Androgenetic alopecia: Treatment results with topical minoxidil

Androgenetic alopecia: Treatment results with topical minoxidil

Androgenetic alopecia: Treatment results with topical minoxidil Janet L. Roberts, M.D. Portland, OR A double-blind 12-month trial was conducted to eva...

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Androgenetic alopecia: Treatment results with topical minoxidil Janet L. Roberts, M.D. Portland, OR A double-blind 12-month trial was conducted to evaluate the safety and efficacy of topical minoxidil in patients with androgenetic alopecia. During the first 4 months of the study, patients applied a topical solution containing either 2% minoxidil, 3% minoxidil, or placebo to their scalps twice daily. At the end of the fourth month, patients taking placebo were crossed over to treatment with 3% minoxidil solution. Of 60 patients emolled in the study, 43 were evaluable at month 12. Hairs were counted in a I-inch target area and classified as vellus, indeterminate, and terminal; the latter two classifications were combined as nonvellus hairs for further statistical analysis. All three groups had significant increases in total, nonvellus, and terminal hair counts between baseline and month 4 and between month 4 and month 12. At month 4 the average total hair counts increased from a baseline mean of 158.2 to 270.2 in the 2% minoxidil group, from 156.6 to 287.0 in the 3% minoxidil group, and from 162.6 to 246.9 in the placebo group. At month 12 the means were 415.6,448.5, and 471.1 in the 2% minoxidil, 3% minoxidil, and placebo-3% minoxidil crossover subjects, respectively. The increases from month 4 to month 12 were highly significant for each group (p = 0.0001). Average increases in nonvellus hair counts between months 4 and 12 were 216, 181, and 264 in the 2% minoxidil, 3% minoxidil, and placebo-to-3% minoxidil crossover groups, respectively, all highly significant differences from zero (p = 0.0001). The increases in nonvellus and total hair counts primarily reflect increases in terminal hairs. A decrease from baseline in the diameter of the balding area was noted in 84.6% of 39 patients whose diameters were measured at month 12. Side effects possibly related to minoxidil, consisting of localized, minimal scalp irritation, occurred in two subjects. Topical minoxidil, either in a 2% or 3% solution, thus appears to be a safe and effective therapy for androgenetic alopecia. (J AM ACAD DERMATOL 1987;16:705-10.)

Minoxidil, a piperidinopyrimidine derivative, is a potent peripheral vasodilator. Recent trials of topical minoxidil have confirmed its ability to stimulate hair regrowth in androgenetic alopecia, as well as in some patients with alopecia areata. I' 3 The present study was initiated to determine the safety and efficacy of topical minoxidil in treating

patients with progressive androgenetic alopecia. During the first 4 months of this 12-month study a 2% minoxidil solution was compared with a 3% solution and with placebo; from months 5 through 12 all patients receiving placebo were crossed over to the 3% minoxidil treatment group. MATERIAL AND METHODS Study design

From the Department of DennatoJogy, Oregon Health Services University. Reprint requests to; Dr. Janet L. Roberts, Oregon Health Services University, 3181 SW Sam Jackson Park Rd., Portland, OR 97210.

Patients were randomized to 4 months of treatment with either 2% or 3% topical minoxidil or placebo. The subjects themselves administered 1.0 ml of the

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Table I. Study population evaluable at 4 months

Table ll. Pretreatment hair loss in patients evaluable at 4 months Treatment group (no. of patients)

Treatment group Minoxidil Characteristic

2%

I

Minoxidil 3%

Placebo

Mean age (yr) 35 36 34 Sex (M/F) 16/1 17/0 18/0 Mean duration of baldness (yr) 11.15 11.65 10.43 Diameter of bald area (cm) 9.93 9.84 9.71

Degree

2%

3 3V 4 5 5 Anterior

0

6 assigned solution in the morning and again in the evening, after approximately 12 hours. The active mixture consisted of vehicle (propylene glycol, 95% alcohol, and water) and sufficient minoxidil to make either a 2% or 3% solution; placebo consisted of vehicle only. Clinical visits were scheduled at 2 weeks and again 1 month after the initial treatment and thereafter on a monthly basis for I year. Hair counts were performed at baseline and at each clinical visit, with an individual template used for each patient. A I-inch diameter circle on the template was centered over the posterior vertex and hairs within the circle were counted with the aid of magnification and bright illumination. After 4 months patients receiving placebo were crossed over to treatment with the 3% minoxidil solution. Minoxidil serum levels were monitored at week 2 and at 4 and 12 months. Additional samples were drawn if an extra visit was necessary. Info~ation collected at baseline included the subject's age, sex, height, weight, and race. The initial state of baldness was assessed according to its duration and pattern, diameter of the bald area, and areas of apparent thinning. The condition of the area of the scalp to be treated was examined for erythema, dryness or scaling, stinging or burning, folliculitis, and scarring. A complete medical history was taken and a physical examination performed before starting the trial; use of concomitant medications and any significant signs or symptoms were recorded.

Patient characteristics Of the 60 subjects with androgenetic alopecia enrolled in the study, 52 completed 4 months and 43 thl' full 12 months of the study. Seventeen subjects were de clared nonevaluable during the study because ofprotoco violations, noncompliance, or early termination. One

6 4 5 2 0

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3%

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1 2

Placebo

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patient discontinued treatment after suffering a cerebral hemorrhage, which was not related to minoxidil use. All but six of the subjects were men. Five of the women were determined to have female pattern baldness and were dropped from the study; the sixth woman was evaluated as having male pattem baldness and remained in the trial. Patients ranged in age from 18 to 49 years and were not statistically different in height and weight. There were no differences between treatment groups in the duration of baldness, which ranged from 15 months to 23 years with an overall average of 11.1 years (Table I). The majority of subjects (91.7%) had diameters of baldness between 5 and 15 cm (mean 9.8 cm). When apparent thinning was evaluated, a total of 93.3% of patients had a receding hairline whereas 90% had temporal thinning and all but one patient had generalized thinning. I Degrees of hair loss in patients evaluable at month 4 are listed by treatment group in Table II. Before treatment, three patients (two in the 3% minoxidil treatment group and one in the placebo group) had diffuse mild erythema of the scalp with scaling. Another patient in the 3% minoxidil group had mild pretreatment stinging and burning of the scalp. Except for a genitourinary abnormality in one patient, no other significant clinical findings were detected during pretreatment physical and laboratory evaluations. The most commonly listed concomitant medications were vitamins, minerals, and dietary supplements used for health maintenance.

Efficacy variables The primary evaluation of efficacy included hair counts and subjective assessments of hair growth. Hair

Volume 16 Number 3, Part 2 March 1987

types were classified as tenninal, indetenninate, or velIus. To obtain as much infonnation as possible about the effects of the experimental treatment on hair growth, these three classifications were further combined into a total hair count and a nonvellus hair count. Total hair count was the aggregate of tenninal, indeterminate, and vellus hair. Nonvellus hair count was derived from combining terminal and indetenninate hair counts. The rate of change of hair counts over time was calculated for each patient from baseline to month 4, from months 4 to 8, and from months 8 to 12. The change in diameter of the balding area from baseline to 12 months was recorded for the 39 subjects who completed the study. Subjective variables included physician and patient evaluation of hair growth and patient satisfaction, rated on a visual analog scale. Patients were asked to evaluate hair growth according to the following categories: o = no visible growth; 1, 2, and 3 = minimal, moderate, and dense new hair growth, respectively.

Safety Safety data, evaluated at every clinical visit, included vital signs, pitting edema, the presence or absence of cardiac arrhythmias, pericardial friction rubs, and pulmonary rales. At baseline and at months 4 and 12 an electrocardiogram, echocardiogram, chest roentgenogram, serum chemistry, urinalysis, and complete blood count were performed. Any adverse effect, reported by either the patient or investigator, was recorded.

Statistical analysis Continuous and categoric variables were collected; the statistical analysis performed depended on the nature of the response. Comparisons between groups were made only for the first 4 months of the study. After the placebo group was crossed over to active treatment with the 3% minoxidil solution (months 5 to 12), analysis was restricted to within-group comparisons. Analysis of variance techniques were used to evaluate continuous measures for treatment group differences. Paired t tests were used to address within-group comparisons of continuous variables. The X2 test for homogeneity was used for analysis of categoric variables. When the response distribution was too sparse, response categories were reduced by pooling. Multiple between-group comparisons for contingency tables with only two response categories were made by Fisher's exact test. McNemar's test was used to examine changes in patients' responses between time points.

Topical minoxidil for androgenetic alopecia 707

A P value ~0.05 was considered statistically significant; a p value >0.05 but <0.10 was considered marginally significant. Data were analyzed by the Statistical Analysis System, a data management and statistical software package. RESULTS

Fifty-two subjects were evaluable at 4 months, 17 in each of the active treatment groups and 18 in the placebo group. Month 12 evaluable subjects numbered 14 each in the 2% and 3% minoxidil groups and 15 in the placebo-to-3% minoxidil crossover group, for a total of 43. Efficacy All three treatment groups had a significant increase in total, nonvellus, and terminal hair counts between baseline and'month 4 and again between month 4 and month 12. An increase in the total hair count during the course of the study was observed in all three treatment groups (Fig. 1). The highest rate of growth between baseline and month 4 was in the 3% minoxidil treatment group, followed by the 2% treatment group and placebo, although differences were not statistically significant. Between months 4 and 8 the placebo group that was switched to the 3% minoxidil treatment had a sharp increase in overall hair count. The average total hair count increases from month 4 to month 12 for the 2% minoxidil group (185 hairs), the 3% minoxidil group (151 hairs), and the placebo-crossover group (226 hairs) were all significantly different from zero (p = 0.0001). An increase in nonvellus hair count was seen in all three groups during the course of the study. As with the total hair count, the highest growth rate between baseline and month 4 was in the 3% minoxidil-treated patients, followed by the 2% minoxidil and the placebo groups. Between months 4 and 8 the rate of nonvellus hair growth of the 2% and 3% treatment groups remained the same whereas the placebo-to-3% minoxidil crossover group had sharp increases in the growth rate of nonvellus hair. Between months 4 and 12 the 2%, 3%, and placebo-crossover groups had average increases of 216, 181, and 264 nonvellus hairs, re-

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Journal of the American Academy of Dermatology

Roberts

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spectively. These increases were significantly different from zero for each group (p == 0.0001). The patterns of the terminal hair count means over time were analogous to the nonvellus hair count means. Because only a very small number of indeterminate hairs were present in the I-inch target area, the nonvellus hair count consisted primarily of terrninal hairs, and the average increases quoted for both are the same. In addition, vellus hairs originally increased in number but were lower than baseline values in all treatment groups by month 12 (average decreases of 31, 30, and 38 vellus hairs for the 2% minoxidil, 3% minoxidil, and placebo-to-3% minoxidil crossover groups, respectively, were significantly different from zero: p == 0.010, p == 0.011, and p = 0.008, respectively). Hence the increase in total hair counts reflects increases in terminal hair counts for all groups. The average increases in terminal hairs between baseline and month 4 of 99, 120, and 66 hairs in the 2% minoxidil, 3% minoxidil, and placebo groups, respectively, were all highly significantly different from zero (p == 0.0001 for the minoxidil groups; p == 0.004 for placebo subjects) (Fig. 2). Additionally, highly significant increases in terminal hair counts (p == 0.0001) were found from

month 4 to the end of the study for all three groups. Mean increases were 216, 181, and 264 for the 2% minoxidil, 3% minoxidil, and placebo-to-3% minoxidil crossover groups, respectively. According to the investigator's visual estimates of hair growth by month 4, 57.7% of patients had some hair growth, with 36.5% having growth that was evaluated as nonvellus. By month 12, 48.8% of patients rated their satisfaction as between 8 and lOon a visual analog scale of 0 to 10, with 10 assigned the value of very satisfied. At the conclusion of the study the bald area on 39 patients was remeasured and 84.6% of those patients showed a decrease in diameter. The mean diameter of the balding area over the vertex decreased from 9 cm at baseline to 7 em at month 12 in the 2% minoxidil group, from 10 em to 7 em in the 3% minoxidil group, and from 9 em to 7 cm in the placebo-to-3% minoxidil crossover group. The decrease was statistically significant in all groups (p < 0.004). Minoxidil blood levels Serum levels of minoxidil were measured at the prescribed intervals and whenever a patient required an extra medical visit. At week 2, serum

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Number 3, Part 2 March 1987

Topical minoxidil for androgenetic alopecia 709

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levels ~0.8 ng/ml were recorded for 58.8% of the 2% minoxidil group, 25% of the 3% minoxidil group, and 94.4% of those receiving placebo. At month 4, 76% of the patients in both active treatment groups and 100% in the placebo group had serum levels <0.8 ng/m!. At month 12, 66.7% of patients sampled had mean levels ~0.8 ng/ml. One patient had a level of 30 ng/ml, an inexplicable finding that could be the result of contamination or other errror.

minoxidil solution. No other variations from baseline were observed in vital signs. Two minor electrocardiographic abnormalities were noted during the study period and one pericardial effusion was found on echocardiograrn. Results of clinical evaluation and repeat studies of these patients were normal. The abnormalities, although unexplained, were not thought to be related to minoxidil use.

Side effects

Results of the present trial indicate that topical minoxidil is effective in stimulating hair growth in patients with androgenetic alopecia. In a randomized double-blind trial of 56 patients with hereditary male pattern baldness treated twice daily with 2% or 3% topical minoxidil solution, De Villez l found cosmetically acceptable hair growth in 32% of patients. In the De Villez study the number of indeterminate hairs present at the onset of treatment was the single best indicator of whether the patient was likely to regrow hair while using topical minoxidil. Subjects with more than 100 indeterminate hairs in a 2.5 cm diameter circle in the center of the bald area had the best clinical response. Smaller balding area (diameter < 10 em) and shorter duration of baldness « 10 years) also

Two adverse reactions were considered possibly related to treatment: a sensation described as burning scalp in one patient in the 2% minoxidil treatment group at month 4 and a pruritic scalp in another patient. No clinically significant changes were observed in any laboratory tests, including serum chemistries, urinalyses, and complete blood counts. At month 4, average decreases in systolic blood pressure of 3.6 mm Hg, 4.2 nun Hg, and 4.9 mm Hg were seen for the 3% and 2% treatment groups and the placebo group, respectively. Diastolic blood pressure decreased by 5.2 and 3.8 mm Hg in the placebo and 2% treatment groups, respectively, and by 1.5 mm Hg in those using the 3%

DISCUSSION

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Roberts

seemed to correlate with the ability to regrow cosmetically acceptable hair. No systemic side effects developed from the topical treatment. In another recently published double-blind controlled trial of 126 men with early male pattern baldness,2 treatment with 2% or 3% solutions of topical minoxidil for 4 months resulted in a significant increase in terminal hair growth when compared with placebo. After 4 months the patients taking placebo were crossed over to topical minoxidil and subsequently showed a significant increase in the number of terminal hairs. No significant physical or laboratory changes were attributed to topical minoxidil. Side effects were minimal, consisting oflocal dryness, irritation, or pruritus in the area of drug application in five out of 126 patients; one of the five was receiving placebo. In this current series of patients with androgenetic alopecia, topical applications of rninoxidil were effective in producing increased hair growth. At the end of the 12-month evaluation, when all 43 subjects were receiving active treatment, total hair counts increased from a baseline mean of 159.1 to 445.9 in the 2% treatment group, from 153.6 to 454.4 in the 3% minoxidil patients, and from 162.9 to 471.3 in the placebo-crossover subjects. The increase in the terminal and total hair counts in the placebo group at month 4 may have been the result of the stimulatory effect of the vehicle solution or to increased circulation during massage of the scalp while applying the solution.

Journal of the American Academy of Dermatology

Increased growth of terminal, total, and vellus hair was observed on a month-to-month basis as the study progressed. All three study groups had an initial increase in vellus hair followed by a decrease to baseline (in the placebo-crossover group) or below baseline (in patients using the 2% or 3% minoxidil solution for 12 months). This appeared to be the result of vellus hairs developing into terminal hairs. A cessation of hair loss was also observed during treatment with topical minoxidil. No significant physical or laboratory changes were attributed to topical minoxidil. Side effects were localized and consisted of minimal scalp irritation. In conclusion, treatment with 2% or 3% topical minoxidil solution appears safe and effective in producing substantial hair regrowth in patients with androgenetic alopecia. Long-term therapeutic trials currently in progress will determine whether the hair growth is sustained, or even increased, with continued therapy. REFERENCES I. De Villez RL. Topical minoxidil therapy in hereditary androgenetic alopecia. Arch DermatoI1985;121:197-202. 2. Olsen EA, Weiner MS, Delong ER. Pinnell SR. Topical minoxidil in early male pattern baldness. JAM ACAD DERMATOL 1985;13:185-92. 3. Weiss ve, West DP, Fu TS, et al. Alopecia areata treated with topical minoxidil. Arch Dermatol 1984;120:457-63.