Low-dose Oral Minoxidil in the Treatment of Alopecia: Evidence and Experience-based Consensus Statement of Indian Experts

ABSTRACT

Alopecia is a highly prevalent condition worldwide including in India. There are different types of alopecia with differing etiology, presentation, and hence treatment. Androgenetic alopecia represents the most common form of hair loss affecting male as well as female population termed as male and female pattern hair loss, respectively. Several treatment options are available for the treatment of alopecia with often unsatisfactory results resulting in psychological distress among such patients. Topical minoxidil is known to be effective in the treatment of alopecia. However, oral minoxidil is not currently approved for the treatment of alopecia. This expert consensus is prepared to provide guidance to the clinicians regarding the use of oral minoxidil in the treatment of alopecia. Extensive literature review was performed to prepare the draft consensus which was then revised based on the suggestions and comments from the experts. The final draft was circulated to the experts for review and approval. This consensus document provides overview of evidence related to oral minoxidil and consensus from the experts for its use in the treatment of minoxidil.

INTRODUCTION

Alopecia is common concern all over the world. Androgenetic alopecia (AGA) is highly prevalent and represents the most common form of alopecia in the society with as many as 85% male and 40% females being affected with it.[1] Male AGA is known as male pattern hair loss, whereas in females, it is known as female pattern hair loss. In a population-based study, Krupa Shankar et al. reported 58% prevalence of male AGA among people from the age group of 30–49 years of age. In all cases, the incidence gradually increases with age.[2,3]

Each type of alopecia has its own etiology, pathogenesis, and hence treatment.[4] AGA is a nonscarring, hereditary condition in which normal hair growth is progressively replaced by smaller and rapid-cycling vellus types of hair follicles. Males may have complete hair loss; however, in female, it is rare. In females with androgenetic hair loss, the hairline remains intact.[4] Alopecia can cause severe psychological stress, especially in many females. This impact in females is generally more as compared to males, considering higher importance given to physical appearance by females. The major factors involved in the pathogenesis of androgenic alopecia include undesirable androgen metabolism at the hair follicle level, elevated activity of Type II isoform of the 5-alpha reductase enzyme, which metabolizes testicular testosterone, genetically susceptible hair follicles, follicular microinflammation, and oxidative stress.[2] In females, it may occur due to dysfunction of ovary or adrenal glands. However, there may also be other causes of contributing to hair loss.[4]

Alopecia areata is an autoimmune disorder. This is also a nonscarring hair loss. In this type, patients often present with sudden, smooth, round patches of hair loss from the scalp or other areas presenting as. This occurs due to abnormal immune response resulting in damage to the hair follicles. There is no permanent damage to the follicle occurs. In most patients, hair regrowth is seen, but relapse is also possible.[4]

Telogen effluvium is hair loss due to stressful condition. Patients presents with loss of large amount of hair. In this condition, the hair loss is often more rapid as compared to that in AGA. These patients often give a history of some triggering factors about 2–4 months before starting to lose hairs. Some of the known stressful conditions include pregnancy, thyroid disease, severe infections, major surgical procedures, or some nutritional deficiency. Some medicines (e.g., anticancer drugs and valproic acid) are also known to cause telogen effluvium. Hair growth is observed after the discontinuation of trigger or removal of the causative agent.[4]

Other types of hair loss include cicatricial alopecia and trichotillomania. In cicatricial alopecia, there destruction of hair follicle is otherwise healthy people. This is scarring type of alopecia. Trichotillomania is a psychological condition in which pulling out of hair causes alopecia.[4]

Several treatment options are available for the treatment of alopecia with often unsatisfactory results resulting in psychological distress among such patients. Topical minoxidil is known to be effective in the treatment of alopecia. Oral minoxidil has been evaluated by different investigators in different types of alopecia but is not currently approved for the treatment of alopecia. This expert consensus is prepared to provide guidance to the clinicians regarding the use of oral minoxidil in the treatment of alopecia.

METHODOLOGY

A panel of expert dermatologists with at least 10 years of experience after their postgraduation was selected for developing the consensus statement. Comprehensive literature search of online databases, including PubMed and Google Scholar was performed to retrieve the relevant articles published in English. Randomized controlled trials, observational studies, systematic reviews, conference abstracts (<3 years old), review articles, case series as well case reports were considered for the development of the first draft of manuscript. The draft was circulated by E-mail to all experts to seek their suggestions. After receiving expert opinions, critical comments and suggestions the draft were revised three times. All suggestions and comments were incorporated in the third document. After three rounds of E-mail exchanges, virtual expert meeting was convened to discuss and finalize the consensus statements. The consensus document first describes pharmacology and published evidence and then consensus statements for the use of oral minoxidil in the treatment of alopecia in the Indian setting.

PHARMACOLOGY OF MINOXIDIL

The structure of minoxidil is shown in Figure 1.

Figure 1.

Structure of minoxidil

After oral administration, minoxidil is well absorbed with peak plasma concentrations achieved within 1 h and decrease rapidly. After oral administration, it is widely distributed and most of the drug is mainly metabolized by glucuronidation. Half-life is about 4.2 h and the metabolite may accumulate in patients with renal impairment.[5]

Currently, oral minoxidil is indicated only in the treatment of symptomatic hypertension or hypertension associated with target organ damage and is not manageable with maximum therapeutic doses of a diuretic plus two other antihypertensive drugs. Recommended initial dosage in patients more than 12 years of age is 5 mg once daily. If required, this dose can be increased for optimum control of blood pressure. Effective dose range for blood pressure control is 10–40 mg.[6]

ORAL MINOXIDIL IN ALOPECIA

Mioxidl is a hair growth enhancer.[7] Topical minoxidil is used in AGA.[8] However, it is associated with challenges related to solubility and absorption.[9] Many patients may prefer oral formulation as compared topical route. Local administration may lead to missing of some parts, especially in patients with extensive hair loss. Moreover, low-dose oral minoxidil can avoid local adverse events including local irritation and allergic contact dermatitis associated with topical application.[10,11]

Oral minoxiil can circumvent the adverse events seen with the topical therapy. Once daily use may help to improve its compliance as compared to topical therapy. Low-dose oral minoxidil is increasingly used and accepted for the treatment of AGA.[8]

Minoxidil is a prodrug. This is converted to its active form, minoxidil sulfate. The positive effect of minoxidil on hair growth is mainly due to its metabolite, minoxidil sulfate, and the enzyme responsible for this conversion is sulfotransferase.[7] At least four human cytosolic sulfotransferases are involved in the catalysation of this activity. Human minoxidil sulfotransferase activity is a combination of these enzyme activities instead of a distinct enzyme activity.[7] Minoxidil is a potassium channel opener and works by different mechanisms of actions including increased hepatocyte growth factor, prostaglandin E and vascular endothelial growth factor expression and epidermal growth factor inhibition. It also is postulated to stimulate the Wnt/b-Catenin pathway.[12] It causes hyperpolarization of the cell members leading to vasodilation. Hair follicles in the telogen phase are shed and replaced with newer thicker hairs in new anagen phase.

CLINICAL EVIDENCE WITH ORAL MINOXIDIL

Several clinical studies and case reports have examined effects of oral minoxidil in different doses in the treatment of different forms of alopecia, mainly AGA. However, it is not approved for its use by the regulatory agencies. In the following section, evidence from the published literature with oral minoxidil is discussed followed by consensus statements from the experts.

Sinclair[13] reported the results of an observational study involving 100 women (mean age 48.44 years) with female pattern hair loss (Sinclair stage 2–5) treated with combination of oral minoxidil 0.25 mg and spironolactone 25 mg per day for 12 months. Mean reduction in hair loss severity score at 6 and 12 months was 0.85 and 1.3, respectively. Improvement in the mean reduction in hair shedding score at 6 and 12 months was 2.3 and 2.6, respectively.

In a single-center study, Rodrigues-Barata et al.[14] examined the effects of low-dose oral minoxidil in female pattern hair loss (n = 148) for at least 6 months as monotherapy or associated with other treatments. The mean age of the patients was 47.2 years with range from 17 to 85 years. The median dose of 1 mg was used daily (range-0.25–2 mg) for a mean period of 9 months. The range of minoxidil use was 6–27 months. Out of all study population, 15.5% patients received oral minoxidil monotherapy, whereas remaining 84.5% patients received other treatment along with it. A total of 79.7% patients showed clinical improvement. Slight improvement was reported in 64.2% patients, whereas 15.5% patients showed marked clinical improvement.

A prospective study by Lueangarun et al.[15] reported results in 30 males with AGA after oral minoxidil 5 mg everyday for 24 weeks. Clinical improvement was observed in all patients whereas 43.3% patients reported marked improvement.

In a study involving 41 male patients with AGA receiving different doses of oral minoxidil (2.5 mg–5 mg), clinical improvement was observed in 90.2% patients.[16]

In a prospective, open-label study, Panchaprateep and Lueangarun[17] examined the effects of oral minoxidil 5 mg once daily given for 24 weeks. In this study, the investigators enrolled 30 male patients between the age group of 24–59 years. These patients had AGA types III vertex to V. The objective outcome parameters of this study included hair counts, hair diameter measurements, and photographic evaluation. The study also examined subjective outcomes with the use of self-administered questionnaire. Physical examinations and laboratory tests were performed for the evaluation of the adverse events associated with oral minoxidil. The results of the study showed significant increase in total hair counts at 12 weeks as well as 24 weeks as compared to baseline [Table 1]. The mean change in total hair count was +26 and +35.1, respectively, with P values of 0.007 for both. Photographic evaluation of the vertex area by the experts showed 100% improvement with score of more than 1. A total of 43% patients showed excellent improvement, i.e., 71%–100% increase. Significant effect was also seen in the frontal area. The effect on the vertex area was more than that observed in the frontal area. Age group wise analysis showed higher score in older patient group (41–60 years) as compared to those between 20 and 40 years of age. At 24 weeks of treatment, younger men had significant increase in number of total hairs than older men (40.7 vs. 25.4 P = 0.029).

Table 1.

Comparative improvement in hair growth at frontal scalp and vertex with very low-dose oral minoxidil

	Frontal scalp (%)	Vertex (%)
New terminal hairs/cm2	48	44
New hairs/cm2	52	40
Density of terminal hairs/cm2	40	44
Total hair density/cm2	60	40

Ramos et al.[18] conducted a randomized open label study for 24 weeks in which 52 patients received either oral minoxidil 1 mg once daily or topical minoxidil 5% solution (1 mL once daily) for the treatment of female pattern hair loss. In this study, they enrolled females from 18 to 65 years of age with female pattern hair loss (Sinclair’s Stage II-IV). The primary efficacy outcome of change in total hair density in target area (parietal) was analyzed with trichoscopic images. The results showed increase in total hair density by 12% and 7.2% in oral minoxidil and topical minoxidil. No significant difference was observed between two groups.

Pirmez and Salas-Callo[19] evaluated the effects of a very low-dose oral minoxidil in male AGA. In this study, the investigators evaluated the effects quantitatively using the trichoscopic examination. In this retrospective study, 25 male patients with AGA who were treated with 0.25 mg/d minoxidil monotherapy were included. These patients had reports of at least 24 weeks of follow-up with their clinical and trichoscopic images. In this study, patients with recent AGA (<6 months) were not included. The age range of patients was from 23 to 53 years with a mean of 36.7 years. A total of 60% patients had severe AGA. Improvement or stabilization after 24 weeks was observed in frontal scalp as well as vertex. Comparative growth at both places for new terminal hairs, new hairs, density of terminal hairs, and total hair density is shown in Table 1.

A trend toward better response was observed in mild-to-moderate AGA in the density of total hairs/cm².

A retrospective study by Perera and Sinclair[20] in 36 women with chronic telogen effluvium treated with dose range from 0.25 to 5 mg per day reported improvement in hair shedding in 86% cases.

Beach[21] published results in 18 patients with oral minoxidil dose of 1.25 mg daily for average 24 weeks. Improvement was seen in 28% of patients.

A study involving 12 patients with female AGA (Ludwig scale 1–3) reported the results of oral minoxidil. The starting dose of oral minoxidil was 0.50 mg per day. At 3 months, the dose was increased to 1.5–2 mg/day. The patients were evaluated at baseline and after 24 weeks. The efficacy parameters included were global clinical photography and quantitative digital videotrichoscopic assessment. The results of this study showed significant increase in hair density, total hair, and terminal hairs in the frontal area. There was no significant difference in miniaturized hair count, hair thickness, triple follicular unit, double follicular unit or single follicular unit in the frontal area.[22] Wambier et al.[23] reported their results in 12 patients with alopecia areata with oral minoxidil in the dose of 2.5 mg daily in women and 2.5 mg twice daily in men with tofacitinib for 6 months. A total of 67% patients achieved SALT 75. Cranwell and Sinclair,[24,25] Sinclair[26] and Yang and Thai,[27] in cases reports have reported improvement in alopecia in different dose ranges of oral minoxidil (0.25–1 mg).

SAFETY OF ORAL MINOXIDIL IN PATIENTS WITH HAIR LOSS

A prospective, open-label study by Panchaprateep and Lueangarun[17] evaluating the effect of oral minoxidil 5 mg once daily given for 24 weeks in male patients with AGA reported hypertrichosis (93%) and pedal edema (10%) as common adverse events. There were no serious cardiovascular adverse events or significant abnormal laboratory findings.

In an observational study by Sinclair[13] involving 100 women with female pattern hair loss (Sinclair stage 2–5) treated with combination of oral minoxidil 0.25 mg and spironolactone 25 mg per day for 12 months, mean change in systolic and diastolic blood pressure was − 4.52 mmHg and − 6.48 mmHg, respectively. There was no abnormality in blood tests. Six out of eight patients who developed mild side effects continued treatment, whereas two with urticaria discontinued treatment. In a single-center study, Rodrigues-Barata et al.[14] adverse effects were noted in 19% of patients. Hypertrichosis was the major adverse event. Tachycardia (1.3%), lower limb edema (0.67%), and general malaise (0.67%) were other adverse events. A total of 2% discontinued treatment. In a study by Lueangarun et al.,[15] oral minoxidil 5 mg per day for 24 weeks produced hypertrichosis and pedal edema in 93% and 10% patients, respectively. Another study by Jimenez-Cauhe et al. reported hypertrichosis and pedal edema in 24.3% and 4.8% patients, respectively (dose of oral minoxidil 2.5–5 mg/day). A retrospective study by Perera and Sinclair[20] reported facial hypertrichosis in 36.11% women with chronic telogen effluvium treated with oral minoxidil in the dose range of 0.25–2.5 mg. In a randomized trial by Ramos et al.,[18] hypertrichosis was observed in 27% patients, whereas pretibial edema was observed in 4% patients receiving oral minoxidil. No difference between two groups was observed in terms of changes in mean blood pressure over time. There were no hypotension-related events reported in patients receiving minoxidil. Moreover, there no patient required discontinuation of the treatment.

In a retrospective study, Pirmez and Salas-Callo[19] used very low-dose oral minoxidil (0.25 mg/day) in male AGA with at least 24 weeks’ follow-up and reported pedal edema in 1 (4%) and body hypertrichosis in 5 (20%) patients. No difference in mean arterial pressure or fainting/dizziness episodes was reported. None of the patients discontinued treatment with oral minoxidil. Another retrospective study by Vañó-Galván et al.[11] reported safety analysis in 1404 patients (67.2% females) with a mean age of 43 years. Hypertrichosis was observed as the most adverse effect in 15.1% patients leading to treatment withdrawal in 0.5% patients. Light headedness, fluid retention, tachycardia, headache, periorbital edema, and insomnia were reported in 1.7%, 1.3%, 0.9%, 0.4%, 0.3%, and 0.2% patients, respectively. Systemic adverse events resulted in treatment discontinuation in 1.2% patients. In this study, no life-threatening adverse were reported. Minority of patients (n = 43) required discontinuation of therapy mainly due to hypertrichosis. Low-dose oral minoxidil is devoid of serious hemodynamic side effects including change in mean arterial pressure or adverse events such as fainting or dizziness.[19] A study examined the effect of minoxidil in different doses, i.e., 2.5, 5, and 10 mg in normotensive healthy volunteers. With these doses, minoxidil did not show significant adverse impact on the blood pressure.[28] Table 2 describes studies involving more than 20 patients with alopecia treated with oral minoxidil. Other small studies, case series or case reports (Wambier, et al. [n = 12][23] and Beach, [n = 18]),[21] case series (Sinclair, (n = 2)[26] and case reports,[24,25] Yang Thai,[27] are not included in the table.

Table 2.

Summary of effectiveness and safety of oral minoxidil in the treatment of different types of alopecia

Authors	Study details	Dose of oral minoxidil	Efficacy outcomes	Safety outcomes
Sinclair[13]	Prospective study in 100 females with androgenetic alopecia	Oral minoxidil 0.25 mg+spironolactone 25 mg/day for 12 months	Mean decrease in Sinclair score  6 months: 0.85  12 months: 1.3 Mean reduction in hair shedding score  6 months: 2.3  12 months: 2.6	Hypertrichosis 4% Mean reduction in blood pressure: Systolic: 4.52 mmHg Diastolic: 6.48 mmHg
Rodrigues-Barata et al.[14]	A retrospective study involving 148 females with androgenetic alopecia	Oral minoxidil for minimum 24 weeks  0.25 mg (n=3)  0.5 mg (n=60)  1 mg (n=85), daily	Clinical improvement in 79.7% patients Marked clinical improvement in 15.5% patients	Hypertrichosis 17% Tachycardia in 1.3% patients Lower limb edema 0.67%
Lueangarun et al.[15]	Prospective study in 30 male patients with androgenetic alopecia	Oral minoxidil 5 mg every day for 24 weeks	Clinical improvement: 100% patients Marked clinical improvement: 43.3% patients Increase of total hair count: 19.3%	Hypertrichosis: 93% Pedal edema: 10% Postural hypotension not reported Tachycardia not reported ECG changes: 10%
Jimenez-Cauhe et al.[16]	A study of 41 male patients with androgenetic alopecia	Oral minoxidil 5 mg (n=31) and 2.5 mg (n=10), per day for 24 weeks to 12 months	Clinical improvement: 90.2% patients Marked clinical improvement: 26.8% patients	Hypertrichosis: 24.3% Pedal edema: 4.8% No postural hypotension Tachycardia: 1 patient
Panchaprateep and Lueangarun[17]	Prospective, open label study among patients with androgenetic alopecia (n=30)	5 mg	Significant increase in hair growth at week 12 and 24 compared to baseline More improvement in the vertex area as compared to frontal area	Hypertrichosis (93%) Pedal edema (10%) No serious cardiovascular adverse events No significant laboratory abnormality
Ramos et al.[18]	Randomized open label trial in 52 patients; female pattern hair loss	1 mg oral minoxidil versus 5% topical minoxidil solution	After 24 weeks, increase in total hair density by 12% and 7.2% in patients taking oral versus topical minoxidil respectively (P=0.10)	Hypertrichosis in 27% patients and pretibial edema in 4% patients receiving oral minoxidil No hypotension-related events reported in patients receiving minoxidil No patient required discontinuation of the treatment
Pirmez and Salas-Callo[19]	Retrospective study in 25 male patients with androgenic alopecia with >24 weeks of follow-up and availability of clinical and trichoscopic images	0.25 mg/day	Improvement or stabilization for all analysed parameters. A trend toward better response in patients with mild-to-moderate AGA in DTH/cm2	Pedal edema 1 (4%) Hypertrichosis 5 (20%) No difference in mean arterial pressure No reports of fainting or dizziness
Vañó-Galván et al.[11]	Retrospective, multicenter study from 6 countries (n=1404)	Mean 1.63 mg oral minoxidil for>3 months for hair loss of any cause	NA	Hypertrichosis in 15.1% patients lightheadedness, fluid retension, tachycardia, headache, periorbital edema and insomnia in 1.7%, 1.3%, 0.9%, 0.4%, 0.3% and 0.2% patients respectively. Systemic adverse events leading to treatment discontinuation in 1.2% patients. No life-threatening adverse events
Perera and Sinclair[20]	A retrospective study in 36 female patients with chronic telogen effluvium	Oral minoxidil in different doses for 6 months  0.25 mg (n=5)  0.5 mg (n=4)  1 mg (n=19)  2.5 mg (n=8)	Improvement of hair shedding in 86% patients	Facial hypertrichosis 36.11% Pedal edema 2.7% Transient postural dizziness 5.5%

AGA - Androgenetic alopecia; NA - Not available; ECG – Electrocardiogram; DTH - Density of terminal hair

SUMMARY

Topical minoxidil is associated with limitations including local side effects and twice daily administration may affect the compliance of the patient. Low-dose oral minoxidil may circumvent these limitations. Low-dose oral minoxidil can be used in male as well as female patients with alopecia. This consensus statement described available evidence and expert views on the use of low-dose oral minoxidil in the treatment of alopecia. The consensus statements (Box 1) may help dermatologist to use low-dose oral minoxidil for alopecia treatment more rationally.

Box 1.

Consensus statement for oral minoxidil in alopecia

Oral minoxidil is currently not approved for use in alopecia. However, many dermatologists use it off-label for the treatment of alopecia. Whenever oral minoxidil is used for alopecia, patients should be informed about the same, before using it

Before initiation of low dose oral minoxidil, patients should be asked about history of cardiovascular disease, pedal edema, and fluctuation in blood pressure

Some evidence is available for use of oral minoxidil in alopecia including alopecia areata or male and female pattern hair loss and telogen effluvium

Available evidence shows well tolerated safety profile of the low dose oral minoxidil in patients with alopecia

Oral minoxidil can be used in patients with alopecia having inflammatory dermatosis of scalp who find topical application messy and/or irritating, patients who can’t tolerate topical minoxidil, history of irritant contact dermatitis with topical minoxidil, patients who find it cumbersome to adhere to

twice daily application schedule of topical minoxidil and patients with diffuse un-patterned alopecia For females, treatment may be initiated with 0.625 mg/day (considering the availability of scored tablet of 2.5 mg). If needed, dose may be increased every 3 months up to a maximum of 2.5 mg/day[11]

For male patients, treatment may be initiated with 1.25 mg/day. If required, dose may be increased by 1.25 mg every 3 months up to a maximum of 5 mg/day[11]

Most of the available evidence is from small studies or case series using small dose oral minoxidil up to 12 months [Table 1]

After initiation of low-dose oral minoxidil, visible hair growth may be seen after 3 months. If there is no satisfactory response after 3 months, consider up-dosing as stated above. If there is no response with dose mentioned above, discontinue it. In case patient with chronic hair loss condition is responding and tolerating it well, low-dose oral minoxidil may be used indefinitely

Minoxidil should be avoided in patients having allergy to minoxidil or any excipient in the oral formulation or pheochromocytoma[6]

It should be used carefully in patients receiving other antihypertensive agents

It should be used carefully in females with hirsutism

Minoxidil should be used carefully in patients with fluid and water retention, pericarditis, pericardial effusion, other heart diseases, renal failure,[6] and liver disease

As low dose oral minoxidil is used in patients who do not show effective results with topical preparation, its combination with topical minoxidil may not provide additional benefit. However, if needed, low-dose oral minoxidil may be used with topical minoxidil or other topical hair growth promoting agents Patients should be informed and counselled about risk of postural hypotension, headache, giddiness, hypertrichosis, and pedal edema in some cases

Weekly blood pressure monitoring should be done during initial period of starting low dose oral minoxidil

During treatment also periodic monitoring of blood pressure is required

If decided to discontinue, low dose oral minoxidil used for the treatment of alopecia should be slowly discontinued

Patients may receive other concomitant treatment for alopecia when receiving low dose oral minoxidil

It should be avoided in pregnancy and during breast feeding.[6] If a female is planning pregnancy, she should consider discontinuing it 3 months before conceiving

Use of low dose oral minoxidil should be used carefully in children with alopecia

Females who develop hypertrichosis can use hair removal methods such as laser, shaving, bleaching or waxing

Add eflornithine hydrochloride cream to the treatments for hypertrichosis due to low dose minoxidil therapy

Patients should immediately contact their physician in case they develop ankle edema or any other cardiovascular adverse events with low-dose oral minoxidil therapy

Conflicts of interest

There are no conflicts of interest.