- Email: [email protected]
Topical minoxidil for hair regrowth
Topical minoxidil for hair regrowth Evelyn E. Vanderveen, M.D., Charles N. Ellis, M.D., Sewon Kang, M . P . H . , Patrice Case, M.D., John T. Headington, M.D., John J. Voorhees, M.D., and Neil A. Swanson, M.D. A n n Arbor, M I Minoxidil, a potent peripheral vasodi!ator used orally for refractory hypertension, has produced hypertrichosis. To determine the efficacy and safety of 1% or 5% topical minoxidil for the stimulation of scalp hair regrowth, we studied fifteen normotensive patients, five with androgenic alopecia and ten with alopecia areata diagnosed clinically and by biopsy, for 12 months. Three of five patients with androgenic alopecia using 5% minoxidil for 12 months noted hair regrowth, ranging from minimally observable hair to an appreciable restoration of larger, pigmented, terminal hair in one patient. Among the patients with androgenic alopecia, regrowth response corresponded to the serum minoxidil blood levels. None of the patients with alopecia areat a receiving either [% or 5% min~xtdil noted hat~ regrowth despite comparable minoxidil blood levels. Improved local absorption of topical minoxidil solution may promote hair regrowth in androgenic alopecia. (J AN ACAD D~RMATOL11:416-421, 1984.)
Minoxidil ( 2 , 4 - diamino- 6- piperidinopyrimi dine-3-oxide; Loniten) is a potent peripheral vasodilator used orally for refractory hypertension. Systemic minoxidil has caused hypertrichosis in a high percentage o f male and female patients, ranging from 30% to 100% in different reports. 2,a'* Hair growth has been noted on the temples and sideburn areas, between the eyebrows, and on the back, arms, legs, and scalp. Although the hair growth induced in hypertensive patients has generally been undesirable, oral minoxidil has re-
Table I. Androgenic alopecia treated for 12 months with minoxidil
From the Clinical Pharmacology Unit, Department of Dermatology, University of Michigan Medical School, and the Dermatology Service, Ann Arbor Veterans Administration Medical Center, Presented in part at the National Clinical Dermatology Conference, Chicago, June 25, 1983. Accepted for publication Feb. 8, 1984. Reprint requests to: Dr. Evelyn E. Vanderveen, Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109-00 t0/313-764-5140. *Novak E, Chapman KP: Personal communication, Upjohn Pharmaceutical Co,, Kalamazoo, MI.
versed androgenic alopecia. 4''~ To our knowledge, however, there have been no reports that the use of oral minoxidil has resulted in improvement in patients with alopecia areata. Because of the unwanted hypertrichosis and other side effects (including tachycardia and sodium and fluid retention) induced by oral minoxidil, the local application of a topical preparation of minoxidil for hair regeneration is being investi-
416
Response
Regrowth Good Minimal No regrowth
Case No.
Dose (%)
Duration hair loss (yr)
1 2 3 4 5
5 5 5 1 1
5 8 30 5 10
Response time (wk)
8 4 20 ---
Volume l 1 Number 3 September, 1984
Fig. 1. A. Pretreatment appearance of patient with early-onset androgenic alopecia. Bitemporal recession is present. B, Appem'ance after 12 months of topical 5% minoxidil use. gated. We have examined the efficacy and safety o f topical minoxidil for the stimulation of scalp hair growth in patients with either androgenic alopecia or alopecia areata. In this article we will show that (1) topical minoxidil in a 1% and 5% concentration was well tolerated locally and systemically, (2) a modest hair growth response was clinically evident in early androgenic alopecia with 5% topical minoxidil, (3) the hair growth response in androgenic alopecia correlated with the blood minoxidil levels, and (4) topical minoxidil in a 1% and 5% concentration was not effective in alopecia areata. METHODS
Twenty-four normotensive patients from 18 to 50 years of age entered the study. Nine patients had androgenic alopecia and fifteen patients had alopecia
Minoxidil for hair regrowth
417
Fig. 2. Pretreatment appearance of patient shown in Fig. 1. areata. The diagnosis was made clinically and by scalp biopsy. No patient had received therapy for alopecia for 1 month prior to beginning our protocol. The study was conducted over a 12-month period. Patients received either 1% or 5% topical minoxidil or the vehicle only, as supplied by Upjohn Pharmaceutical Co. (Kalamazoo, MI). The vehicle consisted of 20% distilled water, 50% alcohol, and 30% propylene glycol. For the first 6 months the solutions were administered in a double-blind fashion. After 6 months, patients previously using only the vehicle were offered 5% minoxidil solution for an additional 6 months. The solution was applied in the morning and evening with a filtered applicator top supplied by Upjohn; patients covered the treatment sites with petrolatum after the evening application. We evaluated patients' blood pressures (1) monthly by obtaining sphygmomanometer pressures and (2) every 3 months by measuring the systolic, diastolic, and mean blood pressure levels at 5-minute intervals for 30 minutes with a Roche ultrasound sphygmoma-
418
Journal of the American Academy of Dermatology
Vanderveen et al
Table II. Alopecia areata Disease duration
(%)
Previous
Or)
treatment*
1 2 3 4 5
1 5 5 1 5
2.0 1.5 ! 6.0 4.0 1.5
S-1,F-3 F-3 S- 1 S-1 S-1,3
6 7 8 9 10
5 5 5 5 5
10.0 6.0 20.0 1.0 14.0
F-1,2,3,4 F-2 S-1 S-1 S-1,S-4
11 12
---
10.0 19.0
S- 1 F-3
Dose Treatment response
Minoxidil, 12 mo Regrowth (vellus only) No regrowth Vehicle, 6 mo, followed by minoxidil, 6 mo No regrowth
Vehicle only, 6 mo Regrowth (complete) No regmwth
Case No.
I
....
Comments
Alopecia Alopecia Alopecia Alopecia Alopecia
totalis totalis areata'~ areata universalis
Alopecia universalis Alopecia universalis Alopecia universalis Alopecia totalis Diffuse alopecia areata Alopecia areatat Alopecia areata
F: Failure; S: success. *h Steroid injections, 2: dinitrochlorobenzene (DNCB); 3: squaric acid dibutylester (SADBE); 4: psoralen and UVA phototherapy (PUVA) tAlopecia totalis for the 6 months prior to entry into the study.
nometer. On a monthly basis we monitored pulse, weight, and local skin tolerance, specifically skin irritation, erythema, folliculitis, and scaling. In addition, we obtained, every 1 to 2 months, a complete blood count; selected serum chemistry studies (electrolytes, blood urea nitrogen, creatinine, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase); serum thyroxine, Ta uptake, and free thyroxine index; serum testosterone and minoxidil levels; and a urinalysis. An electrocardiogram was obtained every 3 months. We evaluated hair growth on the basis of clinical changes from pretreatment appearance and scalp biopsies at pretherapy and after 3, 6, and 12 months of treatment. RESULTS Fifteen patients completed 1 year in the study. The nine patients who did not finish the study either elected to stop after the 6-month blind trial or left the study later because of a failure of hair growth response. Over the 12-month period there were no statistically significant changes in blood pressure. Furthermore, there were no significant changes in the pulse, weight, local skin condition, complete blood count, serum chemistry studies, serum
testosterone levels, thyroid function studies, urinalysis, or electrocardiograms of any of the patients.
Androgenic alopecia Five of the patients with androgenic alopecia completed the 12-month study. Their characteristics and results are indicated in Table I. These patients had a history of evident hair loss ranging from 5 to 30 years before entering this study. Three patients using 5% minoxidil solution for 12 months noted some hair regrowth. Two of these three patients grew minimally detectable small pigmented terminal hairs in the scalp areas that previously had only vellus hairs. Hair regr0wth occurred after 4 and 20 weeks, respectively. The third patient had an appreciable restoration of larger, thicker pigmented terminal hair. This patient first noted an apparent increase in the density of the hair on the anterior scalp after 8 weeks of topical minoxidil. This response was progressive and sustained throughout the study (Fig. 1). He also noted a small but perceptible increase in hair growth along the temporal margin, with some filling in of the temporal angle (Figs. 2 and 3). A
Volume l 1 Number 3 September, 1984
Minoxidil for hair regrowth 419
ANDROGENIC
ALOPECIA
,6,=1% @ =5%
¢3 0
o,
[]
rn Z m
4
_.1
1.4. 0 .-J LU
>
I.l.I ._1 Z
=_.
LI.I
I
NO I RESPONSE
i MINIMALI RESPONSE
I
GOOD ( RESPONSE
HAIR GROWTH Fig. 4. Mean minoxidil blood levels and corresponding
Fig. 3. Appearance, after 12 months, of patient shown in Figs. 1 and 2. Note modest but perceptible increase in hair growth along temporal margins. fine scaling o f the skin was present over the anterior scalp where minoxidil was applied, but this was of little significance to the patient. The patient has continued using the 5% topical minoxidil solution, and at 18 months his hair growth has been sustained but there has been little additional scalp hair regrowth. There has also been no documentable hair growth at locations distant from the treatment site. The scalp biopsies from the patients with androgenic alopecia who noted regrowth revealed follicular hypertrophy as measured by an increased mean hair shaft diameter. This finding is consistent with the results of previous minoxidil trials .6 Two patients using 1% topical minoxidil for the full 12 months noted no regrowth. One additional patient using only the vehicle for 6 months noted n o regrowth, as expected.
hair growth response in five patients with androgenic alopecia who completed the 12-month study.
Alopecia areata Five patients with alopecia areata received topical minoxidil for a full 12 months. Their characteristics and results are indicated in Table II. Three of the patients noted the growth of barely perceptible vellus hairs over the entire scalp after 12 months. We considered this regrowth response to be only minimal. Two of these three patients were determined to have used the 5% solution, and one patient had received the 1% solution. The patients' disease duration ranged from 1.5 to 16 years; all had alopecia totalis. Two other patients with alopecia areata or universalis using the 1% and 5% solutions, respectively, noted no regrowth after 12 months. In these two patients the duration of disease was 4 years or less. Thus both the duration and severity of disease failed as predictors of the minimal response to 12 months of therapy with topical minoxidil.
Journal of the American Academy of Dermatology
Vanderveen et al
420
DISCUSSION
ALOPECIA AREATA A =1%
5
"
0
o,
0
=5%
i,,n
z_
4
._1 x~"
o
LL
o
2
_.1 i,i _1 z ILl
=E
(
,t
I
I
I MINIMAL I
RESPONSE
RESPONSE
NO
HAIR GROWTH
Fig. 5. Mean minoxidil blood levels and corresponding hair growth response in five patients with alopecia areata who completed the 12-month study. Seven patients with alopecia areata originally received only the vehicle (Table II). Six patients had no benefit. The seventh patient, who had alopecia totalis, had complete hair regrowth while receiving only the vehicle; the spontaneous regrowth rate was 14% during placebo administration. O f the patients who initially received the placebo, five had subsequently used the 5% solution for 12 months at the time this report was written. All had alopecia totalis or universalis; the duration of their disease ranged from 1 to 20 years. Although their initial characteristics were similar to those of the patients who achieved a velluslike regrowth, none have had cosmetically valuable regrowth. Again, we were unable to document hair growth at locations distant from the treatment site. Scalp biopsies from the patients with alopecia areata revealed only persistent peribulbar inflammation after treatment with minoxidil. This finding represented no change from pretreatment biopsies. Incomplete telogen-to-anagen conversion occurred in two treated subjects.
The mechanism of action of minoxidil in stimulating hair growth is not known. Since no endocrine abnormalities have been found to explain this abnormal growth, it is considered to be hypertrichosis without virilism.* Burton and Marshall 2 have suggested that minoxidil, a vasodilator, may act by increasing blood flow to the . hair follicles. Ebling and Rook 7 noted in 1979 that prolonged cutaneous hyperernia can induce increased hair growth. The clinical response in androgenic alopecia may be associated with the local absorption of minoxidil, as reflected in the minoxidil blood level (Fig. 4). Two patients with androgenic alopecia using 1% minoxidil had no detectable minoxidil blood level and noted no regrow~h. The three patients with regrowth used the 5% solution and had mean blood levels of 0.5, 2. O, and 4.5 ng/ml 2 hours after topical application. A level of 4 ng/ml is approximately 6% of the mean minoxidil blood level present 2 hours after oral ingestion of a 5 nag pill.* (The lowest dose used for the treatment of hypertension is 5 mg/day.) The patients with androgenic alopecia who had the highest minoxidil blood levels also had the best clinical responses. Since the medication was applied only on the scalp, the minoxidil levels obtained in the blood must be due to local absorption, which may be important in determining the response in androgenic alopecia. Among the patients with alopecia areata, the relationship between the minoxidil blood levels and the clinical response was not as evident. As shown in Fig. 5, four patients had blood levels less than 2 rig/m1; two had no response and two had velluslike growth. Only one patient had a minoxidil blood level greater than 4 ng/ml but had a minimal clinical response with only barely perceptible velluslike growth. In this study we were unable to achieve results comparable to those of Weiss et als and of Fenton and Wilkinson, 9 who noted encouraging results with 1% topical minoxidil in alopecia areata. One apparent difference between our study and that of Weiss et al is in the method of application of *Novak E, ChapmanKP: Personalcommunication.UpjohnPharmaceutical Co,, Kalamazoo, MI,
Volume 11 Number 3 September, 1984
minoxidil. They reported application with a glass rod to the scalp, whereas in our study the application of minoxidil involved a filtered applicator top supplied by the manufacturer. Blood levels of minoxidil were not reported by the other investigators; therefore we have no evidence with regard to differences in drug delivery between our studies and the studies Cited. During the double-blind period, when patients were using the 1%, 5%, or vehicle solutions only, approximately 40% of the patients with alopecia areata in our study did grow hair. Regrowth consisted of isolated patches of terminal hairs and was consistent with the normal hair growth pattern for these patients. Early in the study we believed that the hair growth could be due to minoxidil and were at first encouraged by this response. However, the patient who noted the best regrowth at 6 ~haonths was found to be using the vehicle only. The other patients who regrew patchy areas did not sustain this growth and, after 12 months, were essentially unchanged from their pretreatment appearance. None of the patients with alopecia areata noted any appreciable, sustained growth response with minoxidil. It is important, in our opinion, for investigators to cautiously interpret apparent regrowth in alopecia areata to avoid being misled by spontaneous patchy regrowth. No changes were detected in blood pressure throughout the year-long trial. This finding was predictable because oral minoxidil administration does not lower the blood pressure in normotensive patients.* Topical treatment was WeU tolerated by ail of our patients.
Minoxidil for hair regrowth 421
We believe that topical minoxidil may have potential for use in the reversal of androgenic alopecia. The efficacy of this drug may be improved bY increas!ng its local absorption, perhaps by using other vehicles or delivery systems. Ongoing studies with larger patient populations will provide more details regarding the effectiveness of topical minoxidil in patients with alopecia and may further explain the role of the serum nainoxidil level during topical minoxidil therapy. REFERENCES 1. Dargie HJ, Dollery CT, Daniel J: Minoxidil in resistant hypertension. Lancet 2:515-518, 1977. 2. Burton JL, Marshall A: Hypertrichosis due to minoxidil. Br J Dermatol 101:593-595, 1979. 3. Javier R, Dumler F, Park JH, et ah Long-term treatment with minoxidil in patients witll severe renal failure. J Cardiovasc Pharmacol 2(suppl):S149-S155, 1980. 4. Zappacosta AR: Reversal of baldness in patient receiving minoxidil for hypertension. N Engl J Med 303:14801481, 1980. 5. Seidman M, Westfried M, Maxey R, et al: Reversal of male pattern baldness by minoxidil. Cutis 28:551-553, 1981. 6. Headington JT, Novak E: Histological findings in androgenic alopecia treated with topical minoxidil. Br J Dermatol 107($22):20-21, !982. 7. Ebling FJ, Rook A: Hair, in Rook AJ, Wilkinson DS, Ebling FJ, editors: Textbook of dermatology, vol. 2, ed. 3. Oxford, 1979, Blackwell Scientific Publications, chap. 55, p. 1757. 8. Weiss VC, West DP, Mueller CE: Topical minoxidil in aloPecia areata. J AM ACAD Dt~RMATOL5:224-226, i981, 9. Fenton DA, Wilkinson JD: A controlled trial of topica~ minoxidil in the treatment of alopecia areata. Br J Dermatol 109($24):36-37, 1983.
*Novak E, Chapman KP: Personalcommunication.UpjohnPharmaceutical Co., Kalamazoo, MI.
BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes of the JOURNALOFTHEAMERICANACADEMYOFDERMATOLOGYare availableto subscribers(only)for the 1984 issues from the Publisher at a cost of $53.50 ($65.00 international)for volume !0 (January-June)and volume ll (July-December). Shipping charges are included.Each bound volumecontainsa subjectand authorindex and all advertisingis removed. Copies are shipped within 30 days after publicationof the last issue in the volume. The bindingis durable buckramwith the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. ContactThe C. V. Mosby Company,CirculationDepartment, 11830 Wesfline Industrial Drive, St. Louis, Missouri 63146, USA;phone (800) 325-4177, ext. 351. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular journal subscription.
Minoxidil ( 2 , 4 - diamino- 6- piperidinopyrimi dine-3-oxide; Loniten) is a potent peripheral vasodilator used orally for refractory hypertension. Systemic minoxidil has caused hypertrichosis in a high percentage o f male and female patients, ranging from 30% to 100% in different reports. 2,a'* Hair growth has been noted on the temples and sideburn areas, between the eyebrows, and on the back, arms, legs, and scalp. Although the hair growth induced in hypertensive patients has generally been undesirable, oral minoxidil has re-
Table I. Androgenic alopecia treated for 12 months with minoxidil
From the Clinical Pharmacology Unit, Department of Dermatology, University of Michigan Medical School, and the Dermatology Service, Ann Arbor Veterans Administration Medical Center, Presented in part at the National Clinical Dermatology Conference, Chicago, June 25, 1983. Accepted for publication Feb. 8, 1984. Reprint requests to: Dr. Evelyn E. Vanderveen, Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109-00 t0/313-764-5140. *Novak E, Chapman KP: Personal communication, Upjohn Pharmaceutical Co,, Kalamazoo, MI.
versed androgenic alopecia. 4''~ To our knowledge, however, there have been no reports that the use of oral minoxidil has resulted in improvement in patients with alopecia areata. Because of the unwanted hypertrichosis and other side effects (including tachycardia and sodium and fluid retention) induced by oral minoxidil, the local application of a topical preparation of minoxidil for hair regeneration is being investi-
416
Response
Regrowth Good Minimal No regrowth
Case No.
Dose (%)
Duration hair loss (yr)
1 2 3 4 5
5 5 5 1 1
5 8 30 5 10
Response time (wk)
8 4 20 ---
Volume l 1 Number 3 September, 1984
Fig. 1. A. Pretreatment appearance of patient with early-onset androgenic alopecia. Bitemporal recession is present. B, Appem'ance after 12 months of topical 5% minoxidil use. gated. We have examined the efficacy and safety o f topical minoxidil for the stimulation of scalp hair growth in patients with either androgenic alopecia or alopecia areata. In this article we will show that (1) topical minoxidil in a 1% and 5% concentration was well tolerated locally and systemically, (2) a modest hair growth response was clinically evident in early androgenic alopecia with 5% topical minoxidil, (3) the hair growth response in androgenic alopecia correlated with the blood minoxidil levels, and (4) topical minoxidil in a 1% and 5% concentration was not effective in alopecia areata. METHODS
Twenty-four normotensive patients from 18 to 50 years of age entered the study. Nine patients had androgenic alopecia and fifteen patients had alopecia
Minoxidil for hair regrowth
417
Fig. 2. Pretreatment appearance of patient shown in Fig. 1. areata. The diagnosis was made clinically and by scalp biopsy. No patient had received therapy for alopecia for 1 month prior to beginning our protocol. The study was conducted over a 12-month period. Patients received either 1% or 5% topical minoxidil or the vehicle only, as supplied by Upjohn Pharmaceutical Co. (Kalamazoo, MI). The vehicle consisted of 20% distilled water, 50% alcohol, and 30% propylene glycol. For the first 6 months the solutions were administered in a double-blind fashion. After 6 months, patients previously using only the vehicle were offered 5% minoxidil solution for an additional 6 months. The solution was applied in the morning and evening with a filtered applicator top supplied by Upjohn; patients covered the treatment sites with petrolatum after the evening application. We evaluated patients' blood pressures (1) monthly by obtaining sphygmomanometer pressures and (2) every 3 months by measuring the systolic, diastolic, and mean blood pressure levels at 5-minute intervals for 30 minutes with a Roche ultrasound sphygmoma-
418
Journal of the American Academy of Dermatology
Vanderveen et al
Table II. Alopecia areata Disease duration
(%)
Previous
Or)
treatment*
1 2 3 4 5
1 5 5 1 5
2.0 1.5 ! 6.0 4.0 1.5
S-1,F-3 F-3 S- 1 S-1 S-1,3
6 7 8 9 10
5 5 5 5 5
10.0 6.0 20.0 1.0 14.0
F-1,2,3,4 F-2 S-1 S-1 S-1,S-4
11 12
---
10.0 19.0
S- 1 F-3
Dose Treatment response
Minoxidil, 12 mo Regrowth (vellus only) No regrowth Vehicle, 6 mo, followed by minoxidil, 6 mo No regrowth
Vehicle only, 6 mo Regrowth (complete) No regmwth
Case No.
I
....
Comments
Alopecia Alopecia Alopecia Alopecia Alopecia
totalis totalis areata'~ areata universalis
Alopecia universalis Alopecia universalis Alopecia universalis Alopecia totalis Diffuse alopecia areata Alopecia areatat Alopecia areata
F: Failure; S: success. *h Steroid injections, 2: dinitrochlorobenzene (DNCB); 3: squaric acid dibutylester (SADBE); 4: psoralen and UVA phototherapy (PUVA) tAlopecia totalis for the 6 months prior to entry into the study.
nometer. On a monthly basis we monitored pulse, weight, and local skin tolerance, specifically skin irritation, erythema, folliculitis, and scaling. In addition, we obtained, every 1 to 2 months, a complete blood count; selected serum chemistry studies (electrolytes, blood urea nitrogen, creatinine, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase); serum thyroxine, Ta uptake, and free thyroxine index; serum testosterone and minoxidil levels; and a urinalysis. An electrocardiogram was obtained every 3 months. We evaluated hair growth on the basis of clinical changes from pretreatment appearance and scalp biopsies at pretherapy and after 3, 6, and 12 months of treatment. RESULTS Fifteen patients completed 1 year in the study. The nine patients who did not finish the study either elected to stop after the 6-month blind trial or left the study later because of a failure of hair growth response. Over the 12-month period there were no statistically significant changes in blood pressure. Furthermore, there were no significant changes in the pulse, weight, local skin condition, complete blood count, serum chemistry studies, serum
testosterone levels, thyroid function studies, urinalysis, or electrocardiograms of any of the patients.
Androgenic alopecia Five of the patients with androgenic alopecia completed the 12-month study. Their characteristics and results are indicated in Table I. These patients had a history of evident hair loss ranging from 5 to 30 years before entering this study. Three patients using 5% minoxidil solution for 12 months noted some hair regrowth. Two of these three patients grew minimally detectable small pigmented terminal hairs in the scalp areas that previously had only vellus hairs. Hair regr0wth occurred after 4 and 20 weeks, respectively. The third patient had an appreciable restoration of larger, thicker pigmented terminal hair. This patient first noted an apparent increase in the density of the hair on the anterior scalp after 8 weeks of topical minoxidil. This response was progressive and sustained throughout the study (Fig. 1). He also noted a small but perceptible increase in hair growth along the temporal margin, with some filling in of the temporal angle (Figs. 2 and 3). A
Volume l 1 Number 3 September, 1984
Minoxidil for hair regrowth 419
ANDROGENIC
ALOPECIA
,6,=1% @ =5%
¢3 0
o,
[]
rn Z m
4
_.1
1.4. 0 .-J LU
>
I.l.I ._1 Z
=_.
LI.I
I
NO I RESPONSE
i MINIMALI RESPONSE
I
GOOD ( RESPONSE
HAIR GROWTH Fig. 4. Mean minoxidil blood levels and corresponding
Fig. 3. Appearance, after 12 months, of patient shown in Figs. 1 and 2. Note modest but perceptible increase in hair growth along temporal margins. fine scaling o f the skin was present over the anterior scalp where minoxidil was applied, but this was of little significance to the patient. The patient has continued using the 5% topical minoxidil solution, and at 18 months his hair growth has been sustained but there has been little additional scalp hair regrowth. There has also been no documentable hair growth at locations distant from the treatment site. The scalp biopsies from the patients with androgenic alopecia who noted regrowth revealed follicular hypertrophy as measured by an increased mean hair shaft diameter. This finding is consistent with the results of previous minoxidil trials .6 Two patients using 1% topical minoxidil for the full 12 months noted no regrowth. One additional patient using only the vehicle for 6 months noted n o regrowth, as expected.
hair growth response in five patients with androgenic alopecia who completed the 12-month study.
Alopecia areata Five patients with alopecia areata received topical minoxidil for a full 12 months. Their characteristics and results are indicated in Table II. Three of the patients noted the growth of barely perceptible vellus hairs over the entire scalp after 12 months. We considered this regrowth response to be only minimal. Two of these three patients were determined to have used the 5% solution, and one patient had received the 1% solution. The patients' disease duration ranged from 1.5 to 16 years; all had alopecia totalis. Two other patients with alopecia areata or universalis using the 1% and 5% solutions, respectively, noted no regrowth after 12 months. In these two patients the duration of disease was 4 years or less. Thus both the duration and severity of disease failed as predictors of the minimal response to 12 months of therapy with topical minoxidil.
Journal of the American Academy of Dermatology
Vanderveen et al
420
DISCUSSION
ALOPECIA AREATA A =1%
5
"
0
o,
0
=5%
i,,n
z_
4
._1 x~"
o
LL
o
2
_.1 i,i _1 z ILl
=E
(
,t
I
I
I MINIMAL I
RESPONSE
RESPONSE
NO
HAIR GROWTH
Fig. 5. Mean minoxidil blood levels and corresponding hair growth response in five patients with alopecia areata who completed the 12-month study. Seven patients with alopecia areata originally received only the vehicle (Table II). Six patients had no benefit. The seventh patient, who had alopecia totalis, had complete hair regrowth while receiving only the vehicle; the spontaneous regrowth rate was 14% during placebo administration. O f the patients who initially received the placebo, five had subsequently used the 5% solution for 12 months at the time this report was written. All had alopecia totalis or universalis; the duration of their disease ranged from 1 to 20 years. Although their initial characteristics were similar to those of the patients who achieved a velluslike regrowth, none have had cosmetically valuable regrowth. Again, we were unable to document hair growth at locations distant from the treatment site. Scalp biopsies from the patients with alopecia areata revealed only persistent peribulbar inflammation after treatment with minoxidil. This finding represented no change from pretreatment biopsies. Incomplete telogen-to-anagen conversion occurred in two treated subjects.
The mechanism of action of minoxidil in stimulating hair growth is not known. Since no endocrine abnormalities have been found to explain this abnormal growth, it is considered to be hypertrichosis without virilism.* Burton and Marshall 2 have suggested that minoxidil, a vasodilator, may act by increasing blood flow to the . hair follicles. Ebling and Rook 7 noted in 1979 that prolonged cutaneous hyperernia can induce increased hair growth. The clinical response in androgenic alopecia may be associated with the local absorption of minoxidil, as reflected in the minoxidil blood level (Fig. 4). Two patients with androgenic alopecia using 1% minoxidil had no detectable minoxidil blood level and noted no regrow~h. The three patients with regrowth used the 5% solution and had mean blood levels of 0.5, 2. O, and 4.5 ng/ml 2 hours after topical application. A level of 4 ng/ml is approximately 6% of the mean minoxidil blood level present 2 hours after oral ingestion of a 5 nag pill.* (The lowest dose used for the treatment of hypertension is 5 mg/day.) The patients with androgenic alopecia who had the highest minoxidil blood levels also had the best clinical responses. Since the medication was applied only on the scalp, the minoxidil levels obtained in the blood must be due to local absorption, which may be important in determining the response in androgenic alopecia. Among the patients with alopecia areata, the relationship between the minoxidil blood levels and the clinical response was not as evident. As shown in Fig. 5, four patients had blood levels less than 2 rig/m1; two had no response and two had velluslike growth. Only one patient had a minoxidil blood level greater than 4 ng/ml but had a minimal clinical response with only barely perceptible velluslike growth. In this study we were unable to achieve results comparable to those of Weiss et als and of Fenton and Wilkinson, 9 who noted encouraging results with 1% topical minoxidil in alopecia areata. One apparent difference between our study and that of Weiss et al is in the method of application of *Novak E, ChapmanKP: Personalcommunication.UpjohnPharmaceutical Co,, Kalamazoo, MI,
Volume 11 Number 3 September, 1984
minoxidil. They reported application with a glass rod to the scalp, whereas in our study the application of minoxidil involved a filtered applicator top supplied by the manufacturer. Blood levels of minoxidil were not reported by the other investigators; therefore we have no evidence with regard to differences in drug delivery between our studies and the studies Cited. During the double-blind period, when patients were using the 1%, 5%, or vehicle solutions only, approximately 40% of the patients with alopecia areata in our study did grow hair. Regrowth consisted of isolated patches of terminal hairs and was consistent with the normal hair growth pattern for these patients. Early in the study we believed that the hair growth could be due to minoxidil and were at first encouraged by this response. However, the patient who noted the best regrowth at 6 ~haonths was found to be using the vehicle only. The other patients who regrew patchy areas did not sustain this growth and, after 12 months, were essentially unchanged from their pretreatment appearance. None of the patients with alopecia areata noted any appreciable, sustained growth response with minoxidil. It is important, in our opinion, for investigators to cautiously interpret apparent regrowth in alopecia areata to avoid being misled by spontaneous patchy regrowth. No changes were detected in blood pressure throughout the year-long trial. This finding was predictable because oral minoxidil administration does not lower the blood pressure in normotensive patients.* Topical treatment was WeU tolerated by ail of our patients.
Minoxidil for hair regrowth 421
We believe that topical minoxidil may have potential for use in the reversal of androgenic alopecia. The efficacy of this drug may be improved bY increas!ng its local absorption, perhaps by using other vehicles or delivery systems. Ongoing studies with larger patient populations will provide more details regarding the effectiveness of topical minoxidil in patients with alopecia and may further explain the role of the serum nainoxidil level during topical minoxidil therapy. REFERENCES 1. Dargie HJ, Dollery CT, Daniel J: Minoxidil in resistant hypertension. Lancet 2:515-518, 1977. 2. Burton JL, Marshall A: Hypertrichosis due to minoxidil. Br J Dermatol 101:593-595, 1979. 3. Javier R, Dumler F, Park JH, et ah Long-term treatment with minoxidil in patients witll severe renal failure. J Cardiovasc Pharmacol 2(suppl):S149-S155, 1980. 4. Zappacosta AR: Reversal of baldness in patient receiving minoxidil for hypertension. N Engl J Med 303:14801481, 1980. 5. Seidman M, Westfried M, Maxey R, et al: Reversal of male pattern baldness by minoxidil. Cutis 28:551-553, 1981. 6. Headington JT, Novak E: Histological findings in androgenic alopecia treated with topical minoxidil. Br J Dermatol 107($22):20-21, !982. 7. Ebling FJ, Rook A: Hair, in Rook AJ, Wilkinson DS, Ebling FJ, editors: Textbook of dermatology, vol. 2, ed. 3. Oxford, 1979, Blackwell Scientific Publications, chap. 55, p. 1757. 8. Weiss VC, West DP, Mueller CE: Topical minoxidil in aloPecia areata. J AM ACAD Dt~RMATOL5:224-226, i981, 9. Fenton DA, Wilkinson JD: A controlled trial of topica~ minoxidil in the treatment of alopecia areata. Br J Dermatol 109($24):36-37, 1983.
*Novak E, Chapman KP: Personalcommunication.UpjohnPharmaceutical Co., Kalamazoo, MI.
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