Pallavan Pharmacy College, Kolivakkam, Kanchipuram District. 631502
Minoxidil is a popular treatment for hair loss that was approved for androgenetic alopecia several decades ago and has been used off-label for various other hair loss conditions, including alopecia areata and scarring alopecias, with varying degrees of success. It works through multiple biological pathways, including vasodilation and anti-inflammatory effects, to promote hair growth, and its effectiveness may depend on individual differences in sulfotransferase activity. Minoxidil is widely used for androgenetic alopecia, a common type of hair loss affecting millions of people, and recent studies have explored alternative forms of administration, including oral and sublingual minoxidil, with promising results. Originally developed as an antihypertensive medication, minoxidil's side effect of hypertrichosis led to its use for hair growth, and despite its widespread use, more research is needed to fully understand how it works. Minoxidil promotes hair growth by enhancing blood flow and nutrient delivery to the hair follicle through its vasodilator and potassium channel opener effects, and consistent use is necessary to maintain results, although side effects can occur, including irritant and allergic contact dermatitis.
Minoxidil was discovered in 1970 and originally developed to treat hypertension, but its unexpected side effect of hair regrowth led to its use in treating androgenetic alopecia. This discovery prompted the creation of a topical formulation, which was first introduced in a 2% concentration and later in a stronger 5% formula. (1) Millions of people in the US experience pattern hair loss, with an estimated 50 million men and 30 million women affected. Genetic predisposition and androgen receptor variations play a significant role in this condition. Currently, two FDA-approved treatments exist: Oral Finasteride, a 5-alpha-reductase inhibitor that reduces DHT levels and is effective for men, and Topical Minoxidil, a solution that stimulates hair growth. (7) Initially used as an antihypertensive, minoxidil's unexpected side effect of hypertrichosis led to its repurposing as a hair growth agent. (6) Minoxidil promotes hair regrowth through increased cutaneous blood flow and potassium channel activation. While its mechanism of action is not fully understood, its efficacy has been consistently demonstrated. Common adverse effects include facial hypertrichosis and contact dermatitis, scalp pruritus, scalp scaling. Beyond its primary use for AGA, minoxidil has been used off-label for other types of alopecia, including Telogen effluvium (TE), Alopecia areata (AA), Frontal fibrosing alopecia (FFA), Central centrifugal cicatricial alopecia (CCCA), Traction alopecia (TA), Eyebrow hypotrichosis, Monilethrix, Chemotherapy-induced alopecia (CIA). (2) For a long time, oral minoxidil wasn't typically used for hair loss due to concerns about its side effects at higher doses. One of the main issues was the tendency to cause sodium and fluid retention, which could lead to oedema and weight gain. To mitigate this, doctors often prescribed beta blockers to help manage these effects and control heart rate. While oral minoxidil has been linked to some serious cardiac conditions, more recent research has focused on using low-dose, which seem to reduce these risks while still providing benefits for hair loss treatment. This shift has sparked renewed interest in oral minoxidil's potential for treating alopecia. (3) Androgenetic alopecia or male-pattern hair loss occurs when hair follicles shrink due to the influence of dihydrotestosterone, leading to progressive hair loss. This condition affects many people, with its prevalence increasing with age - approximately 73% of men and 57% of women over 80 are affected. Research suggests that this condition can have emotional impacts such as feelings of self-conscious preoccupation and diminished attractiveness. Currently, there are FDA-approved medications like minoxidil and finasteride, as well as low-level laser light therapy (LLLLT), available to address this condition. However, a comprehensive analysis of the effectiveness of these treatments has not been conducted. (5)
Pharmacological insights of Minoxidil:
Figure 1: Chemical structure of Minoxidil
Minoxidil's chemical structure (2,6-diamino-4-piperidinopyrimidine-1-oxide) enables it to effectively promote hair growth. The Minoxidil Solution (MS) formulation contains ingredients like ethanol and propylene glycol (PG) to enhance solubility, but these can cause irritation. A newer PG-free Minoxidil Foam (MF) formulation was developed to minimize irritation while improving delivery. This foam version is more convenient, dries quickly, and targets the affected area more precisely. Minoxidil works by widening blood vessels and stimulating cell growth through potassium channel activation. Its active metabolite, minoxidil sulfate, produced by the enzyme sulfotransferase in hair follicles, is key to its effectiveness. However, individual variations in enzyme activity can impact treatment response. Certain medications, like aspirin, can reduce the enzyme's activity, diminishing minoxidil's benefits. When applied topically, minoxidil is minimally absorbed systemically, and most of the absorbed amount is eliminated through the kidneys. (1)
Physiological actions of Minoxidil:
Long-term use of Minoxidil has shown to effectively promote hair growth and reduce hair loss. When the treatment is discontinued, hair loss tends to resume within 12 to 24 weeks. Studies have found that Minoxidil accelerates the transition of hair follicles from the telogen phase to the anagen phase, leading to increased hair density. Clinical trials have demonstrated significant improvements in hair growth and reduced hair loss, particularly at higher concentrations (5% formulation). The medication appears to work by enhancing blood flow and stimulating cell growth in the hair follicles through β-catenin activity and increased VEGF expression. It also increases the production of factors that promote perifollicular vascularization and hair growth. Additionally, it influences the production of prostaglandin E2, which helps maintain the anagen phase. Overall, Minoxidil has been shown to be effective in promoting hair growth and reducing hair loss. (1)
Effect of Minoxidil oh Hair Follicle Dynamics:
The process by which minoxidil fosters hair growth is multifaceted, potentially encompassing several key actions, including prolonging the anagen phase (active growth phase) of the hair follicle cycle, shortening the telogen phase (resting phase), and increasing hair diameter by enhancing the thickness of individual hair strands. Through these actions on the hair cycle and hair fibre thickness, minoxidil promotes hair growth, enhances hair density, and increases the length and diameter of hair fibres. Although the precise molecular details of its mechanism remain unclear, its impact on the hair cycle and fibre diameter plays a significant role in its effectiveness for addressing hair loss conditions such as androgenetic alopecia (AGA). (9)
Impact of Minoxidil in Humans:
The impact of minoxidil on typical human hair growth remains somewhat enigmatic, with the majority of studies examining its efficacy in addressing androgenetic alopecia (AGA). In cases of male pattern baldness (male AGA), minoxidil has demonstrated a swift increase in hair growth, noticeable within 6-8 weeks of initiating treatment and reaching its peak effect around 12-16 weeks. This prompt response is likely attributed to minoxidil's ability to stimulate follicles in the telogen phase (resting phase) to transition into the anagen phase (active growth phase), rather than reversing the miniaturization of hair follicles. Additionally, minoxidil may extend the duration of the anagen phase, as suggested by the increased hair length observed in areas affected by hypertrichosis (excessive hair growth). Histopathological investigations have yielded mixed findings, with some studies indicating an increase in the anagen/telogen ratio and an augmentation in mean hair diameter, while others have reported less definitive results. The observed increase in mean hair diameter might be the result of preferential recruitment of large diameter hairs rather than individual follicle hypertrophy. Given the complexity of minoxidil's mechanism of action, further research is necessary to gain a comprehensive understanding of its effects on human hair growth and its potential applications in treating hair loss conditions. (9)
Impact of Minoxidil in Animals:
Studies have explored the impact of minoxidil on hair growth using different experimental models. In one investigation involving rats, topical application of minoxidil was found to reduce the duration of the telogen phase (resting phase), enabling hair follicles to transition into the anagen phase (active growth phase) more rapidly, while not influencing the length of anagen itself. In a primate model, the stump-tailed macaque, which exhibits androgenetic alopecia (AGA) closely resembling human balding, topical minoxidil was shown to prevent scalp hair loss and stimulate regrowth in animals experiencing baldness. Histological examination demonstrated that minoxidil treatment resulted in an increased proportion of hair follicles in anagen, a decrease in telogen follicles, and an enlargement of hair follicle size. These results imply that minoxidil's mechanism of action involves regulating the hair growth cycle and promoting hair growth, making it a potential therapeutic option for treating AGA and other hair loss conditions. (9)
Minoxidil Sulphation:
The sulphated derivative of minoxidil, minoxidil sulphate, is the active form responsible for the drug's antihypertensive effects, achieved through the relaxation of vascular smooth muscle. This biochemical reaction is facilitated by sulphotransferase enzymes. Research has identified minoxidil sulphotransferase activity in various tissues, including rat liver, human liver, platelets, and keratinocytes, as well as in mouse vibrissae follicles, rat pelage, and rat keratinocytes. In the scalp skin of stump tail macaques, sulphotransferase activity is largely localized in the hair follicle. Human cytosolic sulphotransferase enzymes are encoded by five known genes, responsible for sulphating phenols and catecholamines, oestrogens, and hydroxysteroids. Notably, interindividual variations in scalp sulphotransferase activity are correlated with activity levels in platelets. The mechanism of action of minoxidil sulphate involves the opening of adenosine triphosphate (ATP)-sensitive potassium channels (KATP channels) in the plasmatic membrane. These KATP channels are present in multiple tissues and cell types, including heart, pancreas, vascular smooth muscle, and central nervous system. Potassium channel activity may also be required for early-stage cell proliferation by G1 progression of the cell cycle. Minoxidil may increase DNA synthesis, as demonstrated in hepatocyte cultures. Other potassium channel openers, such as diazoxide and pinacidil, can cause hypertrichosis in humans, similar to minoxidil. Studies have shown that minoxidil, Cromalin, and P-1075 (a pinacidil analogue) stimulate hair growth in balding macaques, and increase thymidine uptake in hair growth cultures of mouse vibrissae follicles and human hair follicle organ cultures. (10)
Mechanism of Action of Minoxidil:
Minoxidil, appears to have a multifaceted impact on hair growth, influencing various biological processes. Its effects may include vasodilation to improve blood flow, anti-inflammatory properties to reduce inflammation, and modulating the Wnt/β-catenin signalling pathway that regulates hair follicle activity. Additionally, it may impact the duration of the anagen (hair growth) and telogen (resting) phases, contributing to its overall efficacy in promoting hair growth. By targeting multiple mechanisms, this treatment may achieve a more comprehensive effect on hair follicle health, also exhibiting antiandrogen effects. (6)
1.Circulatory Enhancer:
The action of Minoxidil triggers a response that opens ATP-sensitive potassium (KATP) channels, leading to vasodilation and improving circulation. This enhanced blood flow may provide hair follicles with increased access to vital nutrients and oxygen. As a result, hair growth may be stimulated, and follicle health improved. By easing vascular tension and reducing systolic and diastolic blood pressure, this treatment may also have a beneficial effect on blood pressure, which could further support its role in promoting hair growth. (6)
2.Inflammatory Suppressant:
One theory is that Minoxidil fosters hair growth by mitigating perifollicular microinflammation. Studies have shown that it can suppress T-lymphocyte activity and decrease the production of pro-inflammatory substances, such as interleukin-1α and prostacyclin. By reducing localized inflammation, this treatment may promote a healthier environment for hair to grow. This potential anti-inflammatory mechanism could be a key factor in its effectiveness for addressing hair loss. Furthermore, reduced inflammation may lead to increased hair density and growth rate, and anti-inflammatory effects may help counteract the negative impact of inflammation on hair follicle stem cells. Additionally, Minoxidil's anti-inflammatory properties may complement its vasodilatory effects, enhancing overall hair growth promotion, which suggests that its anti-inflammatory action plays a significant role in its therapeutic benefits for hair loss treatment. (6)
3.Activator of wnt/b-catenin signalling
Minoxidil may promote hair growth by triggering the production of Vascular Endothelial Growth Factors (VEGF) that stimulate vascularization. VEGF can activate the β-catenin signalling pathway, which supports the development and regeneration of hair follicles through the Wingless-Int (Wnt) pathway. Additionally, the increased vascularization may help prolong the anagen phase of hair follicles, particularly in cases of Androgenetic Alopecia (AGA), leading to improved hair growth and regeneration. This mechanism is further supported by the potential benefits of enhanced vascularization, including increased oxygen and nutrient delivery to hair follicles, VEGF's role in angiogenesis supporting healthy hair follicle growth and maintenance, and the crucial involvement of the β-catenin signalling pathway in hair follicle development and cycling, all of which highlight the importance of VEGF and β-catenin signalling in minoxidil's hair growth-promoting effects. (6)
4.Androgen Suppression:
Research suggests that Minoxidil might have a role in blocking the effects of androgens. In lab studies, it's been shown to decrease the activity of 5α-reductase type 2 in human keratinocyte cells. However, other studies have yielded mixed results, with some indicating a potential increase in 5α-reductase activity in dermal papilla cells from balding scalps or no effect in animal models like the golden hamster. As a result, the evidence for Minoxidil's antiandrogenic properties is not yet conclusive. The complexity of this issue is further highlighted by variability in 5α-reductase expression and activity across different cell types and tissues, suggesting that Minoxidil's potential antiandrogenic effects may be dependent on specific cellular or tissue contexts. Ultimately, additional research is needed to clarify the mechanisms underlying Minoxidil's potential antiandrogenic properties and their relevance to hair growth promotion, underscoring the need for further investigation into this multifaceted topic. (6)
5.Genetic Replication and Cellular growth:
Minoxidil appears to enhance DNA synthesis in the hair follicle bulb, promoting the anagen phase. By stimulating secondary germ cells in telogen follicles, it can potentially accelerate the transition from the telogen phase to the anagen phase, leading to earlier hair growth initiation. This mechanism may be further supported by increased cell proliferation and growth in the hair follicle, enhanced hair follicle development and maintenance, and potential prolongation of the anagen phase, ultimately leading to thicker and longer hair. These factors highlight the potential benefits of Minoxidil's effects on DNA synthesis and hair growth initiation, underscoring its role in promoting hair growth. (6)
6.Role of Minoxidil in Anagen and Telogen Phase:
Minoxidil may influence hair growth by altering the balance between the anagen and telogen phases of hair follicles. In one study, a topical Minoxidil solution was found to shorten the telogen phase, allowing hair growth to commence earlier. Another study showed that a higher concentration of Minoxidil solution affected both anagen and telogen phases and enlarged hair follicles. In human trials, topical application of a lower concentration of Minoxidil increased the number of hairs in the anagen phase while reducing the number of hairs in the telogen phase. These findings suggest that Minoxidil can promote hair growth by regulating the hair growth cycle. (6)
7.Autoimmune
Researchers have explored the potential benefits of Minoxidil for treating Alopecia Areata, an autoimmune disorder that causes hair loss. One theory is that applying Minoxidil directly to the scalp may reduce local immunological events, allowing hair to regrow. This potential mechanism is supported by its possible role in modulating cytokine activity to regulate immune responses, enhancing hair follicle survival and reducing inflammation, as well as stimulating hair growth through increased blood flow and nourishment to the hair follicles. Although these findings are promising, the precise impact of Minoxidil on the body's immune system in vivo remains unknown, necessitating further research to fully understand its effects and optimize treatment approaches. (6)
Effects of Minoxidil on cells:
The hair follicle is a multifaceted structure comprising a diverse array of cell types, including epithelial, dermal, immune, and pigmented cells, as well as a vascular and neural network. The interplay between these cellular components governs their differentiation and, subsequently, the hair cycle. Investigations focusing on mouse hair follicles have revealed that both minoxidil and minoxidil sulphate tend to accumulate in melanocytes and pigmented cells of the suprapapillary region of the follicle. This targeted accumulation may contribute to the mechanism by which minoxidil influences hair growth, highlighting the complex interactions between various cell types in the hair follicle. (10)
1.Synthesis of Collagen:
Investigators discovered that minoxidil suppressed the activity of the enzyme lysyl hydroxylase in human skin fibroblast cultures, resulting in the production of collagen deficient in hydroxylysine. One of the primary steps in collagen synthesis involves the hydroxylation of lysine residues, which is facilitated by a family of lysyl hydroxylases. This hydroxylation process is vital for the formation of enzymatic cross-linking. In fibrotic disorders characterized by excessive collagen accumulation, the increased cross-linking renders collagen more resistant to proteolytic degradation. Minoxidil's impact on collagen production is most pronounced on LH1 mRNA levels, involved in the hydroxylation of triple helical lysine. By reducing the levels of LH1 mRNA, minoxidil decreases lysyl hydroxylase activity, potentially limiting the formation of hydroxyallysine cross-links. Some research suggests that this effect could contribute to minoxidil's potential anti-fibrotic properties. However, other studies, such as those by Zuurmond et al., attribute minoxidil's effects on collagen to alterations in the collagen matrix rather than a reduction in fibrosis. (10)
2.Cytoplasmic Growth:
Research has indicated that minoxidil can have a dual effect on cell growth, promoting proliferation at certain concentrations while inhibiting it at higher levels. Studies have found that elevated concentrations of minoxidil can impede the growth of skin fibroblasts, as demonstrated by Murad and Pinnell. The variability in results from cell culture experiments may be attributed to the presence of aminoglycoside antibiotics, which block potassium channels and are often added to cell culture media, as hypothesized by Sanders et al. In experiments where these aminoglycoside antibiotics were absent, minoxidil was shown to enhance the growth of skin fibroblasts, but this effect was not observed when the antibiotics were present. Furthermore, the aminoglycosides partially diminished the ability of human keratinocytes to respond to minoxidil's growth-promoting effects. (10)
3.Effect on Androgen Receptor:
The mechanism of action of minoxidil on hair growth appears to be distinct from androgen pathways, given its ability to promote hair growth in both androgen-dependent and androgen-independent hair follicles. Nevertheless, research conducted by Sato et al. reveals that minoxidil stimulates the activity of 17 beta-hydroxysteroid dehydrogenase, an enzyme that catalyses the dehydrogenation of 17-hydroxysteroids in steroidogenesis, particularly converting testosterone to androstenedione. Furthermore, minoxidil exhibits a small inductive effect on 5-alpha-reductase, another enzyme involved in androgen metabolism. These findings imply that although minoxidil's primary mechanism may not be directly linked to androgen pathways, it may still exert some influence on androgen metabolism within the hair follicle, particularly in dermal papilla cells. (10)
4.Synthesis of Prostaglandin:
Studies have found that minoxidil enhances the production of specific signalling molecules, including PGE2 and leukotriene B4, in dermal papilla cells, while reducing the production of prostacyclin. This effect may be due to the activation of prostaglandin endoperoxidase synthase-1. Additionally, minoxidil increases the expression of the EP2 receptor, a specific receptor for PGE2, which is the most upregulated target gene of β-catenin signalling in human DPCs. The increased expression of EP2 may contribute to the prolongation of the anagen phase. (10)
5.Vascular effects:
Researchers examined the impact of topical application of minoxidil, at varying concentrations (1%, 3%, and 5%), on blood flow in the balding scalp using laser Doppler velocimetry (LDV) and photo pulse plethysmography. The results indicated an increase in skin blood flow, particularly with the 5% solution. However, another study by Bunker and Dowd found no significant change in skin blood flow after applying a 3% minoxidil solution to the scalp in a group of men, although they did respond to 0.1% hexyl nicotinate, a known vasodilator. A separate investigation by Sakita et al. using electronic microscopy observed changes in the hair follicle vasculature in individuals treated with minoxidil, noting an increase in capillary fenestrations. (10)
6.VEGF:
A research study found that minoxidil enhances the production of VEGF, a protein that promotes the formation of new blood vessels around hair follicles, leading to increased hair growth. VEGF's expression in human dermal papilla cells is boosted by minoxidil in a dose-dependent fashion. The increased perifollicular vascularization is thought to contribute to the accelerated hair growth observed with minoxidil's use. (10)
Pharmacokinetics of Minoxidil:
Absorption:
The body absorbs oral Minoxidil quickly through the gastrointestinal tract, with peak plasma concentrations appearing in the bloodstream within a short time frame, typically within an hour. Topical application of Minoxidil, however, results in much less absorption, with only a small fraction (approximately 1.2-1.4% for 2-3% solutions) of the applied amount entering the bloodstream. Consequently, serum concentrations of Minoxidil are typically very low, often barely detectable, usually below 5 ng/mL. Research has shown that even when applied topically, Minoxidil's presence in the blood can be minimal and variable. Interestingly, the amount absorbed through topical application is estimated to be equivalent to a relatively low oral dose, with two applications of 5% topical Minoxidil predicted to be equivalent to around 5.4mg oral dose. (6)
Distribution and Metabolism:
The metabolism of Minoxidil into its active sulphated metabolite is critical for its effectiveness, as this metabolite is responsible for its therapeutic benefits. When ingested orally, Minoxidil is primarily metabolized in the liver through glucuronidation, hydroxylation, and sulfation. It has been observed that Minoxidil has minimal binding to plasma proteins and does not cross the blood-brain barrier. In the case of topical Minoxidil application, follicular sulfotransferase plays a crucial role in activating the medication, highlighting the importance of local biochemical processes in its mechanism. (6)
Excretion:
Minoxidil is cleared from the body fairly rapidly when taken orally, with an elimination half-life of 3-4 hours. The kidneys play a key role in removing it from the body, with most of it being excreted in the urine within 12-20 hours. After topical application is stopped, the body efficiently eliminates the absorbed amount, with approximately 95% of systemically absorbed Minoxidil being cleared within 4 days. (6)
Androgenetic aloplecia:
Androgenetic alopecia (AGA), also known as male/female pattern baldness, is a common hereditary condition characterized by progressive hair thinning and loss, particularly on the scalp. It affects approximately 50% of men and women by age 50, with varying degrees of severity. The condition is influenced by genetics, hormones, and aging, with dihydrotestosterone (DHT) playing a key role in hair follicle miniaturization. Family history also contributes to the risk, and other factors such as stress, nutritional deficiencies, and certain medical conditions may also play a role. AGA disrupts the normal hair growth cycle, leading to a shorter growth phase and a longer resting phase, resulting in progressive hair thinning and increased shedding. Symptoms typically start at the temples in men and the crown in women, with gradual progression over time. Diagnosis involves clinical examination, medical history evaluation, and sometimes scalp biopsy. While lifestyle modifications such as stress management, a balanced diet, and gentle scalp care may help promote hair growth, understanding the condition early on can help individuals make informed decisions about managing their hair loss. Each person's experience with AGA is unique, and ongoing research may lead to a better understanding of the condition.
Patients:
The clinical trial's methodology involved assessing 70 individuals with mild to moderate androgenetic alopecia (AGA) for study eligibility. Ineligible participants included those who had recently used topical or systemic treatments for AGA, patients with other causes of hair loss such as inflammatory or scarring alopecia, hyperandrogenism, or hormonal disorders, and those with hypersensitivity to minoxidil or severe systemic diseases like renal, cardiovascular, or hepatic issues. Additionally, patients with hypotension/hypertension or those on antihypertensive therapy, as well as pregnant or breastfeeding women, were excluded. One person declined participation, and four others were deemed ineligible. Eligible participants underwent a thorough scalp examination and trichoscopy to rule out other hair loss causes, staging of AGA using the Norwood-Hamilton scale (for males) or Ludwig scale (for females), and various laboratory tests, including haematological, liver and kidney function, thyroid function, electrolytes, and pregnancy tests (for females). Blood pressure and body weight were also monitored during follow-up visits, ensuring a comprehensive evaluation that prioritized safety and accuracy. (12)
Treatment protocol:
The study involved 65 participants who were randomly assigned into two groups based on a block randomization strategy. One group received a daily dose of 1 mg oral minoxidil, while the other group applied topical minoxidil 5% (with men using 1 cc twice daily and women using 1 cc once daily). The treatment lasted for 6 months, during which patients were required to return for assessments at 3 and 6 months after treatment initiation. The medications used in the study were prepared under the supervision of pharmaceutical consultants at the University Pharmacy Faculty laboratory. (12)
Figure 2: Flow chart of study
Evaluvation:
1.Photographic evaluation:
To assess hair growth, standardized photographs of the mid-anterior scalp were taken using a digital camera with consistent positioning, consistent hairstyle, and consistent lighting. A stereotactic positioning device ensured accurate positioning. Close-up photos were also taken of specific areas marked with tattoos located at 12, 16, and 24 cm from the glabella. Two independent investigators, unaware of the treatment details, evaluated the photographs using a standardized 7-point rating scale to rate hair growth compared to the initial state. The scale ranged from +3 (greatly increased) to -3 (greatly decreased), with intermediate ratings for moderately increased (+2), slightly increased (+1), no change (0), slightly decreased (-1), and moderately decreased (-2). (12)
2.Follicular count and Shaft Thickness:
To measure hair growth and thickness, three scalp locations were tattooed (using Jet Black Micro pigment, BioTouch Company, USA) and used as reference points: the frontal point (12 cm from the glabella), the mid-frontal point (16 cm from the glabella), and the vertex point (24 cm from the glabella). High-resolution macrophotographs of these areas were captured using a dermoscopic device (FotoFinder System Gmbh) connected to a camera (Canon EOS M100 camera), and a blinded technician counted the hairs within a 1 cm2 area around each tattoo. Additionally, the thickness of five randomly selected hairs near each tattoo was measured using 3D Slicer 5.2.2 software, and the results were averaged for each location. This method ensured accurate and reliable assessments of hair growth and thickness. (12)
3.Patient self-assessment questionnaires:
Patients rated their treatment satisfaction on a 1-10 scale, with 10 representing the highest satisfaction and 1 indicating the lowest. Their scores were then grouped into four satisfaction categories using a Likert scale: no satisfaction (scores 1-3), low satisfaction (scores 4-5), moderate satisfaction (scores 6-7), and high satisfaction (scores 8-10). (12)
4.Safety evaluvation:
Medication safety was assessed through take-home patient diaries, medical history taking, and physical examinations. Patients reported any symptoms, including postural hypotension, orthopnoea, chest pain, nausea, and sexual dysfunction. Physical exams evaluated vital signs, blood pressure (in both sitting and standing positions), weight, pitting oedema, and the presence of hypertrichosis on the face and body. (12)
5.Statistical Evaluvation:
The study's data analysis utilized SPSS version 23, incorporating descriptive statistics (mean, standard deviation, and frequency) and comparative analyses. For comparisons, Student's t-test was applied to parametric variables, Mann–Whitney U-test to nonparametric variables, and Chi-squared and Fisher exact tests to categorical variables, enabling a thorough examination of the data through All analyses were accurately conducted. (12)
Results:
A total of 65 patients with AGA, consisting of 42 (64.1%) females and 23 (35.9%) males with a mean age of 31.62 ± 9.24 years, were enrolled in the study after evaluating 70 potential participants. The most common AGA classification was Type 2 for males (modified Norwood-Hamilton) and Type 1 for females (Ludwig). The study found significant increases in mean hair diameter at 6 months compared to baseline in both topical and oral minoxidil groups (p < 0.001). However, there was no significant difference between the two groups. Expert panel photographic assessment revealed significant improvements in hair density in the topical minoxidil group at all points (12 cm, p = 0.025; 16 cm, p = 0.034; 24 cm, p = 0.014), but not in the oral minoxidil group, with no significant difference between the groups. Patient satisfaction was high, with over 60% of patients in both groups reporting medium to high satisfaction. (12)
Safety:
The 6-month trial did not encounter any serious adverse effects. However, one patient in the oral minoxidil group experienced orthostatic hypotension, which was readily managed by increasing her daily salt consumption, and she continued the study. Minoxidil-induced telogen effluvium occurred in three patients in the oral minoxidil group and four patients in the topical minoxidil group, leading to discontinuation of all patients in the topical group due to this side effect. Hypertrichosis on the face and extremities was reported by two patients in the oral group and one patient in the topical group, resulting in one patient from each group dropping out due to facial hypertrichosis. (12)
Topical Minoxidil in Treatment of Non-AGA:
1.Alopecia Areata (AA):
Alopecia areata and its variants, alopecia total is and alopecia universalis, are complex, immune-mediated conditions where patients often use topical minoxidil off-label, despite the lack of approval for this specific use. AA is characterized by clearly demarcated patches of non-scarring alopecia that are round or oval in shape, with its variants defined by increased severity—complete alopecia of the scalp in the case of alopecia totalis, and complete alopecia of the entire body in alopecia universalis. Treatment options are limited, and various therapies have been explored, including corticosteroids, topical immunotherapy, biologics, non-corticosteroid systemic immunosuppressants, and JAK inhibitors. The use of minoxidil in treating AA has a biologic basis, as it has been shown to suppress DNA synthesis and leukocyte inhibitory factor in lymphocytes, potentially promoting hair regrowth through a local immunosuppressive effect. However, in vivo studies have yielded mixed results. Some randomized controlled trials have demonstrated benefits of minoxidil in AA. For instance, studies using 1% minoxidil applied once or twice daily showed significant hair regrowth responses, with a cosmetically acceptable hair regrowth response rate of 78.6% in one study and 81% in another. Other trials used 2% minoxidil after an initial 6-week induction course of prednisolone, finding that minoxidil may be effective in maintaining prednisolone-induced hair growth. Conversely, other RCTs have reported no significant effect. These studies varied in minoxidil concentration and treatment duration, with some critiquing the short duration or focus on severe AA cases. The effectiveness of minoxidil may be inversely correlated with disease severity. Despite the inconclusive evidence, many clinicians continue to use minoxidil as part of their treatment regimens for AA. The efficacy of minoxidil may depend on the severity of AA, with better results in milder cases. Further research is needed to determine the optimal use and effectiveness of minoxidil in treating AA. (2)
2.Telogen Effluvium:
Telogen effluvium (TE) is a non-inflammatory, non-scarring hair loss condition often triggered by emotional or physiologic stressors like underlying diseases, surgery, pregnancy, or medication. It occurs when a large quantity of hair follicles enters the telogen (resting) phase and fall out 3–5 months later. Although TE is typically self-limited and treatment isn't usually recommended, topical minoxidil is sometimes offered due to its theoretical benefit. Research suggests that minoxidil may help mitigate stress-induced hair changes. A study on oral minoxidil for chronic TE found a significant reduction in hair shedding after 6 and 12 months, with patients taking daily oral minoxidil (range 0.25–2.5 mg) for 1 year, but further research is needed to confirm the safety and efficacy of both topical and oral minoxidil for treating TE. (2)
3.Scarring Alopecia:
Scarring alopecia encompasses a range of conditions characterized by the destruction of hair follicles and replacement with fibrotic scar tissue, including Frontal Fibrosing Alopecia (FFA), Central Centrifugal Cicatricial Alopecia (CCCA), and chronic Traction Alopecia (TA). Topical minoxidil is frequently suggested as a complementary treatment for various forms of scarring alopecia, despite lacking formal approval. Given the challenges in treating scarring alopecia due to the low likelihood of hair regeneration in scarred areas, the primary objective of using minoxidil is to optimize growth of surviving hair while other therapies address inflammation. Since follicles that are completely destroyed cannot regenerate, the focus is on preserving the health and maximizing the growth potential of surviving hair follicles. (2)
4.Paediatric AA:
Paediatric alopecia areata (AA) is a notable condition affecting dermatology patients, with limited evidence on effective treatments. A recent report involving over 500,000 dermatology patients in the US found that paediatric AA accounts for 18.1% of all AA patients and 0.9% of all paediatric dermatology patients. While common treatments include topical and intralesional corticosteroids, immunotherapy, and topical minoxidil, their efficacy and safety in children are less clear. Children may be more susceptible to side effects from minoxidil, including lack of efficacy, unwanted excessive hair growth (hypertrichosis), and cardiovascular effects like palpitations and dizziness. Due to the limited literature, mostly based on case reports, and lack of randomized clinical trials, healthcare providers should exercise caution when considering minoxidil for paediatric patients, closely monitor for adverse effects, and provide patient education on proper application and potential side effects. (2)
5.Central Centrifugal Cicatricial Alopecia:
Central Centrifugal Cicatricial Alopecia (CCCA) is a prevalent form of hair loss predominantly impacting African American women, with an unclear etiology linked to hairstyling practices and genetic predisposition. The condition progresses gradually, starting at the vertex of the scalp, with follicular degeneration, fibrosis, and inflammation. Treatment typically involves a combination of strategies, including reducing potentially damaging hairstyling practices, administering topical or intralesional corticosteroids to reduce inflammation, and utilizing minoxidil in conjunction with other treatments to potentially slow disease progression and combat follicular miniaturization. Some experts, such as Herskovitz and Miteva, suggest that combining minoxidil with corticosteroids or calcineurin inhibitors may help halt disease progression. However, the current research on CCCA and minoxidil is limited, yielding mixed results, with some reports listing minoxidil as a potential treatment option without discussing efficacy, and others suggesting it may not be beneficial. Specifically, a retrospective review of 15 patients treated with combinations of corticosteroids, minoxidil, and anti-dandruff shampoo, and a case report, found that minoxidil did not produce significant improvements in CCCA patients. Further investigation is necessary to fully understand minoxidil's effects in treating CCCA and determining its potential role in managing the condition. Combining these treatments may help slow disease progression, but further research is necessary to determine the efficacy and potential role of minoxidil in managing CCCA. (2)
6.Frontal Fibrosing Alopecia:
Frontal Fibrosing Alopecia (FFA), a scarring hair loss condition affecting the frontal hairline, is often seen in postmenopausal women. Treatment options are varied and may include topical and intralesional corticosteroids, tetracycline antibiotics, hydroxychloroquine, 5-α-reductase inhibitors, and pioglitazone, with minoxidil sometimes used in combination with other therapies to potentially halt the progression of the disease. A large retrospective study of 355 patients found that 78% used topical minoxidil and corticosteroids as part of their therapy, but efficacy was variable. The effectiveness of minoxidil in treating FFA is debated, with some studies suggesting it may help halt disease progression when combined with other treatments, such as finasteride. One case series reported that patients treated with intralesional corticosteroids and triamcinolone acetonide, finasteride, and minoxidil experienced halted disease progression and increased hair density. However, other reports indicate minoxidil's role is limited, with some studies finding it ineffective or outperformed by oral finasteride and dutasteride. Despite mixed results, minoxidil may still be considered in FFA treatment due to the common comorbidity of androgenetic alopecia (AGA) in FFA patients. Further research is needed to determine minoxidil's potential benefits and limitations in managing FFA and to establish its role in treatment regimens. (2)
7.Eyebrow Hypotrichosis:
Sparse or thin eyebrows, known as eyebrow hypotrichosis, can be a cosmetic concern for many individuals. This condition can occur without a known cause (idiopathic), result from trauma, medical, or surgical treatment, or be associated with underlying health conditions such as hypothyroidism or other hair loss disorders like alopecia areata (AA) or frontal fibrosing alopecia (FFA). Various treatments have been explored, including bimatoprost (a prostamide approved for eyelash hypotrichosis), hair transplantation, and minoxidil. Notably, minoxidil has been studied in several randomized, double-blind trials for eyebrow hypotrichosis. One such study compared the effectiveness of 2% minoxidil lotion to a placebo in 39 participants via a split-face protocol, evaluating outcomes such as global change, eyebrow diameter, hair count, safety, and satisfaction after 16 weeks of treatment. The results showed that topical minoxidil was well-tolerated and effective in promoting eyebrow hair growth. Another study compared the efficacy of minoxidil to bimatoprost in 27 participants using a split-face protocol, finding both treatments to be equally efficacious in improving eyebrow hair diameter and patient satisfaction after 16 weeks of treatment. Although minoxidil was associated with a slightly higher incidence of contact dermatitis, the researchers still preferred it as a first-line treatment option. These studies suggest that minoxidil may be a viable treatment for eyebrow hypotrichosis. (2)
8.Monilethrix:
Monilethrix is a rare genodermatosis characterized by brittle, fragile hair with a beaded appearance (beading of the hair shaft) and keratosis pilaris. The condition results from mutations in the epithelial keratin gene cluster and exhibits an autosomal-dominant inheritance pattern with variable expression. Currently, there is no cure, and treatment options are limited, including retinoids, n-acetylcysteine, griseofulvin, and gentle hair care (avoiding trauma to the hair). Recent case reports and series suggest that minoxidil, both topical and oral, may be a promising treatment option. A 2011 study involving four patients aged 5-47 years found that topical minoxidil increased normal hair shaft growth via video dermatoscopy over a 1-year period without adverse effects. Similar findings were reported in a case study of a 6-year-old patient who experienced some regrowth after a few months of topical minoxidil treatment. Additionally, a 2016 case series demonstrated improved hair growth and density in two adult patients treated with oral minoxidil at doses of 0.25 and 0.5 mg, with sustained benefits and no side effects at 18 and 24 months. While these results are promising, further research is necessary to fully assess the efficacy and safety of minoxidil in treating monilethrix, particularly in paediatric patients. Minoxidil has also been explored as a treatment for other rare hair shaft genodermatoses, such as trichorrhexis nodosa, pili annulati, and pili bifurcate, highlighting the need for more comprehensive studies in both adult and paediatric populations. (2)
9.Traction Alopecia:
Traction alopecia (TA) is a distinct form of scarring alopecia resulting from prolonged tension on the hair follicles, often due to certain hairstyles that inflict trauma on the hair. Unlike other scarring alopecias like frontal fibrosing alopecia (FFA) and central centrifugal cicatricial alopecia (CCCA), the etiology of TA is well understood, and it is often associated with hair care practices. Notably, TA is reversible in its early stages, making timely treatment crucial to prevent permanent damage. In clinical practice, patients with TA are often advised to use minoxidil in addition to adopting lower-risk hairstyles, corticosteroids, and antibiotics. Although clinical trials are lacking, a notable case report documented substantial hair regrowth (assessed visually) in two patients treated with 2% minoxidil alone. Interestingly, both patients had longstanding TA, with symptoms persisting over 1 year after they stopped wearing the traumatic hairstyles. While further research is necessary to confirm the efficacy of minoxidil, its frequent recommendation in the literature suggests it is a commonly utilized treatment approach for TA. (2)
10.Chemotherapy?Induced Alopecia and Permanent Chemotherapy?Induced Alopecia:
Chemotherapy-induced alopecia (CIA) is a distressing side effect of cancer treatment, resulting from apoptotic damage to proliferating hair follicle cells. The hair loss is characterized by either telogen or anagen effluvium, and occurs within weeks of starting treatment. The primary goal in minimizing CIA is preventing the initial cytotoxicity. Scalp cooling has shown promise in preventing CIA, with several randomized trials demonstrating its benefits. Other treatments, including scalp tourniquets, the immunomodulatory compound AS101, and vitamin D3, have been evaluated for prevention with varying degrees of success. Minoxidil has been studied extensively for both prevention and treatment of CIA, but the results are mixed. While minoxidil has not been shown to prevent CIA, it may be beneficial for treating CIA by hastening hair regrowth after chemotherapy. A randomized, double-blind trial found that topical minoxidil increased the duration of time to initial hair loss and reduced the period of baldness by approximately 50.2 days. However, minoxidil appears to be ineffective in treating permanent CIA (PCIA), a condition characterized by persistent hair loss for 6 or more months after chemotherapy cessation. PCIA has been associated with various chemotherapy regimens, including busulfan, cyclophosphamide, and taxanes, such as docetaxel, paclitaxel, and tamoxifen. There are currently no established treatments for PCIA. Topical minoxidil has been found to be ineffective in facilitating hair regrowth in PCIA patients, although oral minoxidil may hold some promise. A case report documented subjective hair regrowth and histological changes (decreased telogen follicles, reversed miniaturization) after 2 years of oral minoxidil treatment (1 mg daily), with no adverse events. Further research is needed to confirm the efficacy of oral minoxidil for PCIA. (2)
Minoxidil Induced Hair Growth via Growth Factor Activation from Adipose Stem Cells:
Adipose-derived stem cells (ASCs) have been found to stimulate hair growth by promoting the activity of dermal papilla (DP) cells in the hair follicle. These ASCs release various growth factors that support hair growth, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (beg). Research has shown that adipocyte lineage cells play a crucial role in regulating the hair growth cycle by contributing to the skin stem cell niche. Grafting ASC-enriched adipose tissue has emerged as a potential treatment for baldness. Certain substances, such as vitamin C and low-dose ultraviolet B (UVB), have been found to enhance the hair-regenerative potential of ASCs. Other factors, including platelet-derived growth factor-D (PDGF-D) and catholicising antimicrobial peptide (LL-37), have also been shown to stimulate the release of growth factors and promote hair growth. Minoxidil, a medication commonly used to treat hair loss, has been found to directly stimulate hair growth by promoting the activity of DP and epithelial cells and increasing blood flow. However, it is unclear whether minoxidil can also indirectly promote hair growth by stimulating ASCs. This study aimed to investigate the potential indirect effects of minoxidil on hair growth via ASCs. (8)
RESULTS:
1.Minoxidil Promotes ASC Mobility:
The impact of minoxidil on adipose-derived stem cells (ASCs) was assessed. Minoxidil did not influence the proliferation of ASCs, even at high concentrations (20 and 50 μM). However, it significantly enhanced their migratory ability, as demonstrated by scratch wound and transwell migration assays. In contrast, minoxidil had no effect on the growth or migration of dermal fibroblast cells, suggesting a specific effect on ASCs. Previous research suggested that minoxidil promotes hair growth by inducing vasodilatation and increasing blood flow to the dermal papilla (DP). The current study found that minoxidil also promotes angiogenesis by ASCs, as shown by an increase in tube formation and the expression of endothelial cell markers (TIE1, VEGFR1, VEGFR2, and EDNRB). Overall, the findings indicate that minoxidil may promote hair growth by enhancing ASC migration and ASC-dependent angiogenesis. (8)
Hair Growth Enhancement In Vivo by Minoxidil-Primed Adipose-Derived Stem Cells:
The experiment revealed that adipose-derived stem cells (ASCs), when pretreated with minoxidil, significantly enhanced hair growth in mice. While naïve (untreated) ASCs had a mild effect on triggering the transition from the telogen to the anagen phase of hair follicles, the minoxidil-pretreated ASCs induced a more pronounced hair growth response. Histological analysis using hematoxylin and eosin (HE) staining showed that the skin sections of mice treated with minoxidil-pretreated ASCs had a higher number of mature hair follicles. Furthermore, immunofluorescence staining for Ki67 revealed increased cell proliferation in the dermal papilla (DP) of these hair follicles. This finding suggests that minoxidil enhances the ability of ASCs to promote the transition from the telogen to the anagen phase, ultimately leading to increased hair growth. (8)
Minoxidil Modulates the Expression of PD-ECGF and PDGF-C in ASCs through the ERK Pathway:
The molecular mechanisms underlying the effects of minoxidil on adipose-derived stem cells (ASCs) were investigated. Previous studies have shown that the mitogen-activated protein kinase (MAPK) pathway regulates the expression of growth factors, including vascular endothelial growth factor A (VEGFA) and fibroblast growth factor 1 (FGF1). The researchers found that minoxidil activated the MAPK pathway, leading to increased levels of phospho-ERK, which was reduced by the specific MEK inhibitor PD98059. Furthermore, PD98059 reversed the minoxidil-induced increase in platelet-derived endothelial cell growth factor (PD-ECGF) and platelet-derived growth factor-C (PDGF-C). However, the minoxidil-induced upregulation of chemokine ligand 1 (CXCL1) was not affected by PD98059, suggesting that minoxidil regulates growth factor expression through multiple mechanisms, including the MAPK pathway. These findings provide insight into how minoxidil promotes hair growth by stimulating the release of growth factors from ASCs. The study showed that CXCL1, PD-ECGF, and PDGF-C can induce the anagen phase of the hair cycle and increase the number of mature hair follicles. Additionally, CXCL1 and PDGF-C promoted the growth of isolated mouse vibrissal hair follicles in organ culture. (8)
ASC Mediated Growth Factors CXCL1, PD-ECGF, and PDGF-C Promotes DP Cell Proliferation:
Research has shown that minoxidil promotes hair growth by prolonging the anagen phase through its proliferative and anti-apoptotic effects on dermal papilla (DP) cells. To investigate the potential mechanisms underlying this effect, the researchers examined whether CXCL1, platelet-derived endothelial cell growth factor (PD-ECGF), or platelet-derived growth factor-C (PDGF-C) could stimulate the proliferation of DP cells. The study found that each of the growth factors increased the growth of DP cells in a dose-dependent manner. In contrast, the growth factors did not affect the growth of human dermal fibroblast cells, suggesting a specific effect on DP cells. Further analysis revealed that the growth factors increased the number of DP cells in the S-phase of the cell cycle, as evidenced by 5-bromo-2'-deoxyuridine (BrdU) labeling, and enhanced the overall rate of cell proliferation. These findings suggest that minoxidil may work, at least in part, by stimulating the release of CXCL1, PD-ECGF, and PDGF-C from adipose-derived stem cells (ASCs), which in turn promote the growth of DP cells. (8)
PDGF-C, CXCL1, and ECGF Promotes Hair Growth:
Research has shown that growth factors secreted by adipose-derived stem cells (ASCs), including vascular endothelial growth factor (VEGF), fibroblast growth factor-1 (FGF1), basic fibroblast growth factor (bFGF), and platelet-derived growth factor-A (PDGF-A), play a crucial role in regulating hair follicular stem cell activity and inducing the anagen phase of the hair cycle. We hypothesized that minoxidil might promote hair growth indirectly by enhancing the release of growth factors from ASCs. To test this idea, we compared the expression patterns of untreated naïve and minoxidil-treated ASCs. Minoxidil significantly upregulated the expression of platelet-derived endothelial cell growth factor (PD-ECGF), chemokine ligand 1 (CXCL1), and platelet-derived growth factor-C (PDGF-C). When these growth factors were injected into the subcutaneous dermis of shaved mice, they triggered the anagen phase of the hair cycle and increased the number of mature hair follicles. Furthermore, CXCL1 and PDGF-C also promoted the growth of isolated mouse vibrissal hair follicles in organ culture. These findings suggest that minoxidil promotes hair growth, at least in part, by stimulating the release of growth factors from ASCs that promote hair growth. (8)
Use of PDGF-C, CXCL1, or PD-ECGF Acts Synergistically with Minoxidil to Induce Hair Growth:
The findings indicate that the increased expression of CXCL1, platelet-derived endothelial cell growth factor (PD-ECGF), and platelet-derived growth factor-C (PDGF-C) triggered by minoxidil promotes hair growth by stimulating the proliferation of dermal papilla (DP) cells. Given minoxidil's established use in treating androgenetic alopecia, the researchers investigated whether combining these growth factors with minoxidil would have a synergistic effect on inducing the anagen phase of the hair cycle. In an experiment involving shaved mice, the researchers compared hair growth in those treated with 2% minoxidil alone to those treated with minoxidil plus either CXCL1, PD-ECGF, or PDGF-C. The results showed that co-administration of each growth factor with minoxidil increased hair weight compared to using minoxidil alone, suggesting that combining these growth factors with minoxidil may enhance its efficacy in promoting hair growth. (8)
Minoxidil Responders and Non-responders:
About 60% of men with androgenetic alopecia (AGA) do not benefit from topical minoxidil treatment. The follicular sulfotransferase assay (FSA), a biomarker test measuring the activity of sulfotransferase enzymes in hair follicles, can identify individuals who are likely to respond to minoxidil treatment and those who are not, enabling personalized treatment approaches.
SULT Enzyme Assay:
Discovering compounds that modulate sulfotransferase activity is crucial, as upregulating SULT1A1 expression in the scalp may enhance the efficacy of minoxidil therapy, as suggested by Roberts et al. in 2014 Dermatologic Therapy. Nonetheless, studies examining the relationship between minoxidil and sulfotransferase activity often suffer from small sample sizes. To establish the follicular sulfotransferase assay (FSA) as a reliable biomarker for predicting response to minoxidil therapy, more rigorous investigations with larger cohorts and advanced molecular biology tools are necessary. These future studies would provide stronger evidence and potentially lead to more personalized treatment approaches for hair loss.
FSA Test for Minoxidil Response:
The follicular sulfotransferase assay (FSA) might also forecast a patient's response to oral minoxidil treatment. In a study involving 13 women with female pattern hair loss (FPHL), those with sulfotransferase activity levels, measured in optical density (OD), below 0.254 did not respond to oral minoxidil treatment, which is a lower threshold than the standard cutoff value of 0.4 for topical minoxidil. This discrepancy may be attributed to the fact that oral minoxidil is partially metabolized by liver sulfotransferase. Furthermore, research has shown that a genetic variant of the SULT1A1 enzyme, identified through a buccal swab and PCR analysis, can predict the efficacy of oral minoxidil treatment in FPHL patients.
FSA and topical minoxidil:
The enzyme responsible for activating minoxidil is sulfotransferase, specifically the SULT1 family, which is present in both the lower sheath of hair follicles and the liver. This enzyme catalyses the conversion of minoxidil into its active sulphate form, minoxidil sulphate, within the outer root sheath of hair follicles. Notably, the SULT1A1 isoenzyme is primarily responsible for this sulfonation process in hair follicles. Research has demonstrated that the follicular sulfotransferase assay (FSA), measuring sulfotransferase activity in hair follicles, can accurately predict patient response to minoxidil treatment, with a high degree of sensitivity (95%) and specificity (73%). Patients with low enzyme activity, indicated by an optical density (OD) reading below 0.4, are less likely to benefit from minoxidil therapy. Variability in sulfotransferase expression in the scalp between individuals may account for the differing responses to minoxidil treatment observed in clinical practice.
Minoxidil Applications in Hair Disorders:
The US Food and Drug Administration (FDA) has given its approval for topical minoxidil to address androgenetic alopecia (AGA). This medication has also been utilized off-label to manage various other hair conditions, including alopecia areata (AA), scarring alopecia, and disorders affecting the hair shaft. Furthermore, minoxidil has been applied to enhance hair growth in other body areas, such as the eyebrows and beard, beyond its primary approved use. (1)
Chronic Telogen Effluvium:
A common form of non-scarring alopecia, characterized by excessive telogen hair shedding due to stressful events like pregnancy, major illness, or surgery, can persist for extended periods. When hair loss lasts over six months, it's considered chronic telogen effluvium (CTE). Managing CTE can be challenging, and various treatments have been explored, including minoxidil. While research on topical application of minoxidil for telogen effluvium has been limited, oral minoxidil may offer a potential solution. A recent review of female patients with CTE found that daily treatment with oral doses of minoxidil, ranging from 0.25 to 2.5 mg, led to significant decreases in hair shedding after six months and one year. However, some patients experienced side effects, including mild facial hypertrichosis, dizziness, and altered blood pressure. (1)
Alopecia areata:
Alopecia areata (AA) is a condition where the immune system attacks hair follicles, resulting in hair loss that can range from small patches to complete loss of scalp (alopecia totalis) and body (alopecia universalis) hair. Despite various treatment options, none have been officially approved by the FDA. Minoxidil is sometimes used off-label, either alone or in combination with other treatments, to stimulate hair growth. Initial studies showed limited effectiveness, with hair growth only occurring in mild cases. However, higher concentrations of minoxidil, such as 5% minoxidil solution (MS), may be more effective, particularly in cases with extensive hair loss (>75% scalp involvement). Combination therapy, including prior use of systemic corticosteroids followed by application of minoxidil, may also lead to better outcomes. Research on minoxidil's effects on perifollicular Langerhans cells and T cell infiltration has yielded mixed results, making its impact on the immune system unclear. While minoxidil may promote some hair growth, it does not appear to alter the underlying disease process or induce remission. As a result, it is often used in conjunction with other treatments as adjuvant therapy. Oral administration of minoxidil has also been studied, and while it may be more effective than the topical form, it requires careful management due to potential side effects, including sodium and water retention, headache, palpitation, and facial hypertrichosis. To minimize these risks, patients must adhere to a strict sodium intake limit. (1)
Hair shaft disorders:
A rare genetic hair disorder known as monilethrix, characterized by fragile, beaded hair shafts, has been treated with topical 2% minoxidil solution (MS). Four individuals with monilethrix applied 1 mL of MS twice daily for a year, resulting in increased normal hair growth in affected areas after 6 and 12 months, with no adverse reactions reported. The treatment's effectiveness may be due to its ability to prolong the anagen phase of hair growth. Topical minoxidil has also shown promise in addressing loose anagen hair syndrome (LAS). A 2-year-old girl with LAS treated with 5% MS applied for 20 months experienced significant improvement that persisted even after treatment cessation. However, topical application may not be suitable for all hair shaft disorders, as it can exacerbate brittleness. In such cases, a low dose of oral minoxidil has been used with promising results. One patient with monilethrix experienced reduced hair shedding, increased hair length, and improved hair density with 0.25 mg oral minoxidil once daily, with benefits maintained over 18-24 months. Another patient, a 6-year-old girl with LAS who did not respond to 5% MS, showed improvement in hair colour, density, and length within three months of starting oral minoxidil at 0.5 mg daily. (1)
Androgenetic alopecia:
Androgenetic alopecia (AGA) is characterized by the gradual transformation of terminal hairs into miniaturized hairs, leading to hair thinning and loss. In addition to the miniaturization of hair follicles, the condition is also influenced by the enzyme 5-alpha reductase, which converts testosterone to dihydrotestosterone (DHT), a key contributor to hair follicle miniaturization. Research has consistently shown that topical application of minoxidil is effective in treating androgenetic alopecia, with all concentrations demonstrating superior results compared to a placebo. Studies have reported significant increases in hair density, particularly with higher concentrations of minoxidil, such as 2% and 5% minoxidil solutions (MS). However, side effects such as dermatitis, headaches, and hypertrichosis can occur, especially with higher concentrations. A novel formulation of minoxidil, minoxidil sulphate-based solution (MXS), has shown promise for individuals who do not respond to conventional treatment. Additionally, oral administration of minoxidil has been explored as a treatment option for patients who are not satisfied with topical treatment, with some studies demonstrating positive outcomes. A predictive test measuring sulfotransferase activity in plucked hair follicles has been developed to identify individuals who are likely to respond to minoxidil, allowing for more targeted treatment approaches. Treatment with minoxidil should be continued indefinitely to maintain hair growth, as discontinuation can lead to hair shedding within a few months. (1)
Chemotherapy-induced alopecia:
Chemotherapy often leads to hair loss, a distressing side effect for many patients. A clinical trial found that applying 1 mL of 2% minoxidil solution (MS) to the entire scalp twice daily reduced the duration of alopecia by approximately 50 days. However, other studies have shown that MS may not be effective in preventing hair loss in patients undergoing certain types of chemotherapy, such as doxorubicin-based chemotherapy for gynaecologic malignancies and solid tumours. Even high doses of 1.5 mL 5% MS twice daily failed to promote significant hair regrowth in breast cancer patients. As a result, the efficacy of topical minoxidil for chemotherapy-induced alopecia remains uncertain. In contrast, low-dose oral minoxidil (1 mg once daily) might hold promise for treating permanent chemotherapy-induced alopecia (PCIA). A patient with a history of acute myeloid leukaemia experienced increased hair growth within 6 weeks and substantial regrowth after 2 years of treatment, with improvements confirmed through histological examination showing reemerged anagen follicles and decreased miniaturization. (1)
Scarring alopecia:
Prompt medical intervention is crucial for scarring alopecia to preserve remaining hair follicles and prevent further progression. Central centrifugal cicatricial alopecia, a common scarring alopecia among African American women, typically starts at the vertex and spreads toward the periphery. Research has shown that combining high-potency topical steroids with topical minoxidil may not yield significant improvement, but some individuals may experience a reduction in disease severity score. Topical minoxidil has also been used for frontal fibrosing alopecia (FFA), where 50% of patients who received combination therapy with 2% minoxidil solution (MS) and systemic steroids or finasteride experienced slowed disease progression. Additionally, minoxidil may be beneficial for traction alopecia, particularly in its early stages where it is still reversible and non-scarring. In some cases, 2% minoxidil alone has led to notable hair regrowth in patients who did not respond to other therapies, such as topical triamcinolone. As a result, topical minoxidil may be a useful adjunct to other treatments for scarring hair loss conditions. (1)
Body hair enhancement:
Eyebrows are a key facial feature, and sparse or thin eyebrows can be a concern, particularly for those with eyebrow hypotrichosis. Studies have demonstrated that topical minoxidil solution (MS) can stimulate eyebrow growth, with notable enhancements in density and thickness observed after 16 weeks of application. Both 1% and 2% concentrations of MS have shown efficacy in treating eyebrow hypotrichosis, although higher concentrations, such as 3% MS, may increase the risk of skin irritation, including contact dermatitis. In comparison to an established treatment option, 0.03% topical bimatoprost, 3% MS has proven to be equally effective for eyebrow enhancement. Furthermore, minoxidil has also been found to promote beard growth, yielding significant improvements in hair count and individual satisfaction. Overall, minoxidil is regarded as a safe and effective solution for enhancing eyebrow and beard growth. (1)
ADR of Minoxidil:
While topical minoxidil is typically well-tolerated, some individuals may experience adverse reactions, including irritant contact dermatitis and allergic contact dermatitis due to propylene glycol (PG) or minoxidil itself. The frequency of these reactions can vary depending on the concentration of minoxidil, with 2% minoxidil solution (MS) having a lower incidence than 5% MS. To determine the cause of the reaction, a patch test may be necessary. If an allergy to PG is identified, alternative vehicles such as butylene glycol, glycerine, or polysorbate can be used, and a PG-free formula like minoxidil foam (MF) may be prescribed. A particular side effect, hypertrichosis, is more common with higher concentrations of minoxidil and tends to occur more frequently in female patients. This effect typically resolves on its own after treatment cessation, with spontaneous resolution occurring first on the face and arms, followed by the legs. Systemic side effects are rare with topical application, but oral minoxidil can lead to more serious adverse effects, including sodium and fluid retention, cardiovascular issues such as ischemic heart disease, pericardial effusion, and pulmonary hypertension, and excessive hair growth. These potential risks should be carefully weighed against the benefits of treatment. The oral formulation is metabolized by the liver via conjugation with glucuronic acid and excreted by the kidneys, with its vasodilation property persisting for up to 72 hours. However, the potential benefits of oral treatment may not outweigh the risks associated with its use. (1)
Side Effects of Minoxidil:
Topical minoxidil solution has a favourable safety profile and is widely available over-the-counter. However, some users may experience a common side effect known as "shedding" or telogen effluvium, where hairs in the telogen phase are encouraged to fall out early, making way for new growth in the anagen phase. Long-term application is required to maintain benefits, and some individuals may develop contact dermatitis to specific ingredients in the preparation, such as propylene glycol. The most frequent complaints are scalp pruritus and scaling, which can be caused by irritant or allergic contact dermatitis or exacerbation of seborrheic dermatitis. Fortunately, these adverse effects are usually limited to the scalp and do not induce hypotension. The use of oral minoxidil is contraindicated during pregnancy due to its Pregnancy category C classification and potential to cause neonatal hypertrichosis, as well as possible secretion in human milk, posing risks to nursing infants. Although topical minoxidil is considered relatively safer, experts like Rogers and Avram advocate for a conservative approach, recommending avoidance of its use during pregnancy and breastfeeding to minimize potential risks. (6) Allergic contact dermatitis is a possible side effect, often underdiagnosed, and can be caused by minoxidil or other ingredients like propylene glycol and butylene glycol. Identifying and removing the causal agent is crucial for treatment, and alternative vehicles or formulations like minoxidil foam, butylene glycol, glycerine, or polysorbate may be used. Additionally, topical minoxidil can cause hypertrichosis in areas other than the scalp, particularly with higher concentrations (5% MS), and this effect typically resolves after discontinuation. The treatment is not associated with cardiovascular risks, and there is only one reported case of a heart attack potentially linked to its use. (10)
LATEST ADVANCES:
Researchers have developed various formulations to enhance the delivery and efficacy of topical minoxidil solution for treating hair loss. These include:
1. A fixed-dose topical pharmaceutical combination of minoxidil and aminexil for treating alopecia.
2. A pharmaceutical formulation containing clobetasol propionate, minoxidil, and 11-alpha hydroxyprogesterone for treating skin diseases like psoriasis.
3. A novel carrier composition comprising water, glycerin, and polysorbate that reduces solvent evaporation and systemic absorption, providing sustained topical action.
4. A solid lipid nanoparticle suspension that encapsulates minoxidil in a lipid matrix, utilizing phospholipids, propylene glycol, and surfactants to control release.
5. A gel composition featuring minoxidil (2,4-diamino-6-piperidinylpyrimidin-3-oxide), thickening agents such as carbomer, and a polyol, which maintains stability while dissolving high concentrations of minoxidil.
6. A foamable composition comprising minoxidil, an aqueous-alcoholic solvent medium, and a surfactant like oleth-20, delivered in a measured dosage as foam without propellant.
7. A composition combining minoxidil or minoxidil sulphate with antioxidants, organic acids, and a select fatty acid mixture to enhance hair loss treatment.
8. Adhesive solidifying formulations with minoxidil for treating neuropathies, including diabetic neuropathy, which form a solidified layer after application of a volatile solvent system and a non-volatile solvent system.
9. A topical water-soluble minoxidil composition with high water content and minimal organic solvents, which enhances transdermal delivery and reduces allergy risk by minimizing propylene glycol and ethanol. These formulations aim to improve the efficacy, stability, and safety of topical minoxidil treatment for hair loss. (10)
DISCUSSIONS:
Topical minoxidil, a common treatment for androgenetic alopecia (AGA), has variable efficacy due to individual differences in sulfotransferase levels, whereas oral minoxidil may offer higher follicular accumulation and effectiveness at lower enzyme activity thresholds. Research suggests that oral minoxidil (1 mg/day) is comparable to topical minoxidil (5% solution) in improving hair diameter, with better patient adherence due to its simplicity and reduced side effects. However, topical minoxidil remains a crucial first-line treatment due to its established efficacy and safety profile. A novel approach combining scalp threading with topical minoxidil shows promise in addressing female pattern hair loss, yielding significant improvements in hair density and diameter, potentially by inducing mild inflammation, promoting anagen entry, and increasing growth factor expression. Oral minoxidil is gaining traction for various hair loss conditions, including AGA, alopecia areata, and scarring alopecia, demonstrating effectiveness in both men and women, with dosage requirements varying between sexes (typically 0.25-2.5 mg/day for women and 1.25-5 mg/day for men). However, oral minoxidil may have disadvantages, such as systemic side effects like hypertrichosis, postural hypotension, and oedema, which can be a concern for some patients. Minoxidil promotes hair growth by stimulating the release of specific growth factors from adipose-derived stem cells, enhancing dermal papilla cell proliferation and anagen induction. Originally developed for hypertension, minoxidil's side effect of hypertrichosis led to its use for hair growth, and it's effective and safe for various hair loss conditions at lower dosages. However, caution is advised for patients with renal or hepatic impairment. Overall, minoxidil offers a promising treatment option for hair loss, with both topical and oral forms showing benefits and applications, and the choice between them depends on individual patient needs and tolerance.
CONCLUSION:
Minoxidil is a widely used treatment for hair loss with varying degrees of success depending on the condition being treated, such as androgenetic alopecia, alopecia areata, and scarring alopecias. Topical minoxidil is FDA-approved for treating androgenetic alopecia due to its safety and efficacy profile, while further investigation is required to determine the optimal dosage for oral minoxidil and understand its mechanism of action. Minoxidil may work by triggering a specific biological response, potentially through its sulphated metabolite acting as a potassium channel opener, and researchers believe more studies are needed to fully understand its mechanism and develop more effective treatments. Minoxidil's potential applications extend beyond its approved use for androgenetic alopecia, and combining it with another therapy like PLLA micro threading or using an alternative approach like scalp threading may enhance its effectiveness. A recent study found that a low dose of oral minoxidil (1 mg) was comparable to a 5% topical minoxidil solution in improving hair diameter, with oral minoxidil being more convenient for patients despite side effects like minoxidil-induced telogen effluvium and hypertrichosis, although the topical solution had better overall results. To further advance the treatment of hair loss with minoxidil, future developments are needed, including: more research on optimal dosing for oral minoxidil, better understanding of its mechanism of action, exploration of combination therapies to enhance effectiveness, and investigation of alternative approaches like scalp threading to provide more treatment options for patients. Additionally, studies should focus on minimizing side effects and improving patient outcomes.
REFERENCE
Dr. S. Swarnalatha*, K. Gokulapriya, Minoxidil: A Comprehensive Review of its Mechanism, Efficacy, Safety in Treating Hair Disorders, Int. J. Sci. R. Tech., 2025, 2 (7), 33-51. https://doi.org/10.5281/zenodo.15779509
10.5281/zenodo.15779509
