement slides.Spitalny KC, Farnharn /€, Witherell LE, et al. Alpine slide anaphylaxis. N Engl/ Med. 1984;3 10: 1034.