Key Points
Question
Is oral minoxidil effective in treating androgenetic alopecia in men compared with topical minoxidil, 5%?
Findings
In this double-blind, placebo-controlled randomized clinical trial including 90 men with androgenetic alopecia, daily oral minoxidil, 5 mg, was well tolerated and did not demonstrate superiority over topical minoxidil, 5%, in men with androgenetic alopecia after 24 weeks of treatment.
Meaning
Low-dose oral minoxidil (5 mg per day) had similar efficacy to topical minoxidil, 5%, for men with androgenetic alopecia and can be an option for patients who prefer oral therapy or are intolerant to topical treatment.
This randomized clinical trial compares the efficacy, safety, and tolerability of daily oral minoxidil, 5 mg, with twice-daily topical minoxidil, 5%, for 24 weeks in the treatment of male androgenetic alopecia.
Abstract
Importance
There has been increased interest in low-dose oral minoxidil for androgenetic alopecia (AGA) treatment. However, the efficacy of oral minoxidil for male AGA is yet to be evaluated in comparative therapeutic trials.
Objective
To compare the efficacy, safety, and tolerability of daily oral minoxidil, 5 mg, vs twice-daily topical minoxidil, 5%, for 24 weeks in the treatment of male AGA.
Design, Setting, and Participants
This double-blind, placebo-controlled randomized clinical trial was conducted at a single specialized clinic in Brazil. Eligible men with AGA aged 18 to 55 years classified using the Norwood-Hamilton scale as 3V, 4V, or 5V were included and randomized. Data were collected from January to December 2021, and data were analyzed from September 2022 to February 2023.
Interventions
Participants were randomized 1:1 into 2 groups: oral minoxidil, 5 mg, daily and topical placebo solution; or 1 mL of topical minoxidil, 5%, twice daily and oral placebo for 24 weeks.
Main Outcomes and Measures
The primary outcome was change in terminal hair density on the frontal and vertex regions of the scalp. The secondary outcomes were change in total hair density and photographic evaluation.
Results
Among 90 enrolled participants, 68 completed the study; of these, the mean (SD) age was 36.6 (7.8) years. A total of 33 participants were enrolled in the oral minoxidil group and 35 in the topical treatment group. Both groups were homogenous in terms of demographic data and AGA severity. For the frontal area, the mean change from baseline to week 24 between groups was 3.1 hairs per cm2 (95% CI, −18.2 to 21.5; P = .27) for terminal hair density and 2.6 hairs per cm2 (95% CI, −10.3 to 15.8; P = .32) for total hair density. For the vertex area, the mean change from baseline to week 24 was 23.4 hairs per cm2 (95% CI, −0.3 to 43.0; P = .09) for terminal density and 5.5 hairs per cm2 (95% CI, −12.5 to 23.5; P = .32) for total hair density. According to the photographic analysis, oral minoxidil was superior to topical minoxidil on the vertex (24%; 95% CI, 0 to 48; P = .04) but not on the frontal scalp (12%; 95% CI, −12 to 36; P = .24). The most common adverse effects in the oral minoxidil group were hypertrichosis (22 of 45 [49%]) and headache (6 of 45 [14%]).
Conclusions and Relevance
In this study, oral minoxidil, 5 mg, once per day for 24 weeks did not demonstrate superiority over topical minoxidil, 5%, twice per day in men with AGA.
Trial Registration
Brazilian Registry of Clinical Trials Identifier: RBR-252w9r
Introduction
Androgenetic alopecia (AGA) is the main cause of hair loss among men.1 It occurs due to progressive miniaturization of the hair follicles and shortening of the anagen phase.2 AGA causes low self-esteem and negatively affects the quality of life.3
To our knowledge, oral finasteride and topical minoxidil are the only medications approved by the US Food and Drug Administration (FDA) for the treatment of male AGA.4 Although proven to be effective, these medications pose some clinical challenges. Many patients are reluctant to use finasteride due to the possibility of adverse sexual effects.5 Topical minoxidil, on the other hand, can cause changes to hair texture, hair combing problems, and scalp irritation that may lead to low compliance.6
There has been increased interest worldwide in low-dose oral minoxidil, 0.25 to 5 mg, per day as an alternative therapy for AGA.7 It has already been evaluated in retrospective and noncomparative prospective clinical studies, but to our knowledge, there are no comparative therapeutic trials of low-dose oral minoxidil for male AGA.4
This double-blind, placebo-controlled randomized clinical trial aims to compare the efficacy, safety, and tolerability of oral minoxidil, 5 mg, once per day vs topical minoxidil, 5%, twice per day for 24 weeks for male patients with AGA.
Methods
Patients
A total of 90 male patients aged 18 to 55 years consented to enroll in our research conducted at a specialized clinic in Presidente Prudente, Brazil, from January to December 2021. All had AGA classified as 3V, 4V, or 5V using the Norwood-Hamilton scale.8 The diagnosis was established by a board-certified dermatologist (M. A. P.) based on careful clinical and trichoscopic assessment. We excluded patients who underwent treatment for alopecia within the previous 6 months as well as patients with a history of hair transplant, cardiopathy, nephropathy, dermatoses involving the scalp, any clinical conditions causing hair loss, and hypersensitivity to minoxidil. This project was approved by the Ethics Committee of the Faculdade de Medicina de Botucatu, São Paulo State University (UNESP) and registered in the Brazilian Registry of Clinical Trials. All participants provided written informed consent. The trial protocol can be found in Supplement 1, and the statistical analysis plan can be found in Supplement 2. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
Study Design
This was a double-blind, placebo-controlled parallel randomized clinical trial conducted at a single center, with longitudinal follow-up at 24 weeks. After signing the informed consent form, participants were randomized 1:1 into 2 groups: those who received oral minoxidil, 5 mg, once a day plus placebo solution for topical application twice daily and those who received 1 mL of topical minoxidil, 5%, twice daily plus oral placebo once a day (Figure).
Figure. CONSORT Flowchart.
The participants were sequentially allocated, and treatment packages were distributed in brown, opaque, sealed envelopes randomly numbered in blocks generated by a computerized system operated by a researcher not involved in patient evaluation (H. A. M.). Participants, investigators, and the outcome assessors were blinded to treatment groups.
Clinical and demographic data were assessed at inclusion. Before treatment was started, patients underwent manual measurement of blood pressure and heart rate. They were evaluated again only after 24 weeks. Mean arterial pressure was calculated using the formula (systolic arterial pressure + [2 × diastolic arterial pressure])/3.
Standard panoramic photographs were taken of the frontal, vertex, and parietal areas at 45° and 90° at baseline and week 24. Two circular areas measuring 2 cm2 were shaved on the frontal and vertex areas to leave 1 mm–long hair shafts. These areas were tattooed at the 2 points, and standardized trichoscopic pictures were obtained for hair counting at baseline and week 24. White hair was dyed black for better identification. Moreover, patient histories and physical examinations were performed to evaluate edema, tachycardia, palpitation, hair growth in other body parts, and any additional adverse effects during the treatment.
The oral minoxidil group received capsules of minoxidil, 5 mg, plus a placebo solution to apply to the scalp. The topical minoxidil group received a topical minoxidil solution, 5%, plus placebo capsules. The active pharmaceutical ingredients of the oral treatment and the placebos were manufactured by a compounding pharmacy and had the same excipients and similar visual appearance. The placebo solution contained identical vehicles and diluents of the active solution with minoxidil, 5%, and the same physical appearance and sensory perception. The packaging of both active drugs and placebos were identical.
Participants were instructed to ingest the capsule at bedtime and apply 1 mL of the solution with dry hair twice daily (morning and night). They were advised the solution should remain in contact with the scalp for at least 4 hours before the next wash.
The sample size calculation was based on the expectation of an increase of 35 terminal hairs per cm2 in the oral minoxidil group and 12 terminal hairs per cm2 in the topical minoxidil group, a power of 80%, an α of 5%, a 0.7 correlation coefficient between measurements, and up to 30% of expected dropout, resulting in 45 patients for each group at 2 evaluations (baseline and week 24).9
Effectiveness
Primary Outcome
The primary outcome was change in terminal hair density in the target area. Terminal hairs (diameter of 0.06 mm or more) in the target area in the frontal and vertex regions were blindly counted at baseline and week 24. All images were processed at TrichoLab, Hagen, Germany. Automated hair detection was followed by manual correction by 3 independent operators and inspection by qualified analyst.10,11
Secondary Outcomes
Secondary outcomes included change in total hair density in the target area, assessment of standardized clinical photographs, and assessment of adverse effects, blood pressure, and heart rate. All hairs in the target area in the frontal and vertex regions were blindly counted at baseline and 24 weeks using the same methodology described above.10,11 For assessment of standardized clinical photographs, patients were instructed to maintain the same hairstyle, color, length, and haircut throughout the study. Three dermatologists who were blinded to treatment compared the baseline with the week 24 images. They needed to achieve common agreement using a 5-point comparison scale (Global Aesthetic Improvement Scale), ranging from great worsening (−2), slight worsening (−1), no change (0), slight improvement (1), and great improvement (2).12 Assessment of adverse effects, blood pressure, and heart rate was performed at baseline and 24 weeks.
Statistical Analysis
All patients were analyzed using the intention-to-treat principle at 24 weeks regardless of treatment adherence. Patients who discontinued treatment or were missing data (ie, dropouts) were not included in the final efficacy analysis.13
To represent categorical variables, we used counts and frequencies. Additionally, we calculated 95% CIs using 5000 bootstrap resamplings. Their proportions were compared using Pearson χ2 and χ2 tests for trend. Continuous variables were represented by means with SDs or medians with IQRs if indicated by the Shapiro-Wilk test.14
The longitudinal comparison of patient outcomes between times was performed using a generalized linear model of mixed effects with a robust covariance matrix (Šidák post hoc correction) and adequate probability distribution for each sample.15 Data analysis was performed with the IBM SPSS version 29.0 (IBM), and 1-tailed P values less than .05 were considered significant for the change of hair density.16
Results
A total of 90 male participants with AGA were enrolled in the study. Table 1 presents the main clinical and demographic data. Most participants had mild to moderate AGA, and the groups were homogeneous. A total of 68 completed the study and had 24-week follow-up data; of these, the mean (SD) age was 36.6 (7.8) years. There were 12 dropouts (27%) in the oral minoxidil group; 11 were unable to attend appointments during the COVID-19 pandemic, and 1 had headache. In the topical minoxidil group, 10 patients (22%) did not complete the treatment; 7 were unable to attend appointments during the COVID-19 pandemic, 1 had insomnia, 1 had persistent scalp eczema, and 1 had intense hair shedding. There was no difference between the proportions of dropouts between groups.
Table 1. Baseline Clinical and Demographic Data of 90 Men With Androgenetic Alopecia Included in the Study.
| Characteristic | No. (%) | |
|---|---|---|
| Oral minoxidil (n = 45) | Topical minoxidil (n = 45) | |
| Age, mean (SD), y | 37.2 (8.4) | 35.9 (7.1) |
| Phototype | ||
| I-II | 16 (36) | 11 (24) |
| III | 20 (44) | 27 (60) |
| IV | 9 (20) | 7 (16) |
| Level of education | ||
| Elementary school | 1 (2) | 0 |
| High school | 11 (24) | 13 (29) |
| Graduate school | 33 (73) | 32 (71) |
| Norwood-Hamilton scale grade | ||
| 3V | 24 (53) | 27 (60) |
| 4V | 16 (36) | 13 (29) |
| 5V | 5 (11) | 5 (11) |
| BMI, mean (SD)a | 27.1 (3.9) | 28.1 (4.3) |
| HR, mean (SD), beats per min | 71.6 (8.6) | 70.3 (9.6) |
| Blood pressure, mean (SD), mm Hg | ||
| Systolic | 123.3 (12.2) | 122.2 (10.4) |
| Diastolic | 81.3 (6.6) | 81.3 (6.9) |
| MAP, mean (SD), mm Hg | 95.3 (8.0) | 95.0 (7.4) |
Abbreviations, BMI, body mass index; HR, heart rate; MAP, mean arterial pressure.
Calculated as weight in kilograms divided by height in meters squared.
Table 2 presents the main outcomes of the study. At 24 weeks, the mean changes from baseline in terminal and total hair density were not different between the groups. For the frontal area, the mean change from baseline to week 24 between groups was 3.1 hairs per cm2 (95% CI, −18.2 to 21.5; P = .27) for terminal hair density and 2.6 hairs per cm2 (95% CI, −10.3 to 15.8; P = .32) for total hair density. For the vertex area, the mean change from baseline to week 24 was 23.4 hairs per cm2 (95% CI, −0.3 to 43.0; P = .09) for terminal density and 5.5 hairs per cm2 (95% CI, −12.5 to 23.5; P = .32) for total hair density. The percentage increase in terminal hair density was 27.1% (95% CI, 6.5-47.8) higher for the oral minoxidil group (P = .005) in the vertex and 13.1 (95% CI, −11.5 to 37.5%; P = .15) in the frontal scalp. For total hair density, there was an increase of 2.1% (95% CI, −8.1 to 12.3; P = .27) in the oral minoxidil group compared with the topical minoxidil group in the vertex and a decrease of 0.2% (95% CI, −8.4 to 8.0; P = .89) in the frontal area.
Table 2. Main Outcomes of 68 Participants Who Completed the Study at Baseline at Week 24.
| Measure | Oral minoxidil (n = 33) | Topical minoxidil (n = 35) | Difference (95% CI)a | P valueb | ||
|---|---|---|---|---|---|---|
| Baseline | Week 24 | Baseline | Week 24 | |||
| Density of hair, mean (SD), cm2 | ||||||
| Frontal | ||||||
| Terminal | 91.2 (47.6) | 101.5 (54.4) | 105.3 (42.2) | 109.7 (49.0) | 3.1 (−18.2 to 21.5) | .27 |
| Total | 190.2 (61.2) | 201.0 (61.4) | 207.4 (63.7) | 215.5 (58.9) | 2.6 (−10.3 to 15.8) | .32 |
| Vertex | ||||||
| Terminal | 96.8 (48.1) | 111.4 (58.8) | 134.3 (51.4) | 125.4 (61.6) | 23.4 (−0.3 to 43.0) | .09 |
| Total | 190.3 (55.8) | 201.9 (57.7) | 211.6 (67.8) | 216.5 (65.1) | 5.5 (−12.5 to 23.5) | .32 |
| Hair density improvement, % (95% CI) | ||||||
| Frontal | ||||||
| Terminal | NA | 20.0 (4.8-39.9) | NA | 7.0 (−4.7-20.4) | 13.1 (−11.5 to 37.5) | .15 |
| Total | NA | 7.0 (3.0-11.5) | NA | 6.4 (0.7-13.5) | −0.2 (−8.4 to 8.0) | .89 |
| Vertex | ||||||
| Terminal | NA | 21.6 (8.6-34.0) | NA | −5.6 (−17.5-6.4) | 27.1 (6.5 to 47.8) | .005 |
| Total | NA | 8.7 (1.5-16.2) | NA | 4.9 (0-10.8) | 2.1 (−8.1 to 12.3) | .27 |
| GAIS, No. (%) | ||||||
| Frontal | ||||||
| −2 | NA | 1 (3) | NA | 0 | NA | .24 |
| −1 | NA | 1 (3) | NA | 2 (6) | NA | |
| 0 | NA | 11 (33) | NA | 16 (46) | NA | |
| 1 | NA | 11 (33) | NA | 12 (34) | NA | |
| 2 | NA | 9 (27) | NA | 5 (14) | NA | |
| Vertex | ||||||
| −1 | NA | 2 (6) | NA | 1 (3) | NA | .04 |
| 0 | NA | 8 (24) | NA | 18 (51) | NA | |
| 1 | NA | 16 (48) | NA | 14 (40) | NA | |
| 2 | NA | 7 (21) | NA | 2 (6) | NA | |
| HR, mean (SD), beats per min | 72.1 (8.4) | 72.9 (7.6) | 70.2 (9.8) | 72.2 (9.5) | 0.7 (−3.3 to 4.8) | .72 |
| Blood pressure, mean (SD), mm Hg | ||||||
| Systolic | 125.1 (13.2) | 123.0 (9.5) | 121.4 (11.2) | 118.3 (9.9) | 4.7 (0.0 to 9.4) | .07 |
| Diastolic | 81.8 (6.8) | 80.9 (6.8) | 81.1 (6.8) | 79.7 (8.6) | 1.2 (−2.4 to 4.8) | .52 |
| MAP, mean (SD), mm Hg | 96.33 (8.4) | 94.9 (7.1) | 94.6 (7.5) | 92.6 (8.4) | 2.4 (−1.3 to 6.1) | .21 |
Abbreviations: GAIS, Global Aesthetic Improvement Scale; HR, heart rate; MAP, mean arterial pressure; NA, not applicable.
Based on 5000 bootstrap resamplings.
One-tailed P value.
According to the consensus of the 3 dermatologists blinded to treatments, 20 of 33 in the oral minoxidil group (60%) and 17 of 36 in the topical minoxidil group (48%) had clinical improvement in the frontal area, with no significant difference between the groups (difference, 12%; 95% CI, −12 to 36; P = .24). More patients in the oral minoxidil group (23 of 33 [70%]) had clinical improvement in the vertex area than patients in the topical minoxidil group (16 of 35 [46%]) (difference, 24%; 95% CI, 0-48; P = .04).
The changes in the main cardiovascular parameters (eg, heart rate and blood pressure) did not differ between groups (Table 2). Only 3 of 45 patients (7%) in the topical minoxidil group and 1 of 45 (2%) in the oral minoxidil group discontinued treatment due to adverse effects (P = .61). Table 3 shows the adverse effects reported. Hypertrichosis was the main adverse effect reported and was more prevalent in the oral minoxidil group (22 [49%] vs 11 [25%]; P = .02). In both groups, it was generalized, well tolerated, and did not influence patient compliance. Headache was more prevalent in the oral minoxidil group, while local effects (itching and eczema) were more common among those using topical minoxidil.
Table 3. Main Adverse Effects.
| Adverse effect | No. (%) | P value | |
|---|---|---|---|
| Oral minoxidil (n = 45) | Topical minoxidil (n = 45) | ||
| Hypertrichosis | 22 (49) | 11 (25) | .02 |
| Headache | 6 (14) | 1 (2) | .046 |
| Itching on the scalp | 1 (2) | 5 (11) | .09 |
| Nightmares | 1 (2) | 2 (5) | .58 |
| Scalp eczema | 1 (2) | 7 (16) | .02 |
| Shedding | 4 (9) | 7 (16) | .34 |
| Appetite increase | 0 | 1 (2) | .33 |
| Insomnia | 1 (2) | 2 (5) | .58 |
| Lower limb edema | 1 (2) | 0 | .33 |
| Abdominal pain | 1 (2) | 0 | .33 |
| Pain in lower limbs | 1 (2) | 0 | .33 |
There was no difference between the groups regarding variation in mean arterial blood pressure over time. None of the participants reported dizziness, fainting, or vertigo. Resting heart rate also showed no difference between groups. Transient hair loss was experienced during the first 2 months of treatment by 4 patients (9%) in the oral minoxidil group and 7 (16%) in the topical minoxidil group (P = .34).
Discussion
In this study, after 24 weeks, oral minoxidil, 5 mg, once per day improved terminal and total hair density, although it did not show superiority compared with topical minoxidil, 5%. However, in the expert photographic evaluation at the vertex and concerning the percentile increase of terminal hair density in the vertex area, oral minoxidil therapy demonstrated superiority. Both treatments presented a safe profile and were well tolerated.
Oral minoxidil is a potent vasodilator approved by the FDA for the treatment of hypertension, usually in doses of 10 to 40 mg daily. At these doses, the most common adverse effects are hypertrichosis, tachycardia, headache, and edema. It was first described as a therapeutic option in men with AGA in 1980.17 Since then, its topical formulation has been studied for AGA, having received FDA approval in 1988. Numerous clinical trials have proven its effectiveness, but the challenge of patient adherence persists.6
Low-dose oral minoxidil has emerged as a promising alternative to topical minoxidil for the treatment of AGA in recent years. One of its main advantages is to avoid the problems of topical therapy.7 Additionally, it does not cause sexual adverse effects that may be observed with 5α-reductase inhibitors, making it an attractive choice for this condition.5
To our knowledge, the only existing data to date regarding increased hair density with oral minoxidil, 5 mg, once per day for men with AGA comes from the noncomparative prospective study by Panchaprateep and Luengarun18 who observed 30 Thai patients for 24 weeks. In that study, there was an increase in nonvellus hair density of 35.9 hairs per cm2 (23.6%) and in total hair density of 35.1 hairs per cm2 (19.2%) on the vertex region. Here, we observed a similar percentage increase in terminal hair density on the vertex (21.6%; 95% CI, 8.6-34.0) but not in total hair density (8.7%; 95% CI, 1.5-16.2).
The topical minoxidil group had lower-than-expected results in terminal and total hair density. Differences in results among studies may be related to population or environmental factors, evaluation methods, lack of patient compliance, and other reasons. Moreover, this study was carried out during the COVID-19 pandemic, which restricted follow-up visits and precluded identification of those with COVID-19 infection and possible implications, like the frequent reports of infection-induced telogen effluvium.19 Head-to-head randomized clinical trials are essential to compare different therapies. Despite the expectations of the great superiority of oral minoxidil for AGA, up to now, this modality did not prove to be incontestably superior to topical minoxidil either for men or women.
In a previous randomized clinical trial comparing oral minoxidil, 1 mg, with topical minoxidil, 5%, for female pattern alopecia, we found no difference in hair density improvement between the groups.20 However, if the outcomes of these studies are taken together, they suggest a trend toward a greater improvement in the oral minoxidil group. Perhaps this superiority can only be evidenced in larger studies or with a longer follow-up time.
The adverse effects of low-dose oral minoxidil were mild and well tolerated, and only 1 patient stopped the medication due to headache. Hypertrichosis was the most commonly reported adverse effect and was more prevalent in the oral minoxidil group. There were no significant changes in heart rate and blood pressure in the oral minoxidil group, endorsing its negligible hypotensive potential for healthy individuals.21 Large case series have reinforced the safety of low-dose oral minoxidil.22,23
Furthermore, it is known that minoxidil may cause transient hair loss in the first 2 months of treatment due to the early release of hairs in the telogen phase (premature teloptosis). This reaction was previously described in up to 17% of patients using topical minoxidil.24 In our study, this happened in 16% of patients in the topical minoxidil group and only 9% in the oral minoxidil group. It is crucial to inform patients about its transient and self-limited nature to prevent early treatment interruption.
Limitations
Our study has limitations, including its monocentric format, the relatively small sample size, and the substantial rates of follow-up loss. Nevertheless, to our knowledge, this was the first double-blind randomized clinical trial to evaluate the efficacy of oral vs topical minoxidil for men with AGA. Further larger clinical trials with longer follow-up times are needed to compare different doses of oral minoxidil as well as its use with topical minoxidil or 5α-reductase inhibitors.
Conclusions
In conclusion, oral minoxidil, 5 mg, once per day did not demonstrate superiority over topical minoxidil, 5%, twice per day in the treatment of male AGA after 24 weeks. Nevertheless, the overall photographic improvement in the vertex was superior in the oral minoxidil group. Low-dose oral minoxidil has shown to be well tolerated and, therefore, is an option for patients who prefer oral therapy or are intolerant to topical treatment.
Trial Protocol
Statistical Analysis Plan
Data Sharing Statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
Statistical Analysis Plan
Data Sharing Statement
