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Comprehensive review of oral minoxidil in alopecia (2022)
Jay D. Modha MD | Yashdeep Singh Pathania MD
Abstract
Background: There have been various treatment modalities available for alopecia in the form of topical and systemic with a variable response. The compliance of the patients is important in reaping results in alopecia. Minoxidil has come a long way finding its use from topical formulations to systemic at lower doses in different alopecia.
Objective: The objective of this article is to discuss various conditions in alopecia where oral minoxidil has found its role. Methods: A comprehensive literature search was performed relating to oral minoxidil's role in various alopecia. Various clinical trials, case series, and case reports were searched on PubMed and Google Scholar. The references of available studies were also reviewed to collect additional resources. Available data from various studies and case reports were collected and consolidated to provide a concise overview of oral minoxidil indications in various alopecia.
Results: Oral minoxidil has been used in various non-scarring and scarring alopecia at a lower dosage with fewer side effects and with promising results. Androgenetic alopecia and female pattern hair loss were the two conditions where it has been used more commonly than other alopecia, providing a ray of hope along with overcoming the issues related to topical formulations and compliance.
1 | INTRODUCTION
Many serendipitous discoveries led to the current popular FDA (Food and Drug Administration) approved medicines in the field of trichology.1 Minoxidil is one such compound that was initially used as oral therapy for hypertension. In the year 1988, US FDA first approved 2% topical minoxidil for androgenetic alopecia in males. Since then, many commercialized topical formulations containing various preparations (lotions, foam) and concentrations (2%, 5%, and 10%) of minoxidil have dominated the treatment armamentarium of alopecia. Currently, topical minoxidil and oral finasteride (1 mg) are the only FDA-approved therapies in males while topical minoxidil alone is for females. Although associated with significantly favorable results, topical use has several limitations such as repeated application, vehicle inconsistencies, cosmetic drawbacks, financial burden, and limited percutaneous absorption.2 To overcome these shortcomings, recently oral minoxidil is being used widely for various hair loss disorders.
The mechanism of hair growth by minoxidil is yet to be understood completely. Minoxidil (2,4-diamino-6-piperidinopyrimidine3-oxide) is a potent peripheral vasodilator that acts via an opening of sarcolemmal ATP2-dependent potassium channels causing the release of nitric oxide (NO). This leads to a decrease in the telogen phase duration and an increase in the anagen phase of the hair follicles.3 It leads to the upregulation of VEGF (vascular endothelial growth factors) causing increased oxygen and growth factor delivery to the follicles. It also exerts the immunomodulatory effect by modulating the effects of Concavalin A (an intermediary for activating the T lymphocytes), which can be beneficial in autoimmune alopecia.4 Being a prodrug, it is metabolized by hepatic dehydroepiandrosterone sulfotransferase (SULT2A1) to minoxidil sulfate.2 Also follicular sulfotransferase enzyme SULT1A1 in the outer root sheath of the hair follicle converts it into its active metabolite.
Given its diverse range of actions, minoxidil is used orally with the hope of various alopecia management with an effort to achieve higher clinical efficacy and better compliance. This review aims to consolidate the use of oral minoxidil in various non-scarring and scarring alopecias.
2 FEMALE PATTERN HAIR LOSS (FPHL)
3 ANDROGENETIC ALOPECIA
4 TRACTIONAL ALOPECIA
5 CHRONIC TELOGEN EFFLUVIUM
6 HAIR SHAFT DISORDERS
6.1 Loose Anagen Syndrome
6.2 Monilethrix
7 SCARRING ALOPECIA
8 ALOPECIA AREATA
9 CHEMOTHERAPY-INDUCED ALOPECIA (ANAGEN EFFLUVIUM)
9.1 Safety profile
Overall, oral minoxidil is found to be better tolerated with fewer adverse effects. Hypertrichosis was the most common anticipated side effect seen in 20% of patients. Despite this, hypertrichosis was not the reason for discontinuation of the therapy as most of the patients understood it as mild and quite manageable. It should be emphasized that hypertrichosis was a dose-dependent adverse effect per se; more commonly seen with a 5 mg daily dose (more than 50% of the patients) whereas 0.25 mg per day had the lowest incidence (less than 10% of patients).27 However, pragmatic studies with larger sample sizes and longer follow-ups are needed to draw a conclusion and determine the relationship between dose and hypertrichosis. As topical minoxidil induces fast re-entry in the anagen phase of the TABLE 1 hair follicles, provoking a transitory telogen effluvium (TE); similarly increased hair shedding is seen with oral minoxidil lasting 3–6 weeks. Patients should be properly counseled for this anticipated event to avoid premature termination of the therapy. Sinclair et al.28 described this adverse effect in 22 out of 100 patients, yet due to pretherapy counseling, none discontinued the treatment, as well as this hair shedding, stopped after 4–6 weeks in almost all the patients. Acute contact dermatitis seen with topical minoxidil due to propylene glycol is of common occurrence, so, Therianou et al. reported that 0.25 mg twice daily oral minoxidil is a safe and satisfactory alternative in those patients. Cardiovascular side effects were usually minor in nature. Blood pressure monitoring was done in many of the studies, which indicated relatively minor changes7,8 Ramos et al.7 has described that there was no significant difference in the MBP (mean blood pressure) of oral minoxidil group when compared with those using topical minoxidil; however, increased heart rate by 6.5% was observed with oral minoxidil. Postural hypotension was seen in 2% of the patients which was managed with 50 mg of sodium chloride daily as reported by Sinclair et al.6 Pedal edema was reported in 3% of patients, which was more common with 5 mg daily dose. Changes in electrocardiogram were seen in approximately 1% of patients, it was mild in nature and consisted of tachycardia, PVC, and T wave changes in lead 1. However, this was recorded in one study only and other studies did not regularly involve EKG monitoring.29 No severe cardiopulmonary events were found in any of the studies.
Newer pharmacokinetic studies regarding minoxidil (oral/ topical) metabolism revealed that intersubjective variability in the activity of sulfotransferase in hepatic (SULT2A1) and follicular (SULT1A1) ultimately yields lower hair regrowth.30 Weak hair growth due to low follicular SULT1A1 cannot be overcome with ML due to low solubility and saturation absorption kinetics but it can be overcome with OM through dose escalation. Sublingual doses of 0.45 and 0.90 mg minoxidil were evaluated by Sinclair et al.31 as the sublingual route bypasses hepatic first-pass metabolism, sublingual minoxidil could be used to increase follicular minoxidil sulfate bioavailability and thus hair growth. As hepatic sulphation of minoxidil enhances the hemodynamic effect, sublingual minoxidil would decrease the hemodynamic adverse effects and consequently improve the safety profile.
10 CONCLUSION
Hair loss of any type always brings apathy in patients. Treatment with low-dose systemic (oral/ sublingual) minoxidil appears to be the newer therapeutic alternative in managing different alopecia with promising outcomes. Reducing the events of side effects by choosing a lower satisfactory dose seems to be the future direction. The future horizon for systemic minoxidil needs to be explored with pragmatic studies.
Jay D. Modha MD | Yashdeep Singh Pathania MD
Abstract
Background: There have been various treatment modalities available for alopecia in the form of topical and systemic with a variable response. The compliance of the patients is important in reaping results in alopecia. Minoxidil has come a long way finding its use from topical formulations to systemic at lower doses in different alopecia.
Objective: The objective of this article is to discuss various conditions in alopecia where oral minoxidil has found its role. Methods: A comprehensive literature search was performed relating to oral minoxidil's role in various alopecia. Various clinical trials, case series, and case reports were searched on PubMed and Google Scholar. The references of available studies were also reviewed to collect additional resources. Available data from various studies and case reports were collected and consolidated to provide a concise overview of oral minoxidil indications in various alopecia.
Results: Oral minoxidil has been used in various non-scarring and scarring alopecia at a lower dosage with fewer side effects and with promising results. Androgenetic alopecia and female pattern hair loss were the two conditions where it has been used more commonly than other alopecia, providing a ray of hope along with overcoming the issues related to topical formulations and compliance.
1 | INTRODUCTION
Many serendipitous discoveries led to the current popular FDA (Food and Drug Administration) approved medicines in the field of trichology.1 Minoxidil is one such compound that was initially used as oral therapy for hypertension. In the year 1988, US FDA first approved 2% topical minoxidil for androgenetic alopecia in males. Since then, many commercialized topical formulations containing various preparations (lotions, foam) and concentrations (2%, 5%, and 10%) of minoxidil have dominated the treatment armamentarium of alopecia. Currently, topical minoxidil and oral finasteride (1 mg) are the only FDA-approved therapies in males while topical minoxidil alone is for females. Although associated with significantly favorable results, topical use has several limitations such as repeated application, vehicle inconsistencies, cosmetic drawbacks, financial burden, and limited percutaneous absorption.2 To overcome these shortcomings, recently oral minoxidil is being used widely for various hair loss disorders.
The mechanism of hair growth by minoxidil is yet to be understood completely. Minoxidil (2,4-diamino-6-piperidinopyrimidine3-oxide) is a potent peripheral vasodilator that acts via an opening of sarcolemmal ATP2-dependent potassium channels causing the release of nitric oxide (NO). This leads to a decrease in the telogen phase duration and an increase in the anagen phase of the hair follicles.3 It leads to the upregulation of VEGF (vascular endothelial growth factors) causing increased oxygen and growth factor delivery to the follicles. It also exerts the immunomodulatory effect by modulating the effects of Concavalin A (an intermediary for activating the T lymphocytes), which can be beneficial in autoimmune alopecia.4 Being a prodrug, it is metabolized by hepatic dehydroepiandrosterone sulfotransferase (SULT2A1) to minoxidil sulfate.2 Also follicular sulfotransferase enzyme SULT1A1 in the outer root sheath of the hair follicle converts it into its active metabolite.
Given its diverse range of actions, minoxidil is used orally with the hope of various alopecia management with an effort to achieve higher clinical efficacy and better compliance. This review aims to consolidate the use of oral minoxidil in various non-scarring and scarring alopecias.
2 FEMALE PATTERN HAIR LOSS (FPHL)
3 ANDROGENETIC ALOPECIA
4 TRACTIONAL ALOPECIA
5 CHRONIC TELOGEN EFFLUVIUM
6 HAIR SHAFT DISORDERS
6.1 Loose Anagen Syndrome
6.2 Monilethrix
7 SCARRING ALOPECIA
8 ALOPECIA AREATA
9 CHEMOTHERAPY-INDUCED ALOPECIA (ANAGEN EFFLUVIUM)
9.1 Safety profile
Overall, oral minoxidil is found to be better tolerated with fewer adverse effects. Hypertrichosis was the most common anticipated side effect seen in 20% of patients. Despite this, hypertrichosis was not the reason for discontinuation of the therapy as most of the patients understood it as mild and quite manageable. It should be emphasized that hypertrichosis was a dose-dependent adverse effect per se; more commonly seen with a 5 mg daily dose (more than 50% of the patients) whereas 0.25 mg per day had the lowest incidence (less than 10% of patients).27 However, pragmatic studies with larger sample sizes and longer follow-ups are needed to draw a conclusion and determine the relationship between dose and hypertrichosis. As topical minoxidil induces fast re-entry in the anagen phase of the TABLE 1 hair follicles, provoking a transitory telogen effluvium (TE); similarly increased hair shedding is seen with oral minoxidil lasting 3–6 weeks. Patients should be properly counseled for this anticipated event to avoid premature termination of the therapy. Sinclair et al.28 described this adverse effect in 22 out of 100 patients, yet due to pretherapy counseling, none discontinued the treatment, as well as this hair shedding, stopped after 4–6 weeks in almost all the patients. Acute contact dermatitis seen with topical minoxidil due to propylene glycol is of common occurrence, so, Therianou et al. reported that 0.25 mg twice daily oral minoxidil is a safe and satisfactory alternative in those patients. Cardiovascular side effects were usually minor in nature. Blood pressure monitoring was done in many of the studies, which indicated relatively minor changes7,8 Ramos et al.7 has described that there was no significant difference in the MBP (mean blood pressure) of oral minoxidil group when compared with those using topical minoxidil; however, increased heart rate by 6.5% was observed with oral minoxidil. Postural hypotension was seen in 2% of the patients which was managed with 50 mg of sodium chloride daily as reported by Sinclair et al.6 Pedal edema was reported in 3% of patients, which was more common with 5 mg daily dose. Changes in electrocardiogram were seen in approximately 1% of patients, it was mild in nature and consisted of tachycardia, PVC, and T wave changes in lead 1. However, this was recorded in one study only and other studies did not regularly involve EKG monitoring.29 No severe cardiopulmonary events were found in any of the studies.
Newer pharmacokinetic studies regarding minoxidil (oral/ topical) metabolism revealed that intersubjective variability in the activity of sulfotransferase in hepatic (SULT2A1) and follicular (SULT1A1) ultimately yields lower hair regrowth.30 Weak hair growth due to low follicular SULT1A1 cannot be overcome with ML due to low solubility and saturation absorption kinetics but it can be overcome with OM through dose escalation. Sublingual doses of 0.45 and 0.90 mg minoxidil were evaluated by Sinclair et al.31 as the sublingual route bypasses hepatic first-pass metabolism, sublingual minoxidil could be used to increase follicular minoxidil sulfate bioavailability and thus hair growth. As hepatic sulphation of minoxidil enhances the hemodynamic effect, sublingual minoxidil would decrease the hemodynamic adverse effects and consequently improve the safety profile.
10 CONCLUSION
Hair loss of any type always brings apathy in patients. Treatment with low-dose systemic (oral/ sublingual) minoxidil appears to be the newer therapeutic alternative in managing different alopecia with promising outcomes. Reducing the events of side effects by choosing a lower satisfactory dose seems to be the future direction. The future horizon for systemic minoxidil needs to be explored with pragmatic studies.
